Conditions: Prostate Cancer
Keywords: Lupron Bicalutamide Docetaxel
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 26
Healthy volunteers: no

Brief summary:
To assess the safety of treating men with oligometastatic prostate cancer with the following therapy: (1st) Systemic chemo-hormonal therapy with up to 6-months (\~24 weeks) of neoadjuvant androgen deprivation and up to 6 cycles of chemotherapy, (2nd) definitive local tumor control with prostatectomy +/- adjuvant radiation therapy, and (3rd) consolidative stereotactic radiation to oligometastatic lesions. The men will receive a total of 1 year of androgen deprivation. Androgen blockade will be the same throughout the course of treatment.

Detailed description:
Neoadjuvant treatment (month 1 through \~6): All patients will be treated with up to 6 months of androgen deprivation, plus up to 6 cycles of docetaxel chemotherapy. Following docetaxel therapy, patients with a prostate-specific antigen response of at least a 50% decrease from baseline, will proceed to maximum consolidative therapy.

Surgery and Radiation (month 7 though \~11): After completion of neoadjuvant therapy, the men will be treated with definitive local therapy with radical prostatectomy (RP) +/- adjuvant radiation therapy (RT). After definitive local therapy, patients will be treated with consolidative stereotactic body radiation therapy (SBRT) to the metastatic sites.

Follow up: Patients will continue on androgen deprivation for a total of 1 year. They will be followed clinically and monitored with serum testosterone and prostate-specific antigen until 2-years after completion of ADT (Androgen deprivation therapy) treatment. Androgen blockade will be the same throughout the course of treatment.

Arms:
arm 1: (1st) Systemic chemo-hormonal therapy with up to 6-months (\~24 weeks) of neoadjuvant androgen deprivation (Leuprolide Acetate) and up to 6 cycles of chemotherapy (Docetaxel), (2nd) definitive local tumor control with prostatectomy +/- adjuvant radiation therapy, and (3rd) consolidative stereotactic radiation to oligometastatic lesions. The men will receive a total of 1 year of androgen deprivation. Androgen blockade (Bicalutamide) will be the same throughout the course of treatment.

Interventions: intervention 1: Leuprolide Acetate intervention 2: Bicalutamide intervention 3: Docetaxel intervention 4: Prostatectomy intervention 5: Radiation
Intervention descriptions: intervention 1: 22.5mg by intramuscular (IM) injection every 3 months intervention 2: bicalutamide (Casodex) 50mg by mouth daily intervention 3: Docetaxel (taxotere) 75 mg/m2 IV will be given on day 1 every 3 weeks, up to 6 cycles. intervention 4: Removal of the entire prostate gland, plus some surrounding tissue. intervention 5: 5 high dose radiation treatments to the metastatic (tumor has spread to other parts of the body) sites.

Protocol document:
Prot_SAP_000.pdf: 
Definitive therapy for newly diagnosed men with oligometastatic PCa 
PI: Kenneth Pienta, MD 
 
 
Protocol Version:  10, 02/07/2020 
 
 
1
 
A phase II study of definitive therapy for newly diagnosed men with oligometastatic 
prostate cancer  
Johns Hopkins Kimmel Cancer Center 
IRB #: 00070003 
SKCCC Protocol #: J1618 
Protocol Version #: 10 
Protocol date: 02/07/2020 
Principal Investigator: 
Statistician: 
Kenneth Pienta, MD 
Brady Urological Institute  
Email: kpienta1@jhmi.edu 
 
Co-Investigators: 
Phuoc Tran, MD, PhD 
Department of Radiation Oncology 
Email: tranpt21@sbcglobal.net  
 
Mohamad Allaf, MD, 
Email: mallaf@jhmi.edu 
 
Herbert Ballentine Carter,MD 
Email: hcarter@jhmi.edu 
 
Misop Han, MD 
Email: mhan1@jhmi.edu  
 
Bruce J. Trock, PhD 
Brady Urological Institute 
Email: btrock@jhmi.edu 
 
Project Coordinators:  
Harry Cao 
Email: hcao7@jhmi.edu 
 
Rehab Abdallah 
Email: Rabdall1@jhmi.edu  
 
Michael A. Carducci, MD 
Email: Carducci@jhmi.edu 
 
Christian Pavlovich, MD 
Email: cpavlov2@jhmi.edu 
Protocol Manager: 
Ting Wang 
Email: Twang2@jhmi.edu 
 
Tanya O’Neal, RN 
Email: toneal2@jhmi.edu 
 
Sam Denmeade, MD  
Email:DENMESA@jhmi.edu 
 
Mario Eisenberger, MD  
Email: eisenma@jhmi.edu 
 
Emmanuel Antonarakis, MBBCh 
Email: eantona1@jhmi.edu 
 
 
Alan Partin, MD, PhD 
Email: apartin@jhmi.edu 
 
Diane Reyes, CRNP 
Email: dreyes@jhmi.edu 
 
 
NCT02716974


Definitive therapy for newly diagnosed men with oligometastatic PCa 
PI: Kenneth Pienta, MD 
 
 
Protocol Version:  10, 02/07/2020 
 
 
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Study Synopsis 
 
Title: Phase II study of definitive therapy for newly diagnosed men with oligometastatic 
prostate cancer  
 
Objective: To assess the efficacy of treating men with oligometastatic prostate cancer with the 
following therapy: (1st) Systemic chemo-hormonal therapy with up to 6-months (~24 weeks) of 
neoadjuvant androgen deprivation and up to 6 cycles of chemotherapy, (2nd) definitive local 
tumor control with prostatectomy +/- adjuvant radiation therapy, and (3rd) consolidative 
stereotactic radiation to oligometastatic lesions. The men will receive a total of 1 year of 
androgen deprivation. Androgen blockade will be the same throughout the course of treatment. 
 
Study Design: Open label phase II study designed to assess the efficacy and therapeutic benefit 
of multimodality therapy in men presenting with newly diagnosed oligometastatic prostate 
cancer (<5 sites of metastases). A total of sixty patients will be enrolled with the primary 
endpoint of the 2 year PSA progression-free (PSA<0.2 ng/ml) survival rate. 
 
Neoadjuvant treatment (month 1 through ~6): All patients will be treated with up to 6 months of 
androgen deprivation, plus up to 6 cycles of docetaxel chemotherapy. Following docetaxel 
therapy, patients with a PSA response of at least a 50% decrease from baseline, will proceed to 
maximum consolidative therapy.  
 
Surgery and Radiation (month 7 though ~11): After completion of neoadjuvant therapy, the men 
will be treated with definitive local therapy with radical prostatectomy (RP) +/- adjuvant 
radiation therapy (RT). After definitive local therapy, patients will be treated with consolidative 
stereotactic body radiation therapy (SBRT) to the metastatic sites.   
 
Follow up: Patients will continue on androgen deprivation for a total of 1 year, or until 
completion of local and metastatic consolidation (should that extend beyond 1 year).They will be 
followed clinically and monitored with serum testosterone and PSA until 2-years after 
completion of ADT treatment. Androgen blockade will be the same throughout the course of 
treatment.  
 
Primary Center: Johns Hopkins Hospital. Patients not within commuting distance to JHH or its 
affiliate hospitals may undergo adjuvant radiation at radiation centers close to their home. Will 
include Sibley Hospital as a second site for SBRT. 
 
Support: Investigator initiated 
 
Timeline: This study is planned to complete enrollment in four years, with 1-year of additional 
follow-up after completion of ADT treatment of the last subject, for a total of approximately 5 
years. 
 
Concept Rationale: 


Definitive therapy for newly diagnosed men with oligometastatic PCa 
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Protocol Version:  10, 02/07/2020 
 
 
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Patients are increasingly being diagnosed with oligometastatic disease due to the advent of 
sensitive imaging technologies as well as effective therapies that are allowing patients to live 
longer with the diagnosis of cancer. In addition, the fact that novel treatment options with 
acceptable safety profiles, such as stereotactic radiation, cryoablation, and minimally invasive 
surgery, are available to treat limited metastases, has led to a renewed interest in treating 
oligometastatic disease.  Treatment of oligometastatic disease not only has the potential to 
prevent further evolution of genetically unstable clones and metastatic spread, it may improve 
overall disease control and delay more toxic systemic treatment. Therefore, the clinical 
implication of the oligometastatic state is that locally ablative therapies, given with the intent of 
targeting sites of clinically evident metastatic disease could result in long-term survival or cure. 
Treatment of oligometastatic disease may also result in decreased overall tumor burden, 
decreasing morbidity and increasing survival. 1  
 
In addition to preventing further evolution of genetically unstable clones and additional 
metastatic spread, the combination therapies may be more effective in treating hormone-sensitive 
oligometastatic prostate cancer, before it becomes castrate resistant and more aggressive.  
 
 
Neoadjuvant therapy in men with oligometastatic prostate cancer 
 
The standard of care treatment for metastatic prostate cancer is androgen deprivation therapy 
(ADT). [NCCN Clinical Practice Guidelines, Version 1.2015] Although taxanes are the standard 
treatment approach in metastatic castrate-resistant prostate cancer, two recent randomized trials 
2,3 investigated the combination of docetaxel + ADT in treatment naïve metastatic prostate 
cancer. 
In the CHAARTED trial (Phase III, E3805) 790 men with metastatic hormone sensitive prostate 
cancer, treatment naïve, were randomized to either ADT + up to 6 cycles of docetaxel versus 
ADT alone. The primary endpoint was overall survival. Patients were stratified according to high 
volume disease (visceral metastases and/or ≥4 bone metastases) versus low-volume disease, prior 
anti-androgen use > 30 days, age ≥ or < 70 years, ECOG 01- versus 2 and prior adjuvant ADT > 
or ≤ 12 months. After a median follow-up of 28.9 months, the docetaxel + ADT arm had an OS 
of 57.6 months, as compared to ADT alone OS of 44.0 months. Patients with high-volume 
metastatic disease (defined as visceral metastasis or ≥4 bone metastases), treated on the 
docetaxel + ADT arm had an increased OS (49.2 versus 32.2 months in the ADT alone arm, HR 
0.60, p<0.001). The median OS was not yet reached in either arm for those with low-volume 
disease. Other sub-group analyses (PSA < 0.2 at 6 mths/12mths, median time to CRPC, and 
median time to clinical progression) also showed that the combination of ADT + docetaxel was 
superior. In the docetaxel + ADT arm, grade 3/4 febrile neutropenia was 2.3%. 2,4-6 
 
In the GETUG 15 trial 385 men with metastatic hormone sensitive prostate cancer, were 
randomized to ADT + docetaxel versus ADT alone. The protocol allowed for up to 9 cycles of 
docetaxel. The primary endpoint was OS. Secondary endpoints included time to clinical 
progression and time to PSA progression. 81% of those enrolled had bone metastasis and 14.5% 
had visceral organ metastasis. Median number of cycles of docetaxel was 8. At 50 months 
median follow-up, OS was not different between the two arms, ADT + docetaxel versus ADT 
alone (58.9 versus 54.2 months, HR 1.01, p=0.955), despite that the combination therapy did 


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Protocol Version:  10, 02/07/2020 
 
 
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yield a significant improvement in biochemical PFS and clinical PFS (22.9 versus 12.9 months, 
HR 0.72, p=0.005, and 23.5 versus 15.4 months, HR 0.75, p=0.015, respectively). 3,5,6 More 
recently, the authors reported on the comparison between patients’ self assessment of treatment 
related toxicities versus investigators’ evaluation of their patients’ toxicities. [REF] The men 
were invited to complete a 26-symptom questionnaire at 3- and 6- months, while physicians 
assessed 18 symptoms. 220 and 165 patients completed questionnaires at 3- and 6-months. At the 
two assessment points (3 months and 6 months) all symptoms were reported more frequently by 
patients than by physicians. Positive agreement rates between patients and physicians, for the 
most commonly reported symptoms, included hot flushes (61 and 64%), fatigue (50 and 44%), 
sexual dysfunction (29 and 31%), and weight change (24 and 14%). However, ~50% of the time 
physicians did not report patients’ hot flushes and ~90% of the time they did not report patients’ 
joint/muscle pain. In comparison between the two arms, patients randomized to the ADT + 
docetaxel arm had more toxicities that those in the ADT alone arm.  7 
 
Alternatively, an arm of the STAMPEDE trial provides data on men with newly diagnosed 
metastatic prostate cancer who were randomized to standard-of-care therapy with androgen 
deprivation therapy. Cross-over was allowed at progression.  The cohort of 917 men had a 
median follow-up of 20 months. Median failure free survival (FFS-time from randomization 
until biochemical failure, local or distant progression, or death from prostate cancer) was 11 
months, and median OS was 42 months. 2 year FFS and OS were 29% and 72% respectively. 
This study demonstrated poor survival in men starting therapy with androgen deprivation only, 
despite the ability to initiate other treatments at failure of ADT. The median OS in this group was 
shorter than that of the control arm in GETUG-15, and was similar to the control arm in 
CHAARTED. 8 
 
 
Prostatectomy in men with oligometastatic prostate cancer 
 
There is a body of evidence, contrary to historical clinical practice, that treating men with 
metastatic prostate cancer to the lymph nodes at the time of diagnosis with surgery or radiation 
therapy results in increased long-term survival.  Historically, the ideal patient to be cured by 
radical prostatectomy (RP) was one with organ-confined cancer. At that time, the morbidity of 
RP was substantial; therefore the surgery was generally only offered to those where the 
probability of cure was high. More recent data, however, show that RP may provide a survival 
benefit- albeit not a cure - to men with metastatic prostate cancer.  Engel et al. 9 conducted a 
retrospective study (n=938) and found that in men with prostate cancer and positive lymph 
nodes, treated with +/- RP, that the 5- and 10-yr survival rates and the prostate cancer specific 
survival rates, were better in men who had undergone RP.  Cadeddu et al 10 conducted a 
retrospective study (n=38) and found that in men with prostate cancer and positive lymph nodes, 
treated with LND +/- RP, that the 5- and 10-yr prostate cancer specific survival was better in 
men who had undergone LND + RP.  1 
In men with prostate cancer with limited metastases, radical prostatectomy may be advantageous 
in that the primary tumor and its ability to continuously metastasize, to secrete tumor promoting 
growth factors and immunosuppressive cytokines, and to generate bulk-related morbidity, is 
removed. Heidenreich et al. recently evaluated survival outcomes following radical 
prostatectomy (RP) in men with low volume metastatic prostate cancer. RP led to improved 


Definitive therapy for newly diagnosed men with oligometastatic PCa 
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Protocol Version:  10, 02/07/2020 
 
 
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progression-free survival, time to castrate resistance and overall survival, as compared to a 
cohort treated with androgen deprivation therapy alone. 11 Moreover, Abdollah et al. found that 
in men with pN1 prostate cancer, treated with RP and extended lymph node dissection, adding 
adjuvant radiotherapy improved cancer-specific mortality 12. 1 
 
Radiation in men with oligometastatic prostate cancer 
 
Ost et al (2014) conducted a systemic review of the literature of metastasis-directed therapy of 
regional and distant recurrences after curative treatment for PCa (prostate cancer). They found 
that salvage LND and RT appear to be safe in treatments for OM PCa recurrence.13 Culp et al. 14 
studied the impact of survival of definitive treatment of the prostate in men diagnosed with 
metastatic PCa. Using the SEER database, he reviewed 8185 men treated with NSR (no surgery 
no radiation), brachytherapy, or RT. The 5-year OS and disease specific survival (DSS) was 
significantly higher in men with metastases having undergone RT.  1 
Zapatero et al., reported on a study of men with intermediate and high risk localized prostate 
cancer (n=362), treated with RT + long term ADT versus short term ADT, and found that long 
term ADT was superior in 5-year biochemical disease free survival, metastasis free survival, and 
OS 15. 1 
 
SBRT for oligometastatic sites in men with prostate cancer 
 
While much of the literature supporting the oligometastatic states is within the surgical literature, 
there is an increasing body of literature describing the use of stereotactic body radiotherapy 
(SBRT) and stereotactic radiosurgery (SRS), in addition to conventional fractionated 
radiotherapy techniques. SBRT is a noninvasive method of delivering high doses of radiation to 
ablate a target lesion while sparing the neighboring normal tissue, thus reducing long-term 
effects of radiation on the non-malignant tissues.  1 
Although traditionally radiation therapy was thought to be immunosuppressive, there is 
increasing pre-clinical and clinical evidence that high dose, hypofractionated radiation –SBRT- 
may reverse antitumor immunity via CD8+ T-cells and cellular stress signals. Although 
uncommon, the abscopal effect (regression in tumors distant to the targeted field of radiation) is 
an example of recovery of anti-tumor immunity following RT. Thus, an emerging advantage of 
SBRT is the possibility that it may be exploited to benefit the immune system. 1 
Major advancements in radiation treatment planning and delivery have resulted in resurgence in 
the use of radiation therapy (RT) as a treatment for bone metastases. In selected patients, very 
high local control rates have been observed, with minimal toxicity.  Bone metastases represent 
the major metastatic site (>90%) in men with rising PSA following primary treatment for their 
prostate cancer. [adapted from Johns Hopkins Oncology Clinical protocol J12137, 
NA_00069585] 
 
The primary management of metastatic prostate cancer is systemic therapy in the form of 
androgen deprivation therapy (ADT), which rarely eradicates metastatic disease and adversely 


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Protocol Version:  10, 02/07/2020 
 
 
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effects patient quality of life.  Thus, even the ability to defer long-term ADT in men with 
oligometastatic prostate cancer represents a considerable clinical advance. [adapted from Johns 
Hopkins Oncology Clinical protocol J12137, NA_00069585] 
 
The hypothesis of this study is that the combination of systemic therapy with complete androgen 
blockade plus chemotherapy in the neoadjuvant setting, definitive local therapy with 
prostatectomy +/- adjunctive radiation therapy or radiation therapy, and definitive radiation to 
clinically evident metastatic sites with stereotactic ablative radiation therapy, is efficacious in 
patients with oligometastatic disease.  The primary endpoint is the 2 year PSA progression-free 
(PSA<0.2 ng/ml) survival rate of multimodality therapy in men presenting with newly diagnosed 
oligometastatic prostate cancer.  
 
Treatment Plan: 
This is an open label, multi-center, phase II study of neoadjuvant chemohormonal and definitive 
therapy in men with oligometastatic prostate cancer, beginning with up to 6 months of 
neoadjuvant androgen deprivation plus up to 6 cycles of docetaxel chemotherapy.   
 
Androgen deprivation 
Options for androgen deprivation therapy include the following: LHRH agonist or antagonist 
therapy, or surgical castration. Each drug will be dosed at its respective FDA approved dose. 
These dosages are as follows: leuprolide (Lupron Depot-3 Month) 22.5mg by intramuscular (IM) 
injection, or leuprolide (Eligard-3 Month) 22.5mg subcutaneous (SC) injection, or triptorelin 
(Trelstar) 11.25 mg intramuscular (IM injection, or other LHRH agonist including goserelin 
(Zoladex) 10.8 mg, or degarelix (Firmagon) 80mg (SC every 4 weeks) on day 1. 
 
Use of combined androgen blockade (medical or surgical castration combined with anti-
androgen treatment (e.g., bicalutamide (Casodex) 50mg by mouth daily and/or abiraterone 
acetate 1000 mg / day + prednisone 5mg / day) may be given at the investigator’s discretion.   
 
Docetaxel 
Docetaxel (Taxotere) will be given at any of the following doses (75 mg/m2, 65 mg/m2, 55 
mg/m2 or 35 mg/m2 IV) on day 1 of each cycle, up to 6 cycles at physician discretion.   
 
The combination of the LHRH agonist, leuprolide (Lupron), + bicalutamide (Casodex) + 
docetaxel (taxotere) at these doses has been shown to have an acceptable safety profile 3,4. 
 
Following neoadjuvant therapy, there will be a safety checkpoint before proceeding to local 
consolidative therapy: the PSA must have decreased by 50% from baseline in order to proceed to 
maximum consolidative therapy. * 
 
All patients will have discontinued their neoadjuvant chemotherapy prior to definitive therapy. 
After receiving local therapy, all patients will be treated with definitive stereotactic body 
radiation therapy (SBRT) to the metastatic sites.  Patients will continue with adjuvant androgen 


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Protocol Version:  10, 02/07/2020 
 
 
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deprivation for a total of 1 year, and will be monitored clinically and with serum PSAs and 
testosterone until the 3-year endpoint.  
 
 
Definitions: 
 
Oligometastases: Oligometastatic prostate cancer will be defined as prostate cancer with 
up to 5 sites of metastases, including bone lesions, regional and non-regional lymph 
nodes; men with visceral metastases will not be included. 
 
Undetectable PSA:  
PSA ≤ 0.2 ng/mL  
 
PSA increase/PSA recurrence:   
 
PSA >0.2, over two time-points 
 
 
2-year undetectable PSA (time interval): 
 
2 years after completion of systemic consolidative therapy  
 
2-year PSA progression-free survival:  
(PSA<0.2 ng/ml) among men who have non-castrate testosterone levels 2 years 
after enrollment 
*for men with a baseline testosterone ≤200ng/dL, 2-year PSA PFS is defined as a 
PSA <0.2 at baseline level of testosterone, 2 years after enrollment. 
 
Noncastrate testosterone level: 
 
>200 ng/dL 
 
Replacement drugs: 
 
Leuprolide: may be replaced with any LHRH agonist, or the LHRH antagonist degarelix 
Biclutamide: no replacements allowed 
Abiraterone: no replacements allowed 
Docetaxel: no replacements allowed 
 
Drug dose adjustments: 
 
Leuprolide (or replacement): no adjustments allowed. 
Biclutamide: no adjustments allowed 
Abiraterone: dose may be interrupted or adjusted downward, at physician discretion, in 
response to, or to mitigate, toxicity. Dose may decreased to 750mg or 500 mg. 
Docetaxel: dose may be adjusted downward, at physician discretion, in response to, or to 
mitigate, toxicity. Dose may decreased in the following intervals: 65 mg/M2, 55 mg/M2, 
35 mg/M2. 
 
 
 


Definitive therapy for newly diagnosed men with oligometastatic PCa 
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Protocol Version:  10, 02/07/2020 
 
 
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Study schema 
 
 
 
 
 
 
  
 
 
 
 
 
The primary endpoint is the 2 year PSA progression-free (PSA<0.2 ng/ml) survival.  
 
Secondary endpoints will include safety, time to PSA recurrence following completion of 
therapy up to 3 years. 
 
Study Population: Men with newly diagnosed synchronous oligometastatic prostate cancer (T1-
4, N0-1, M1a-b) consisting of 1-5 metastatic lesions who are willing to undergo  (1st) Systemic 
chemo-hormonal therapy with up to 6-months (~24 weeks) of neoadjuvant androgen deprivation 
and up to 6 cycles of chemotherapy, (2nd) definitive local tumor control with prostatectomy +/- 
adjuvant radiation therapy, and (3rd) consolidative stereotactic radiation to oligometastatic 
lesions. 
 
Eligibility Criteria
 
-Oligometastatic 
prostate cancer  
(Any T1-4, N0-1, 
and/or M1a-b (1-5 
metastatic lesions))  
 
-CT scan 
(chest/abdomen/ 
pelvis) 
 
-Bone scan 
 
Endpoints 
 
-Safety 
 
-2-yr undetectable 
PSA rate up to 3 
years 
 
 
 
 
 
NEOADJUVANT 
TREATMENT 
Docetaxel 
75mg/m2, 65 
mg/m2, 55 mg/m2 
or 35 mg/m IV up 
to 6 doses (cycles) 
Prostatectomy +/- 
XRT to pelvic bed  
SBRT to 
oligometastases 
 
Surgery and Radiation 
 
OLIGOMETASTATIC PROTOCOL FOR PATIENTS UNDERGOING PROSTATECTOMY 
 
 
 
LHRH agonist 
36 months 
Given for total 1 year 
Follow-up-
For 2 years after the last 
ADT treatment 


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Protocol Version:  10, 02/07/2020 
 
 
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Number of Patients: We plan to enroll 60 evaluable patients who complete C-ADT. Up to 66 
patients will be enrolled if necessary in order to account for a potential 10% dropout rate. 
 
Inclusion Criteria: 
 
1. Willing and able to provide written informed consent. 
 
2. Age ≥ 18 years 
 
3. Eastern cooperative group (ECOG) performance status ≤2 
 
4. Documented histologically confirmed adenocarcinoma of the prostate 
 
5. Willing to undergo the following therapy: (1st) Systemic chemo-hormonal therapy with up to 
6-months (~24 weeks) of neoadjuvant androgen deprivation and up to 6 cycles of 
chemotherapy, (2nd) definitive local tumor control with prostatectomy +/- adjuvant radiation 
therapy, and (3rd) consolidative stereotactic radiation to oligometastatic lesions. Additionally, 
must be willing to be treated with a full year of androgen deprivation.  
 
6. Oligometastatic prostate cancer: Stage T1-4, N0-1 and/or M1a-b (up to 5 metastatic lesions- 
including bone lesions and non-regional lymph nodes seen on bone scan, contrast enhanced 
CT scan, or PET scan) 
 
7. Able to swallow the study drugs whole as tablets 
 
Exclusion Criteria: 
 
1. Prior local therapy to treat prostate cancer (e.g. radical prostatectomy, radiation therapy, 
brachytherapy) 
 
2. Prior therapy to a metastatic site. 
 
3. Prior systemic therapy for prostate cancer including, but not limited to: 
a. Hormonal therapy (e.g. leuprolide, goserelin, triptorelin, degarelix) 
b. CYP-17 inhibitors (e.g. ketoconazole) 
c. Antiandrogens (e.g. bicalutamide, nilutamide) 
d. Second generation antiandrogens (e.g. enzalutamide, abiraterone) 
e. Immunotherapy (e.g. sipuleucel-T, ipilimumab) 
f. Chemotherapy (e.g. docetaxel, cabazitaxel) 
*Note: may be enrolled if hormone therapy of any kind was recently initiated (<90 days 
duration)). In the event that hormone therapy was initiated prior to study enrollment, the clock 
for 1 year of androgen deprivation would begin at the time of therapy initiation, rather than at 
study enrollment. 
 
4. Ongoing systemic therapy for prostate cancer including, but not limited to: 
a. Immunotherapy (e.g. sipuleucel-T, ipilimumab) 


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b. Non-protocol prescribed chemotherapy (e.g. cabazitaxel) 
 
5. Evidence of serious and/or unstable pre-existing medical, psychiatric or other condition 
(including laboratory abnormalities) that could interfere with patient safety or provision of 
informed consent to participate in this study. 
 
6. Any psychological, familial, sociological, or geographical condition that could potentially 
interfere with compliance with the study protocol and follow-up schedule. 
 
7. Abnormal bone marrow function [absolute neutrophil count (ANC)<1500/mm3, platelet 
count <100,000/mm3, hemoglobin <9 g/dL] 
 
8. Abnormal liver function (bilirubin >ULN; AST, ALT > 2.5 x upper limit of normal) 
 
 
9. Active cardiac disease defined as active angina, symptomatic congestive heart failure, or 
myocardial infarction within previous six months. 
 
10. Prior history of malignancy in the past 3 years with the exception of basal cell and squamous 
cell carcinoma of the skin.  Other malignancies that are considered to have a low potential to 
progress may be enrolled at discretion of PI. 
 
 
Primary Endpoint: To assess efficacy of the following therapy: (1st) Systemic chemo-hormonal 
therapy with up to 6-weeks (~24 weeks) of neoadjuvant androgen deprivation and up to 6 cycles 
of chemotherapy, (2nd) definitive local tumor control with prostatectomy +/- adjuvant radiation 
therapy, and (3rd) consolidative stereotactic radiation to oligometastatic lesions. The men will 
receive a total of 1 year of androgen deprivation, or until completion of local and metastatic 
consolidation (should that extend beyond 1 year) 
 
Efficacy is defined as the 2 year PSA progression-free (PSA<0.2 ng/ml) survival rate.   
 
 
 
Secondary Endpoints:  
 
1. Safety  
Defined as the incidence of Grades 3 and 4 neutropenia and surgical- or radiation-
induced toxicities. 
 
 
2. Time to PSA recurrence. 
Defined as the time from an undetectable PSA (≤0.2 ng/mL) until the PSA is >0.2 over 
two time-points up to 3 years. 
 
 


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Protocol Version:  10, 02/07/2020 
 
 
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Statistical Considerations: 
 
This open label single arm phase II study of treatment for oligometastatic disease will evaluate 
consolidation with prostatectomy (RP) (+/- adjuvant radiation therapy), after systemic 
neoadjuvant chemo-hormonal therapy (C-ADT) and stereotactic body radiation to metastatic 
sites.  Only patients who achieve at least a 50% decrease in PSA following C-ADT will be 
offered RP.  The primary endpoint is efficacy, defined as the 2-year PSA progression-free 
(PSA<0.2 ng/ml) survival rate. 
 
 
Early Stopping Boundaries for Toxicity 
 
Expected non-neutropenic toxicities post prostatectomy or radiotherapy 17: urinary incontinence, 
erectile dysfunction, minimally invasive urological procedures, admission to hospital, rectal or 
anal procedure, secondary malignancy, open surgical procedure. 
 
Expected neutropenic toxicities post chemotherapy:  neutropenia, febrile neutropenia. 
 
We are concerned with 2 very different types of adverse event (AE):  (1) Grade 3-4 neutropenia, 
and (2) Grade 3-4 acute toxicities from surgery or radiation. Because the management and 
sequelae  of these AEs differ we have defined separate stopping boundaries for neutropenic AEs 
and for acute surgical -or radiation -induced AEs.  The study design incorporates safety 
monitoring after each patient, starting with the third patient.  
 
Neutropenic AEs.  We will say that the treatment is feasible and safe if risk of G3/4 neutropenia 
<50%.  Before the study starts, we assume that the average risk of G3/4 neutropenia is around 
30-40%, so we take 35% as our prior probability (95% CI: 22-78%), corresponding to a 
Beta(3.5,6.5) prior distribution for the risk.  Using Bayes rule, we apply the accumulating data 
after each patient to generate posterior probability as a Beta(3.5+a, 6.5+b) distribution, where 
a=number of neutropenic AE, b=number of non-SAEs (Rosner 2016)(30).  As we become more 
certain that the risk exceeds 50%, we want to consider stopping the study.  If the data suggest 
that there are at least 2:1 odds that the risk of neutropenic AEs exceeds 50%, the stopping 
boundary will be crossed, and we will consider that as enough certainty that the true rate exceeds 
50% to stop the trial.   
 
The following table indicates the number of events that will cross the stopping boundary for each 
sample size up to 54 patients. 
 
Number of patients 
(inclusive) 
Trial stops if neutropenic 
AEs reach this value 
5 
5 
6-7 
6 
8-9 
7 
10-11 
8 


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12 
9 
13-14 
10 
15-16 
11 
17-18 
12 
19-20 
13 
21-22 
14 
23-4 
15 
25-26 
16 
27-28 
17 
29-30 
18 
31-32 
19 
33-34 
20 
35-36 
21 
37-38 
22 
39 
23 
40-41 
24 
42-43 
25 
44-45 
26 
46-47 
27 
48-49 
28 
50-51 
29 
52-53 
30 
54 
31 
 
 
Non-neutropenic acute surgical –or radiation-induced AEs.  We will say that the treatment is 
feasible and safe if risk of G3/4 acute non-neutropenic AEs<20%.  Before the study starts, we 
assume that the average risk of such AEs is around 10% (95% CI: 2-38%), corresponding to a 
Beta(1,9) prior distribution for the risk.  Again, we apply the accumulating data after each patient 
to generate posterior probability as a Beta(1+a, 9+b) distribution, where a=number of non-
neutropenic AE, b=number of non-AEs.  As we become more certain that the risk exceeds 20%, 
we want to consider stopping the study.  If the data suggest that there are at least 2:1 odds that 
the risk of non-neutropenic AEs exceeds 20%, the stopping boundary will be crossed, and we 
will consider that as enough certainty that the true rate exceeds 20% to stop the trial.   
 
The following table indicates the number of events that will cross the stopping boundary for each 
sample size. 
 
Number of patients 
(inclusive) 
Trial stops if non-neutropenic 
AEs reach this value 
3-5 
3 
6-10 
4 
11-14 
5 
15-19 
6 
20-23 
7 


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24-28 
8 
29-33 
9 
34-38 
10 
39-42 
11 
43 
12 
 
Operating characteristics of both rules are given below in Section 13. Statistical Methods. 
 
Data Analysis 
The primary study endpoint is efficacy, defined as the 2 year PSA progression-free (PSA<0.2 
ng/ml) survival rate among men who have non-castrate testosterone levels 2 years after 
enrollment.  Since there is no direct comparator trial in this population, this will be compared to 
the historical rate from a randomized trial of men with biochemically-recurrent (non-metastatic) 
prostate cancer after prostatectomy and (for most men) after salvage radiotherapy, with PSADT 
<9 months.  In that trial, at month 18, men who achieved a return to non-castrate testosterone 
blood levels who received abiraterone and degarelix had an undetectable PSA rate of 16% 18.  
Based on these data we will set the null hypothesis at 15% PSA progression-free survival at 2 
years in men with non-castrate testosterone.   
 
Power is based on a 1-sample logrank test for comparing an observed survival to a historical 
control rate 19.  The table below shows PSA progression-free survival, P1, ranging from 30-50% 
compared to a historical rate of 15% (P0). We assume that 60 men will be enrolled in the trial, at 
least 90% will have >50% PSA decrease following C-ADT and go on to RP and SBRT, and that 
80% of those patients (n=43) will have non-castrate testosterone at 2 years. For all comparisons 
α=0.05 and a 2-sided test is used.  Power is calculated using PASS v15 (NCSS Software, 
Kaysville, UT). 
 
The table shows that with N=43, PSA progression-free survival of >0.32 can be detected with 
power >82%.  These estimates may be conservative since the historical control rate is based on 
men without detectable metastases, whereas the current trial includes only men with 
oligometastatic disease. 
 
 
Power (%) 
N 
P0 
P1 
74 
48 
.15 
.30 
82 
48 
.15 
.32 
91 
48 
.15 
.35 
97 
48 
.15 
.40 
>99 
48 
.15 
.50 
 
 


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To conduct the safety analysis, rates of AEs will be calculated with 95% confidence intervals.  
Secondary time-to-event endpoints will be estimated with Kaplan-Meier methods, mean and 
median quality of life scores will be calculated with 95% confidence intervals, and chi-square 
test will be used for comparison of first metastatic sites. We will also compare secondary 
endpoints such as 2 year PSA failure-free survival to expected rates of 10-20% (based on data 
reported by CHAARTED (ASCO 2014) of 23% at 1 year for combined chemo-hormonal 
therapy) using a one-sample chi-square test.  Although power is likely to be suboptimal we will 
also perform exploratory analyses to compare the above endpoints among subgroups such as by 
age, number of initial metastatic sites, and between radiation and surgery. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Table of Contents 
Study Synopsis ...................................................................................................................... 2 
Early Stopping Boundaries for Toxicity ................................................................................. 11 
Data Analysis ....................................................................................................................... 13 
1. Introduction .................................................................................................................... 17 
1.1. Oligometastasis ............................................................................................................ 17 


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2. Overview and Rationale ................................................................................................... 18 
2.1. Biological basis for oligometastasis ............................................................................... 18 
2.1.1. Theories of metastasis ............................................................................................... 18 
2.1.2. Biology of systemic and oligometastases .................................................................... 19 
2.1.3. Preclinical models of oligometastasis ......................................................................... 19 
2.1.4. Clinical evidence of oligometastasis ........................................................................... 20 
2.1.5. Controversies surrounding the treatment of oligometastatic disease .......................... 21 
2.1.6. Rationale for the treatment of oligometastatic disease .............................................. 22 
2.1.7. Rationale for the treatment of oligometastatic prostate cancer .................................. 22 
2.2. Hormone therapy / complete androgen blockade ......................................................... 22 
2.2.1. Hormone therapy in oligometastases ......................................................................... 22 
2.2.2. Hormone therapy / complete androgen blockade in metastatic prostate cancer ......... 23 
2.2.3. Hormone therapy / complete androgen blockade in oligometastatic prostate cancer . 23 
2.3. Chemotherapy .............................................................................................................. 24 
2.3.1. Chemotherapy in oligometastases ............................................................................. 24 
2.3.2. Chemotherapy in metastatic prostate cancer ............................................................. 24 
2.3.3. Chemotherapy in oligometastatic prostate cancer ...................................................... 25 
2.4. Surgery ......................................................................................................................... 25 
2.4.1. Surgery of oligometastastatic sites/metastasectomy .................................................. 25 
2.4.2. Surgery in oligometastatic prostate cancer ................................................................. 26 
2.5. Radiation Therapy / Stereotactic Radiation Therapy (SBRT) ........................................... 26 
2.5.1. Radiation therapy to the prostate in metastatic prostate cancer................................. 26 
2.5.2. SBRT for oligometastases ........................................................................................... 27 
2.5.3. SBRT in oligometastatic prostate cancer ..................................................................... 28 
3.1. Primary Objective ......................................................................................................... 28 
3.2. Secondary Objectives .................................................................................................... 28 
4. Patient Population ........................................................................................................... 29 
4.1. Inclusion Criteria ........................................................................................................... 29 


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4.2. Exclusion Criteria .......................................................................................................... 29 
4.3. Inclusion of Women and minorities ............................................................................... 30 
5. Treatment Plan ................................................................................................................ 30 
5.1. Study Design ................................................................................................................. 30 
5.2. Study schema ............................................................................................................... 31 
5.3. Removal of Patients from Study .................................................................................... 32 
6. Treatment Screening ....................................................................................................... 33 
6.1. Screening (performed within prior to Cycle 1 Day 1) ...................................................... 33 
7. Treatment and Assessments on Study .............................................................................. 34 
7.1. Neoadjuvant Treatment and assessments ..................................................................... 34 
7.2. Surgery and Radiation ................................................................................................... 35 
7.3.  Follow-up..................................................................................................................... 36 
Follow Up (2 years after the last ADT treatment) ................................................................. 36 
8. Study Calendar ................................................................................................................ 36 
9.  Study Assessments.......................................................................................................... 40 
9.1. Definitions .................................................................................................................... 40 
9.2. Imaging ........................................................................................................................ 41 
9.3. Safety ........................................................................................................................... 41 
10. Pharmaceutical Information ........................................................................................... 41 
10.1. Drug Name: leuprolide acetate .................................................................................... 41 
10.2. Drug Name: bicalutamide ............................................................................................ 45 
10.4. Drug Name: docetaxel ................................................................................................. 53 
11. Study Treatments .......................................................................................................... 57 
11.4. Prostatectomy ............................................................................................................ 60 
11.5. Adjuvant Radiation Therapy to Pelvic Bed ................................................................... 60 
12. Data Monitoring and Reporting Requirements ............................................................... 61 
12.1. Principal Investigator .................................................................................................. 61 
12.2. Adverse Event Monitoring and Reporting .................................................................... 61 


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12.3. Evaluating Adverse Events .......................................................................................... 61 
12.4. Serious Adverse Events ............................................................................................... 62 
12.5. Expedited Reporting ................................................................................................... 63 
12.6. Data Entry ................................................................................................................... 63 
12.7. Case Report Forms ...................................................................................................... 64 
12.8. Source documents ...................................................................................................... 64 
12.9. Record Retention ........................................................................................................ 64 
12.10. Protocol Amendments .............................................................................................. 64 
12.11. Informed consent ...................................................................................................... 64 
13. Statistical Methods ........................................................................................................ 65 
13.1. Early Stopping Boundaries for Toxicity ........................................................................ 65 
13.2. Data Analysis .............................................................................................................. 67 
13.3. Multicenter Guidelines ................................................................................................ 68 
References .......................................................................................................................... 70 
Appendix A:......................................................................................................................... 72 
 
 
 
 
 
 
 
 
 
1. Introduction 
 
1.1. Oligometastasis 
Hellman first proposed the theory of oligometastases in 1995 as a sequel to the spectrum theory 
of cancer metastasis. Hellman hypothesized that the process of cancer metastases occurred along 
a continuum, from locally confined cancer to widely metastatic disease. Although the 
phenomenon of limited and treatable cancer metastases had been noted historically, Hellman and 
Weichselbaum proposed the term oligometastases, suggesting that in some patients with a 
limited number of clinically detectable metastatic tumors, the extent of disease exists in a 
transitional state between localized and widespread systemic disease. In this model local control 


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(LC) of oligometastases would have the potential to yield improved systemic control, going 
against the dogma that control of oligometastatic disease would not have a therapeutic benefit 
since it represents a clinical manifestation of a few detectable lesions in the setting of widespread 
occult disease. Oligometastasis continues to be defined as a state of metastatic disease that is 
limited in total disease burden, usually by number of clinically evident or radiographic sites 
(either 1-3 or 1-5), and that is not rapidly spreading to more sites. The clinical implication of 
oligometastasis suggests that if the primary site (if still present) is controlled, or resected, and the 
metastatic sites are ablated (surgically or with radiation), there will be a prolonged disease-free 
interval, and perhaps even cure. As the understanding of the mechanisms underlying cancer 
metastasis have evolved, possible mechanisms for the oligometastatic state must be explained 
and examined within that context. 1 
 
2. Overview and Rationale 
 
2.1. Biological basis for oligometastasis 
2.1.1. Theories of metastasis 
Metastasis is the cause of most cancer-related deaths. In 1889, Stephen Paget theorized that 
circulating tumor cells would “seed” to an amenable “soil”, suggesting that metastasis was not a 
matter of chance. Five years later, in 1894, Halstead theorized that cancer was an orderly disease 
that progressed in a contiguous manner, by direct extension from the primary tumor through the 
lymphatics, to the lymph nodes, and then to distant sites. Halstead proposed that breast cancer 
metastasis was a progressive, anatomical process of contiguous seeding; his hypothesis 
supported the use of radical surgery and radiotherapy. Radical en bloc surgery, radical 
hysterectomy, and primary and regional irradiation for several tumor sites were all based on 
Halstead’s theory of tumor spread.  James Ewing, in 1928, complemented the Paget and Halstead 
theories to propose that cancer cells grow at a particular site because they are directed by the 
direction of blood flow and lymphatics. 1 
The ‘systemic’ theory of metastasis, first suggested by Keynes [15] and further developed by 
Fisher 20, held that clinically apparent cancer was a systemic disease, and that small tumors were 
an early manifestation of systemic disease. In this theory, nodal involvement was not part of an 
orderly contiguous extension but rather a marker of distant metastases. According to this theory, 
local control would not impact survival. 1 
In contrast to the ‘Halsted’ theory and the ‘systemic’ theory, the ‘spectrum’ theory of cancer 
metastases, first described for breast cancer metastases in 1994, held that disease stage at the 
time of initial disease presentation fell into a spectrum ranging from indolent disease to widely 
metastatic, with the degree of clonal evolution determining the ability of the tumor to 
metastasize. The spectrum theory was refined just one year later to describe the limited 
metastasis of any solid tumor and the term ‘oligometastasis’ was coined. 1 
The spectrum theory conceptualized the entire range of metastatic competence, analogous to a 
diapason, which is the entire range of an instrument. To that end, the social sciences concept of a 
diaspora has recently been utilized to inform biologic understanding and therapeutic paradigms 


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of cancer metastasis. A diaspora refers to the scattering or movement of a population from its 
original homeland. In the case of systemic metastases, the diaspora resembles an imperial 
colonization in which the populations spread widely and eventually conquer the new host lands 
(aggressive cancer clones to multiple organs).  Oligometastases resemble trading post diasporas, 
representing a limited number of outposts with limited growth potential (less aggressive cancer 
clones to few organs). Systemic versus oligometastatic diasporas may be dependent on the types 
of mutations present in the cancer cells (quality of the diaspora migrants), the quality of the 
original tumor site (factors in the homeland that cause the population to migrate), and the quality 
of the new hostland (factors that allow immigrants to establish and flourish). 1 
2.1.2. Biology of systemic and oligometastases  
It is now widely accepted that there are discrete steps in tumor metastasis. Initially there is a loss 
in cellular adhesion, followed by increased motility > invasiveness of the primary tumor > entry 
into and survival in the circulation > entry into new organs > eventual colonization of these 
organs. Shortfalls at any stage of this metastatic progression could result in phenotypes of limited 
metastatic potential.  Gupta et al. described specific tumorigenic genes - initiation, progression, 
and virulence genes - that fulfilled specific roles in the metastatic cascade. Initiation genes afford 
a selective advantage to primary tumor cells to enter circulation. Progression genes fulfill rate-
limiting steps for colonization.  Virulence genes provide a selective advantage in cells to 
colonize a secondary site(s). As Weichselbaum and Hellman noted, this paradigm suggests “that 
there may be primary tumor cells with a limited capability in one or more of the necessary 
biological requirements for metastasis; thus proposing a possible biologic explanation of the 
origin of oligometastases” 21. 1 
In 2000, and updated in 2011, Hanahan and Weinberg proposed the, widely accepted, ‘hallmarks 
of cancer’.  The original cancer hallmarks consisted of six transformations in cellular physiology 
that allow cells to survive, proliferate and disseminate, and together support carcinogenesis. The 
update posited that underlying the original hallmarks were two ‘enabling hallmarks’: ‘genome 
instability and mutation’ and ‘tumor-promoting inflammation’. Additionally, the update 
proposed two new ‘emerging hallmarks’: ‘deregulation of cellular energetics’ and ‘avoidance of 
immune destruction’.  The exact sequence in which the transformations occur, and thus the 
appearance of the ‘hallmarks’ (self-sufficiency in growth signals  insensitivity to anti-growth 
signals  tissue evasion and metastasis  limitless replicative potential  sustained 
angiogenesis  evading apoptosis) can vary throughout the course of progression. Despite the 
ordering, collectively, the hallmarks can terminate into a cancer. However, the ordering and the 
degree of specific hallmarks, may potentially allow for a subsequent oligometastatic state. For 
example, cancer cells that lack the hallmarks to actively metastasize still may be able to slough 
into the circulation and inefficiently establish metastases. Other cells may be less efficient at 
proliferation, establishing slow growing metastases.  Warburg (1956) suggested that “We may 
have cells which indeed look like cancer cells but are still energetically insufficient… such cells 
which are clinically not cancer cells, have lately been found not only in the prostate, but also in 
the lungs, kidney, and stomach of elderly persons such cells have been referred to as “sleeping 
cancer cells” 22. 1 
2.1.3. Preclinical models of oligometastasis 


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Traditional clinicopathologic factors are inadequate when attempting to define the potential 
underlying biology of oligometastases.  Several investigations have demonstrated the marked 
genetic and epigenetic heterogeneity present in metastatic cancer sites within the same patient.  
These studies demonstrate that cancer cells at different sites within a patient can have varied 
malignant potential. Preclinical models of tumors with varying degrees of metastatic potential, 
including low metastatic potential exist. Using a cell line derived from B16F1 melanoma, Fidler 
et al. 23found that variant metastatic cells pre-exist in a heterogeneous primary tumor as opposed 
to originating through adaption during metastasis from an otherwise homogenous primary tumor. 
This finding was advanced in later work that showed the KHT sarcoma line demonstrated similar 
heterogeneity whether grown in vitro or in vivo, which suggested that clonal variation seen in 
vitro derived from heterogeneity present in the primary tumor. As an extension of this work in 
the KHT sarcoma line, it was demonstrated that effective metastatic variants developed at a high 
rate with low frequency, as opposed to the more frequent and stable subpopulations of metastatic 
variants. In comparing B16 cell lines, Cillo et al. showed that the more highly metastatic, and 
less genetically stable cell line, generated increased metastatic variants corresponding to 
increased chemotherapy resistance 24. Numerous in vitro studies and analyses of animal models 
have indicated that cells isolated from metastases differ greatly—both genetically and 
phenotypically—from cells isolated from their parental primary tumors. The preclinical models 
point toward variation in individual tumor cells’ metastatic potential, which supports the concept 
of oligometastases. 1 
Given that stochastic models have been used to predict biologic phenomena, a Bayesian model 
has been proposed to predict the chance of occult metastases in the presence of detectable 
oligometastases. Using the size and number of metastases, the proposed model inferred, 1) that 
the probability of occult metastases may increase substantially with minor increases in metastatic 
potential and 2) that extended disease-free periods were predictive of a substantial decrease in 
additional occult disease. Although compelling, such models are in their infancy and as yet 
remain in pre-clinical testing where the host, tumor and experimental factors are controlled. 1 
2.1.4. Clinical evidence of oligometastasis 
Evidence for the evolution of the oligometastatic phenotype comes from various clinical and pre-
clinical sources.  Recent studies of the molecular biology of renal cell cancer metastasis have 
implied biologic differences between less and more aggressive metastases, as well as between 
fewer and multiple metastases. In order to better determine which patients presenting with 
localized RCC harbor an aggressive tumor and may not benefit from surgery, Kosari et al. using 
gene expression profiling, found gene expression alterations associated with an aggressive tumor 
and metastatic potential in the primary tumor 25. From a cohort of 20 resected pulmonary 
metastases taken from 18 patients, Wuttig et al demonstrated the predictive potential of identified 
gene signatures, when comparing disease-free intervals (DFI) and number of metastases, both of 
which are predictive of prognosis in metastatic RCC (mRCC). There were 306 differentially 
expressed genes in comparing DFI ≥5 years and DFI ≤9 months, and 135 differentially expressed 
genes in comparing multiple metastases (≥16) and few metastases (≤8). 26 1 
In colorectal cancer, there is growing evidence that liver-limited disease is a distinct biological 
cohort that may benefit from aggressive management. While only a minority of patients are 
technically resectable, approximately 40% of patients with resected liver limited disease are alive 
5 years after diagnosis compared with less than 1% for those with disseminated disease. There is 


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genetic evidence that patients undergoing hepatic resection for metastatic cancer had a different 
disease than those who did not. For example, it was noted that BRAF V600E mutant tumors, 
which were typically associated with aggressive biology, rarely came to liver resection. In 
addition, novel chromosomal aberrations have been identified that are associated with intra- and 
extra-hepatic recurrence after liver resection. 1 
MicroRNAs, small non-coding RNA known to regulate tumor proliferation and apoptosis, are 
frequently dysregulated in cancer and metastasis. MicroRNA profiling has shown a possible 
method to distinguish patients with oligometastases from those with polymetastatic disease. 
Examples of pro-metastatic microRNAs include microRNA-10b (upregulated in primary breast 
tumors that had metastasized), microRNA-21 (correlated with advanced stage, incidence of 
metastases, and poor outcomes in breast and pancreatic tumors), and microRNA-373/520c 
(increased expression in breast metastases). MicroRNA-210, a known transcriptional target of 
the HIF-1a signaling pathway, was elevated in sera from patients with metastatic castrate-
resistant prostate cancer, as compared to controls, and was correlated with treatment response as 
assessed by change in PSA. Lussiter et al. found microRNA-200c was associated with 
polymetastatic progression in a oligometastatic cell line, derived from patients treated with high-
dose radiotherapy, tested in a xenograft model 27. The investigators then stratified patients with 
resected pulmonary oligometastases into subgroups, based on high-risk versus low-risk of further 
metastatic progression. Differential microRNA expression patterns were identified between these 
two groups (high rate of progression (n=16 prioritized microRNAs) and low rate of progression 
(n=32 prioritized microRNAs) and, in an independent dataset, the expression patterns were 
associated with risk of progression and decreased overall survival. 28 Most recently, Uppal et al. 
identified three microRNAs overexpressed in clinical metastasis samples from patients with 
limited metastatic disease. MicroRNA-127-5p, microRNA-544a, and microRNA-655-3p were 
shown to limit, but not fully inhibit, metastasis in a model of breast cancer lung colonization. 1 
2.1.5. Controversies surrounding the treatment of oligometastatic disease 
Hellman theorized that, 1) whereas some tumors were destined to remain localized, 2) other 
tumors, as they increased in size, acquired an increasingly greater metastatic phenotype, 
suggesting at an early stage these tumors seeded distant sites with clones that had not reached 
full metastatic potential, and finally, 3) that some tumors already had occult distant 
dissemination at the time they are diagnosed. He also proposed that metastatic potential was not 
only directed by the tumor phenotype, but that it was also influenced by the tumor’s location, 
venous drainage, and host factors. Based on Hellman’s theory, later scientists further theorized 
that tumors in the oligometastatic disease state were tumors early in their evolution of metastatic 
progression; therefore they produced metastases that were limited in number and location. These 
data support the presumption of a temporal evolution with an intermediate stage of limited 
metastatic capacity, where oligometastatic tumors may not have acquired the broad array of 
genetic changes required to develop widespread metastases. 1 
The clinical implication of the oligometastatic state is that locally ablative therapies, given with 
the intent of targeting sites of clinically evident metastatic disease could result in long-term 
survival or cure. Treatment of oligometastatic disease may also result in decreased overall tumor 
burden, decreasing morbidity and increasing survival.  These arguments are opposed by the 
concept that clinical metastases are evidence of systemic disease and locally directed treatment 
will not alter the natural history of the disease course within a patient. In this scenario, only 


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systemic therapy may be beneficial.  Indeed, oligometastatic treatment paradigms are 
controversial (due to the limited data available).  Without randomized studies, it is impossible to 
know if treatment of oligometastatic disease helps the patient.  In addition, oligometastatic 
disease may represent indolent disease that does not require potentially toxic treatments. 1 
2.1.6. Rationale for the treatment of oligometastatic disease 
Patients are increasingly being diagnosed with oligometastatic disease due to the advent of 
sensitive imaging technologies as well as effective therapies that are allowing patients to live 
longer with the diagnosis of cancer. In addition, the fact that novel treatment options with 
acceptable safety profiles, such as stereotactic radiation, cryoablation, and minimally invasive 
surgery, are available to treat limited metastases, has led to a renewed interest in treating 
oligometastatic disease.  Treatment of oligometastatic disease not only has the potential to 
prevent further evolution of genetically unstable clones and metastatic spread, it may improve 
overall disease control and delay more toxic systemic treatment. Finally, the definition of 
oligometastases had gradually evolved, which further inflates the increasing population of 
patients diagnosed with oligometastasis. In the absence of data to guide decisions, treatment of 
oligometastatic disease may be seen as a quality-of-life oriented approach, choosing personalized 
treatments with a reasonable risk to benefit ratio and taking into account the patient’s own 
attitude in guiding them toward more or less, intensive therapy. 1  
2.1.7. Rationale for the treatment of oligometastatic prostate cancer 
 
In addition to preventing further evolution of genetically unstable clones and additional 
metastatic spread, the combination therapies may be more effective in treating hormone-sensitive 
disease, before it becomes hormone refractory and more aggressive. While testing in the 
hormone sensitive population will require much longer follow-up to assess efficacy, as compared 
to testing interventions in the castrate-resistant population, we have elected to assess safety as the 
primary endpoint and efficacy as a secondary endpoint. 
 2.2. Hormone therapy / complete androgen blockade 
 
2.2.1. Hormone therapy in oligometastases 
 
We reviewed the literature in search of clinical studies of hormone sensitive oligometastatic 
disease with hormone therapy included as an intervention. We searched PubMed using the terms 
breast, ovarian, and endometrial ‘oligometastases’, ‘oligometastases’, and ‘breast, ovarian, and 
endometrial’ oligometastatic cancer. There were no clinical studies focused solely on ovarian or 
endometrial oligometastatic cancer. Using the terms ‘breast oligometastases’, ‘breast 
oligometastasis’, and ‘oligometastatic breast cancer’; results were as follows, n=20, n=5, and 
n=51, respectively. We omitted reviews (including special features), studies including mixed 
primary tumors, case reports, studies not in the English language, studies not focused on 
oligometastatic breast cancer, and a survey.  There were seven clinical studies remaining; each 
study used a different therapy, none of which included a hormone therapy. 1 
 


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We also searched for ongoing studies with hormone therapy included as an intervention. In 
clinicaltrials.gov multiple trials are underway to determine if the treatment of oligometastatic 
disease is beneficial in cancer. There were no trials for women with oligometastatic ovarian or 
endometrial cancer. For women with oligometastatic breast cancer, six studies are currently open 
investigating several therapies including various chemotherapy regimens, SABR + antibodies, 
SBRT, chemotherapy + antibodies + RT, targeted therapies and RT- however, none of the 
studies included hormone therapy. 1 
 
2.2.2. Hormone therapy / complete androgen blockade in metastatic prostate cancer 
 
The standard of care treatment for metastatic prostate cancer is androgen deprivation therapy 
(ADT). Men with newly diagnosed metastatic prostate cancer, entered into the control arm of the 
Systemic Therapy Multi-Arm Randomized Controlled Trial (STAMPEDE) and treated with ≥2 
years of ADT alone, had a 2-year OS of 72%. The response rate for primary hormonal therapy 
for men with metastatic prostate cancer exceeds 80% and the median duration of response is 
approximately 18-24 months. 1 
In 1941 the relationship was established between prostate adenocarcinoma and androgenic 
hormones 5. These findings were the basis of androgen deprivation therapy (either 
pharmacologic or surgical) becoming first line therapy for men with metastatic prostate cancer. 
ADT continues to the mainstay, gold standard, initial therapy of metastatic prostate cancer, 
however it is not curative. The median time to development of resistance to primary ADT is 18-
36 months. Currently medical castration is achieved with LHRH agonists (leuprolide or other 
LHRH agonists (i.e. goserelin, etc)) all of which are accepted as comparable. 5,6 
 
Combined androgen blockade (CAB) augments androgen ablation by using concurrent LHRH 
agonist and an antiandrogen. CAB may have a modest survival advantage over monotherapy, 
nonetheless it comes with increased risk of adverse effects. 5 
2.2.3. Hormone therapy / complete androgen blockade in oligometastatic prostate cancer 
 
Currently we are awaiting the results of the STAMPEDE study arm for men with newly 
diagnosed M1 disease who are enrolled in a new treatment arm (enzalutamide, abiraterone and 
prednisone with ADT). 1 
We reviewed the literature in search of clinical studies of hormone sensitive oligometastatic 
prostate cancer with hormone therapy included as an intervention. We searched PubMed using 
the terms ‘prostate cancer oligometastasis’, ‘prostate cancer oligometastases’, and 
‘oligometastatic prostate cancer’; results were as follows, n=3, n=19, and n=22, respectively. We 
omitted reviews, studies including mixed primary tumors, studies not focused on oligometastatic 
prostate cancer, case reports, editorials/commentaries, studies that we were not able retrieve, and 
studies with no results reported. There were ten clinical studies remaining with 7 different 
treatment paradigms, of which 5 studies included hormone therapy. 1                                                                     
We also searched for ongoing studies with hormone therapy included as an intervention for 
oligometastic prostate cancer. In clinicaltrials.gov, nine trials are underway investigating a 


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variety of therapies including single agent RT, RT in combination with HT, salvage treatment 
(surgical or RT) of metastases, and combination of HT + immunotherapy, of these nine trials, 3 
include hormone therapy. 1 
 2.3. Chemotherapy 
2.3.1. Chemotherapy in oligometastases 
 
We searched PubMed using the above described ‘oligometastasis’ terms for breast, lung, 
melanoma, colorectal cancer, sarcoma, and prostate cancer. Of those solid tumors, chemotherapy 
was used in breast, lung, colorectal, and sarcoma oligometastases. 1 
 
In clinicaltrials.gov, of the multiple trials underway to determine if the treatment of 
oligometastatic disease is beneficial, 11/41 trials were using chemotherapy (including 
immunotherapy, monoclonal antibodies, tyrosine kinase inhibitors, anti-programmed death 
antibodies, anti-angiogenics) in their therapeutic regimen. 1 
2.3.2. Chemotherapy in metastatic prostate cancer 
 
Although taxanes are the standard treatment approach in metastatic castrate-resistant prostate 
cancer, two recent randomized trials investigated the combination of docetaxel + ADT in 
treatment naïve metastatic prostate cancer. 
 
In the CHAARTED trial (Phase III, E3805) 790 men with metastatic hormone sensitive prostate 
cancer, treatment naïve, were randomized to either ADT + up to 6 cycles of docetaxel versus 
ADT alone. The primary endpoint was overall survival. Patients were stratified according to high 
volume disease (visceral metastases and/or ≥4 bone metastases) versus low-volume disease, prior 
anti-androgen use > 30 days, age ≥ or < 70 years, ECOG 01- versus 2 and prior adjuvant ADT > 
or ≤ 12 months. After a median follow-up of 28.9 months, the docetaxel + ADT arm had an OS 
of 57.6 months, as compared to ADT alone OS of 44.0 months. Patients with high-volume 
metastatic disease (defined as visceral metastasis or ≥4 bone metastases), treated on the 
docetaxel + ADT arm had an increased OS (49.2 versus 32.2 months in the ADT alone arm, HR 
0.60, p<0.001). The median OS was not yet reached in either arm for those with low-volume 
disease. Other sub-group analyses (PSA < 0.2 at 6 mths/12mths, median time to CRPC, and 
median time to clinical progression) also showed that the combination of ADT + docetaxel was 
superior. In the docetaxel + ADT arm, grade 3/4 febrile neutropenia was 2.3%. 2,4-6 
 
In the GETUG 15 trial 385 men with metastatic hormone sensitive prostate cancer, were 
randomized to ADT + docetaxel versus ADT alone. The protocol allowed for up to 9 cycles of 
docetaxel. The primary endpoint was OS. Secondary endpoints included time to clinical 
progression and time to PSA progression. 81% of those enrolled had bone metastasis and 14.5% 
had visceral organ metastasis. Median number of cycles of docetaxel was 8. At 50 months 
median follow-up, OS was not different between the two arms, ADT + docetaxel versus ADT 
alone (58.9 versus 54.2 months, HR 1.01, p=0.955), despite that the combination therapy did 
yield a significant improvement in biochemical PFS and clinical PFS (22.9 versus 12.9 months, 
HR 0.72, p=0.005, and 23.5 versus 15.4 months, HR 0.75, p=0.015, respectively). 3,5,6 More 


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recently, the authors reported on the comparison between patients’ self assessment of treatment 
related toxicities versus investigators’ evaluation of their patients’ toxicities. [REF] The men 
were invited to complete a 26-symptom questionnaire at 3- and 6- months, while physicians 
assessed 18 symptoms. 220 and 165 patients completed questionnaires at 3- and 6-months. At the 
two assessment points (3 months and 6 months) all symptoms were reported more frequently by 
patients than by physicians. Positive agreement rates between patients and physicians, for the 
most commonly reported symptoms, included hot flushes (61 and 64%), fatigue (50 and 44%), 
sexual dysfunction (29 and 31%), and weight change (24 and 14%). However, ~50% of the time 
physicians did not report patients’ hot flushes and ~90% of the time they did not report patients’ 
joint/muscle pain. In comparison between the two arms, patients randomized to the ADT + 
docetaxel arm had more toxicities that those in the ADT alone arm.  7 
 
Alternatively, an arm of the STAMPEDE trial provides data on men with newly diagnosed 
metastatic prostate cancer who were randomized to standard-of-care therapy with androgen 
deprivation therapy. Cross-over was allowed at progression.  The cohort of 917 men had a 
median follow-up of 20 months. Median failure free survival (FFS-time from randomization 
until biochemical failure, local or distant progression, or death from prostate cancer) was 11 
months, and median OS was 42 months. 2 year FFS and OS were 29% and 72% respectively. 
This study demonstrated poor survival in men starting therapy with androgen deprivation only, 
despite the ability to initiate other treatments at failure of ADT. The median OS in this group was 
shorter than that of the control arm in GETUG-15, and was similar to the control arm in 
CHAARTED. 8 
2.3.3. Chemotherapy in oligometastatic prostate cancer 
 
Several trials are currently underway for men with oligometastatic prostate cancer.   In 
clinicaltrials.gov, there are nine trials investigating a variety of therapies including single agent 
RT, RT in combination with HT, salvage treatment (surgical or RT) of metastases, and 
combination of HT + immunotherapy. Of these nine trials, none included chemotherapy. 1 
 2.4. Surgery  
2.4.1. Surgery of oligometastastatic sites/metastasectomy 
 
Historically, most of the surgical data in regards to oligometastatic disease is centered on hepatic 
resection. Perioperative mortality related to hepatic resection has decreased from 20% (before 
1980) to 1%. Recent improvement in overall survival, following hepatectomy, are likely from 
improvements in patient selection (shift in definition of resectability to new criteria based on 
whether a macroscopic and microscopic complete resection of the liver lesion as well as 
complete resection of any extrahepatic disease), surgical technique, and more effective adjuvant 
therapy. The use of portal vein embolization and neoadjuvant chemotherapy has also expanded 
the population of patients who are eligible for resection. In a recent series of patients having 
undergone hepatic resection, despite progression on chemotherapy, the 5-yr survival was 53%. 1 
Secondary resection remains a worthwhile therapeutic goal; patients brought to resection by 
systemic therapy enjoy comparable long-term survival to patients who had resectable disease at 
the time of presentation, and far superior to those receiving palliative systemic chemotherapy. 


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10-20% of patients that develop colorectal liver metastases present with, or are converted by 
systemic treatment to, an oligometastatic state defined as metastatic lesions that are limited in 
number and involving only a single organ. This type of disease is potentially amenable to local 
therapeutic modalities, of which hepatic resection is the most effective. 1 
Surgery, when used to manage oligometastatic disease, tends to be seen as the gold standard as it 
allows for pathologic evaluation and assessment of the surgical margins. In addition, lesions 
greater than 7-8 cm and those difficult to target with SBRT, are better left for surgical 
management. 1 
 
 
2.4.2. Surgery in oligometastatic prostate cancer 
 
There is a body of evidence, contrary to historical clinical practice, that treating men with 
metastatic prostate cancer to the lymph nodes at the time of diagnosis with surgery or radiation 
therapy results in increased long-term survival.  Historically, the ideal patient to be cured by 
radical prostatectomy (RP) was one with organ-confined cancer. At that time, the morbidity of 
RP was substantial; therefore the surgery was generally only offered to those where the 
probability of cure was high. More recent data, however, show that RP may provide a survival 
benefit- albeit not a cure - to men with metastatic prostate cancer.  Engel et al. 9 conducted a 
retrospective study (n=938) and found that in men with prostate cancer and positive lymph 
nodes, treated with +/- RP, that the 5- and 10-yr survival rates and the prostate cancer specific 
survival rates, were better in men who had undergone RP.  Cadeddu et al 10 conducted a 
retrospective study (n=38) and found that in men with prostate cancer and positive lymph nodes, 
treated with LND +/- RP, that the 5- and 10-yr prostate cancer specific survival was better in 
men who had undergone LND + RP.  1 
In men with prostate cancer with limited metastases, radical prostatectomy may be advantageous 
in that the primary tumor and its ability to continuously metastasize, to secrete tumor promoting 
growth factors and immunosuppressive cytokines, and to generate bulk-related morbidity, is 
removed. Heidenreich et al. recently evaluated survival outcomes following radical 
prostatectomy (RP) in men with low volume metastatic prostate cancer. RP led to improved 
progression-free survival, time to castrate resistance and overall survival, as compared to a 
cohort treated with androgen deprivation therapy alone. 11 Moreover, Abdollah et al. found that 
in men with pN1 prostate cancer, treated with RP and extended lymph node dissection, adding 
adjuvant radiotherapy improved cancer-specific mortality 12. 1 
 
 2.5. Radiation Therapy / Stereotactic Radiation Therapy (SBRT) 
 
2.5.1. Radiation therapy to the prostate in metastatic prostate cancer 
 


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Ost et al (2014) conducted a systemic review of the literature of metastasis-directed therapy of 
regional and distant recurrences after curative treatment for PCa (prostate cancer). They found 
that salvage LND and RT appear to be safe in treatments for OM PCa recurrence.13 Culp et al. 14 
studied the impact of survival of definitive treatment of the prostate in men diagnosed with 
metastatic PCa. Using the SEER database, he reviewed 8185 men treated with NSR (no surgery 
no radiation), brachytherapy, or RT. The 5-year OS and disease specific survival (DSS) was 
significantly higher in men with metastases having undergone RT.  1 
Zapatero et al., reported on a study of men with intermediate and high risk localized prostate 
cancer (n=362), treated with RT + long term ADT versus short term ADT, and found that long 
term ADT was superior in 5-year biochemical disease free survival, metastasis free survival, and 
OS 15. 1 
2.5.2. SBRT for oligometastases 
 
While much of the literature supporting the oligometastatic states is within the surgical literature, 
there is an increasing body of literature describing the use of stereotactic body radiotherapy 
(SBRT) and stereotactic radiosurgery (SRS), in addition to conventional fractionated 
radiotherapy techniques. SBRT is a noninvasive method of delivering high doses of radiation to 
ablate a target lesion while sparing the neighboring normal tissue, thus reducing long-term 
effects of radiation on the non-malignant tissues.  The radiation is delivered from many beams 
originating from multiple directions that converge on the target site. Through improved targeting 
and management of tumor motion, SBRT may improve tumor control and reduce treatment-
related toxicity, as compared to conventional fractionated RT. Improved radiation targeting 
allows for higher-dose, hypofractionated, more efficient treatment regimens that can be delivered 
within narrow margins sparring adjacent organs. ‘Hypofractionation’ is the delivery of large 
doses of radiation over a shorter time period as compared to conventional radiation fraction 
sizes. Therapy can generally be completed in 1-5 sessions, as compared to conventional radiation 
therapy that is delivered in smaller doses 5 days/week over ≥6 weeks. 1 
Intracranial stereotactic body radiation therapy (SBRT) has been shown to be a highly effective 
treatment for brain metastases. 29 This suggests that selective small extracranial tumors (either 
primary or metastatic tumors) may be effectively controlled by similar focal high-dose SBRT. 
There is an increasing experience with extracranial SBRT as effective local therapy for metastatic 
lesions. Local control in excess of 75% has been reported for metastatic tumors of the spine, lung 
and liver, which is significantly higher than standard conventional moderate dose radiation. 29-33 
Toxicity has been minimal in multiple U.S., European and Japanese trials of extracranial 
stereotactic radiotherapy to the lung, liver, spine, pelvis and abdomen despite the use of very high 
biological equivalent doses for patients with both organ confined and metastatic cancer. [adapted 
from Johns Hopkins Oncology Clinical protocol J12137, NA_00069585] 
 
SBRT can be used to manage oligometastatic disease presentations that would be associated with 
added morbidity if managed by surgery, such as deep-seated or osseous lesions. Patients who are 
poor surgical candidates may often be treated with SBRT, given that it is noninvasive and has a 
modest morbidity profile. 1  


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Although traditionally radiation therapy was thought to be immunosuppressive, there is 
increasing pre-clinical and clinical evidence that high dose, hypofractionated radiation –SBRT- 
may reverse antitumor immunity via CD8+ T-cells and cellular stress signals. Although 
uncommon, the abscopal effect (regression in tumors distant to the targeted field of radiation) is 
an example of recovery of anti-tumor immunity following RT. Thus, an emerging advantage of 
SBRT is the possibility that it may be exploited to benefit the immune system. 1  
 
2.5.3. SBRT in oligometastatic prostate cancer 
 
Major advancements in radiation treatment planning and delivery have resulted in resurgence in 
the use of radiation therapy (RT) as a treatment for bone metastases. In selected patients, very high 
local control rates have been observed, with minimal toxicity.  Bone metastases represent the major 
metastatic site (>90%) in men with rising PSA following primary treatment for their prostate 
cancer. [adapted from Johns Hopkins Oncology Clinical protocol J12137, NA_00069585] 
 
The primary management of metastatic prostate cancer is systemic therapy in the form of androgen 
deprivation therapy (ADT), which rarely eradicates metastatic disease and adversely effects patient 
quality of life.  Thus, even the ability to defer long-term ADT in men with oligometastatic prostate 
cancer represents a considerable clinical advance. [adapted from Johns Hopkins Oncology Clinical 
protocol J12137, NA_00069585] 
 
 
3. Study Objectives 
  
3.1. Primary Objective 
To assess efficacy of the following therapy: (1st) Systemic chemo-hormonal therapy with 6-
cycles (~24 weeks) of neoadjuvant androgen deprivation and chemotherapy, (2nd) definitive 
local tumor control with prostatectomy +/- adjuvant radiation therapy, and then (3rd) 
consolidative stereotactic radiation to oligometastatic lesions. The men will receive a total of 
1 year of androgen deprivation, or until completion of local and metastatic consolidation 
(should that extend beyond 1 year). 
 
Efficacy will be defined as the 2-year PSA progression-free (PSA<0.2 ng/ml) survival rate. 
 
   
3.2. Secondary Objectives 
1. Safety 
Defined as the incidence of Grades 3 and 4 neutropenia and surgical- or radiation-
induced toxicities. 
 
2. Time to PSA recurrence. 
Defined as the time from an undetectable PSA (≤0.2 ng/mL) until the PSA is >0.2 over 
two time-points up to 3 years. 


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4. Patient Population 
 
Men with newly diagnosed synchronous oligometastatic prostate cancer (T1-4, N0-1, M1a-b) 
consisting of 1-5 metastatic lesions who are willing to undergo  (1st) Systemic chemo-hormonal 
therapy with up to 6-weeks (~24 weeks) of neoadjuvant androgen deprivation and up to 6 cycles 
of chemotherapy, (2nd) definitive local tumor control with prostatectomy +/- adjuvant radiation 
therapy, and (3rd) consolidative stereotactic radiation to oligometastatic lesions. The men will 
receive a total of 1 year of androgen deprivation. 
 
 4.1. Inclusion Criteria 
1. Willing and able to provide written informed consent 
 
2. Age ≥ 18 years 
 
3. Eastern cooperative group (ECOG) performance status ≤2 
 
4. Documented histologically confirmed adenocarcinoma of the prostate 
 
5. Willing to undergo the following therapy: (1st) Systemic chemo-hormonal therapy 
with up to 6-months (~24weeks) of neoadjuvant androgen deprivation and up to 6 
cycles of chemotherapy, (2nd) definitive local control with prostatectomy +/- adjuvant 
radiation therapy, and (3rd) consolidative stereotactic radiation to oligometastatic 
lesions. Additionally, must be willing to be treated with a full year of androgen 
deprivation.  
 
6. Oligometastatic prostate cancer: Stage T1-4, N0-1 and/or M1a-b (up to 5 metastatic 
lesions- including bone lesions and non-regional lymph nodes) 
 
7. Able to swallow the study drugs whole as tablets 
 
4.2. Exclusion Criteria 
1. Prior local therapy to treat prostate cancer (e.g. radical prostatectomy, radiation 
therapy, brachytherapy) 
2. Prior therapy to a metastatic site. 
 
3. Prior systemic therapy for prostate cancer including, but not limited to: 
a. Hormonal therapy (e.g. leuprolide, goserelin, triptorelin, degarelix) 
b. CYP-17 inhibitors (e.g. ketoconazole) 
c. Antiandrogens (e.g. bicalutamide, nilutamide) 
d. Second generation antiandrogens (e.g. abiraterone, enzalutamide) 
e. Immunotherapy (e.g. sipuleucel-T, ipilimumab) 


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f. Chemotherapy (e.g. docetaxel, cabazitaxel) 
*Note: may be enrolled if has recently initiated hormone therapy of any kind (<90 days 
duration). In the event that hormone therapy was initiated prior to study enrollment, the clock for 
1 year of androgen deprivation would begin at the time of therapy initiation, rather than at study 
enrollment. 
4. Ongoing systemic therapy for prostate cancer including, but not limited to: 
a. Immunotherapy (e.g. sipuleucel-T, ipilimumab) 
b. Non-protocol prescribed chemotherapy (e.g. cabazitaxel) 
 
 
5. Evidence of serious and/or unstable pre-existing medical, psychiatric or other 
condition (including laboratory abnormalities) that could interfere with patient safety 
or provision of informed consent to participate in this study. 
 
6. Any psychological, familial, sociological, or geographical condition that could 
potentially interfere with compliance with the study protocol and follow-up schedule. 
 
7. Abnormal bone marrow function [absolute neutrophil count (ANC)<1500/mm3, 
platelet count <100,000/mm3, hemoglobin <9 g/dL] 
 
8. Abnormal liver function (bilirubin >ULN; AST, ALT ≥ 2.5 x upper limit of normal) 
 
 
9. Active cardiac disease defined as active angina, symptomatic congestive heart failure, 
or myocardial infarction within previous six months. 
 
10. Prior history of malignancy in the past 3 years with the exception of basal cell and 
squamous cell carcinoma of the skin.  Other malignancies that are considered to have 
a low potential to progress may be enrolled at discretion of PI. 
 
4.3. Inclusion of Women and minorities 
This study is focused on prostate cancer and therefore includes men only.  
Men from all ethnic and race groups are eligible for this study. 
5. Treatment Plan  
 5.1. Study Design 
The objective of the study is to assess the efficacy of treating men with oligometastatic prostate 
cancer with the following therapy: (1st) Systemic chemo-hormonal therapy with up to 6-months 
(24 weeks) of neoadjuvant complete androgen blockade and up to 6 cycles of chemotherapy, 
(2nd) definitive local tumor control with prostatectomy +/- adjuvant radiation therapy, and (3rd) 
consolidative stereotactic radiation to oligometastatic lesions. Additionally, men will receive a 
total of 1 year of androgen blockade. Androgen blockade will be the same throughout the course 
of treatment. 


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Open label phase II study designed to assess the efficacy and therapeutic benefit of 
multimodality therapy in men presenting with newly diagnosed oligometastatic prostate cancer 
(<5 sites of metastases). A total of sixty patients will be enrolled with the primary endpoint of the 
2 year PSA progression-free (PSA<0.2 ng/ml) survival rate.   
 
 
Neoadjuvant treatment (month 1 through ~6): All patients will be treated with up to 6 months of 
neoadjuvant androgen deprivation plus up to 6 cycles of docetaxel chemotherapy. Following 
docetaxel therapy, patients with a PSA response of at least a 50% decrease from baseline, will 
proceed to maximum consolidative therapy.  
 
Surgery and Radiation (month 7 though ~11): After completion of neoadjuvant therapy, the men 
will be treated with definitive local therapy with radical prostatectomy (RP) +/- adjuvant 
radiation therapy. After definitive local therapy, patients will be treated with consolidative 
stereotactic body radiation therapy (SBRT) to the metastatic sites.   
 
Follow up: Patients treated will continue on androgen deprivation for a total of 1 year. They will 
be followed clinically and monitored with serum testosterone and PSA until 2-years after 
completion of ADT treatment. (Androgen blockade will be the same throughout the course of 
treatment. 
 
 
Neoadjuvant chemohormonal therapy is expected to be safe. Two recent randomized trials 
(CHAARTED and GETUG-AUF15) investigated the combination of docetaxel + ADT in 
treatment naïve metastatic prostate cancer. In the CHAARTED trial (Phase III, E3805) 790 men 
with metastatic hormone sensitive prostate cancer, treatment naïve, were randomized to either 
ADT + docetaxel versus ADT alone. The primary endpoint was overall survival. Data from 
1/16/14 with a median follow-up of 29 months included 137 deaths on ADT alone arm versus 
104 deaths on the ADT + docetaxel arm. In the ADT + docetaxel arm, grade 3-4 neutropenia was 
4%-2%; grade 3 neuropathy was 1% sensory and 1% motor; one patient died while on treatment, 
however there were no deaths attributed to treatment on ADT. 4-6 
 
In the GETUG-AUF 15 trial 385 men with metastatic hormone sensitive prostate cancer, were 
randomized to ADT + docetaxel versus ADT alone. The protocol allowed for up to 9 cycles of 
docetaxel. The primary endpoint was OS. Secondary endpoints included time to clinical 
progression and time to PSA progression. 81% of those enrolled had bone metastasis and 14.5% 
had visceral organ metastasis. Median number of cycles of docetaxel was 8. Grade 3-4 adverse 
events were higher in the docetaxel + ADT arm. The most common grade 3-4 adverse events in 
the docetaxel + ADST arm were neutropenia (32%), febrile neutropenia (7%), and fatigue (7%). 
Docetaxel was dose reduced in 11% of the patients. 3,5,6 
5.2. Study schema 
 
 
OLIGOMETASTATIC PROTOCOL FOR PATIENTS UNDERGOING PROSTATECTOMY 


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The primary endpoint is the 2 year PSA progression-free (PSA<0.2 ng/ml) survival.  
 
Secondary endpoints will include safety and 2-year undetectable PSA rate, time to PSA 
recurrence following completion of therapy up to 3 years. 
 
 5.3. Removal of Patients from Study 
A patient may be removed from the study for a variety of reasons, including: 
 
1. 
An increase in PSA, defined as PSA increased consistently over 3 time-points 
 
2. 
Disease progression of metastatic sites, or new metastatic lesions, demonstrated on 
imaging at completion of chemotherapy. 
 
3. 
Diagnosis of >5 metastases on entry imaging studies before SBRT.  
 
4. 
Worsening symptoms that can be attributed to prostate cancer 
 
5. 
Unacceptable adverse event(s)  
 Patients who develop grade 3 or higher liver function abnormalities: 
o Bilirubin ≥ 3 times institutional upper limit of normal (ULN) 
o AST (SGOT) or ALT (SGPT) ≥ 5 times ULN 
 Patients develop decreased renal function with serum creatinine  ≥ 2.5 times 
baseline level 
 
Eligibility Criteria
 
-Oligometastatic 
prostate cancer  
(Any T1-4, N0-1, 
and/or M1a-b (1-5 
metastatic lesions))  
 
-CT scan 
(chest/abdomen/p
elvis) 
 
-Bone scan 
 
Endpoints 
 
-Safety 
 
-2-yr undetectable 
PSA rate 
 
 
 
 
 
Leuprolide 22.5mg 
IM q3mo
NEOADJUVANT 
TREATMENT 
Docetaxel 
75mg/m2, 65 
mg/m2, 55 mg/m2 
or 35 mg/m2 IV up 
to 6 doses/cycles 
Prostatectomy +/- 
XRT to pelvic bed  
SBRT to 
oligometastases 
 
Surgery and Radiation 
 
Given for total 1 year 
36 months 
Follow-up-
For 2 years after the last 
ADT treatment 


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6. 
Patients develop hypersensitivity or anaphylactoid reactions to leuprolide (Lupron) 
(LHRH analogs), or its replacement drugs, or docetaxel (taxotere). Intercurrent 
illness that prevents further participation 
 
7. 
Experiencing a treatment delay of longer than 4 weeks due to drug, surgical or 
radiation toxicity; however, if the patient is receiving clinical benefit, treatment may 
be delayed for longer than 4 weeks and then resumed at the discretion of the 
Investigator. 
 
8. 
Patient refuses further treatment through the study and/or withdraws consent to 
participate 
 
9. 
Patient is noncompliant with respect to taking drugs, keeping appointments, or 
having tests required for the evaluation of safety and efficacy  
 
10. General or specific changes in the patient's condition that render the patient 
unacceptable for further treatment in this study in the judgment of the investigator. 
 
11. Under no circumstance will care of a withdrawn patient be adversely affected by a 
decision to withdraw or be withdrawn from the study. 
 
6. Treatment Screening 
*All required screening study procedures and assessments must be done within 30 days prior 
to enrollment unless otherwise noted.  Prior to enrollment, patients will be seen by a Medical 
Oncologist, Urologist, and Radiation Oncologist to ensure the patient is aware of risks and 
potential benefits of each type of treatment. 
 6.1. Screening (performed within prior to Cycle 1 Day 1)  
1. Informed consent  
 
2. Medical History  
 
3. Physical Examination and ECOG Performance Status: A complete physical 
examination will be completed at screening and the End of Study visit; symptom-
directed physical examinations will be completed at the times specified in the 
study calendar 
 
4. Patient Height and Weight 
 
5. Vital Signs: Vital sign measurements include measurements of diastolic and systolic 
BP, heart rate, and temperature. 
 
6. Concomitant Medications and Procedures 
 
7. CBC (Complete blood count) with differential and platelet count. 


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8. CMP (Comprehensive Metabolic Panel - Sodium, Potassium, Chloride, BUN, Serum 
Creatinine, Calcium, Total Protein, Albumin, Total Bilirubin, AST, ALT, Alkaline 
Phosphatase, CO2). 
 
9. Serum PSA 
 
10. Serum Testosterone 
 
11. CT scan (chest-abdomen-pelvis) with contrast (within 90 days of study enrollment) 
 
12. Bone scan- whole body (within 90 days of study enrollment) 
13. MRI (optional) 
14. PET scan (optional) 
15. Quality of Life (FACT-P and FACT-Taxane) 
7. Treatment and Assessments on Study 
*All required treatment and end of study procedures and assessments must be done within 7 
days (+/-) of the specified study visit date unless otherwise noted. Long-term follow-up 
procedures and assessments should occur within 21 days (+/-) from the specified study visit 
date. 
 7.1. Neoadjuvant Treatment and assessments   
 
Hormone therapy- 
LHRH analog (3 month injection)- given twice, at beginning of Cycle 1 
chemotherapy, and repeat every 3 months 
 
* At Investigator discretion- Complete androgen blockade may be administered 
by adding the anti-androgen, bicalutamide (50 mg daily, oral) and/or abiraterone 
acetate (1000 mg / day + prednisone 5mg / day), to the LHRH analog 
 
Chemotherapy- administered every 3 weeks, in 6 cycles. The cycles may be 
adjusted to up to every 5 weeks for toxicity and scheduling convenience 
 
Cycle 1-Cycle 6 Docetaxel Administration (intravenous) (± 7 days)  
 Clinical assessment and ECOG Performance Status same day, prior to 
Docetaxel Administration 
 Vital Signs and weight   
 CMP, CBC, PSA  
 CBC- 1-week post 
 Adverse events 
 Concomitant Medications and Procedures 
 
Re-staging, 4 weeks after final cycle of chemotherapy is given (up to month 7) 


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 Physical Examination and ECOG Performance Status 
 Vital Signs: Vital sign measurements include measurements of diastolic 
and systolic BP, heart rate, and temperature. 
 Weight 
 Adverse events 
 CBC (Complete blood count) with differential and platelet count. 
 CMP (Comprehensive Metabolic Panel - Sodium, Potassium, Chloride, 
BUN, Serum Creatinine, Calcium, Total Protein, Albumin, Total 
Bilirubin, AST, ALT, Alkaline Phosphatase, CO2). 
 Serum PSA 
 Serum Testosterone 
 CT scan (chest-abdomen-pelvis) with contrast 
 Whole body bone scan 
 MRI (Optional)  
 
 Quality of Life (FACT-P and FACT-Taxane) 
 
 7.2. Surgery and Radiation  
Surgery (radical prostatectomy), (month 1.5 after final cycle of chemotherapy) 
-Prostatectomy specimen pathologic assessment 
 
-CBC, CMP, PSA, testosterone- within 7 days of surgery 
 
 
 
PSA and clinic visit within 8 weeks after surgery, prior to radiation. 
Adjuvant radiation to pelvic bed (if indicated, given per provider’s discretion); 
given over 6-8 weeks. Indications:  
-Radiation therapy to pelvic bed indicated if positive margins @ 
prostatectomy 
 
-and/or- 
-Radiation therapy to pelvic bed indicated if pT3 and/or R1 (per AUA-
ASTRO guidelines) 
 
 


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SBRT to oligometastatic sites per provider’s discretion . 
7.3.  Follow-up 
Follow Up (2 years after the last ADT treatment) 
 Serum PSA every 3 months 
 Serum Testosterone every 3 months 
 CT scan (chest-abdomen-pelvis) with contrast (only clinically indicated) 
 Whole body bone scan (only clinically indicated) 
 
End of Study Visit at 36 months: 
 Physical Examination and ECOG Performance Status 
 Vital sign measurements  
 Weight 
 CBC (Complete blood count) with differential and platelet count. 
 CMP (Comprehensive Metabolic Panel - Sodium, Potassium, Chloride, 
BUN, Serum Creatinine, Calcium, Total Protein, Albumin, Total 
Bilirubin, AST, ALT, Alkaline Phosphatase, CO2). 
 Serum PSA 
 Serum Testosterone 
 CT scan (chest-abdomen-pelvis) with contrast (only clinically indicated) 
 Whole body bone scan (only clinically indicated) 
 
 
 
 
8. Study Calendar 


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Neoadjuvant 
treatment a 
 
Surgery and Radiation b 
Follow
-Up c,d 
End of 
Study 
Visit e f 
 
Screening g, 
y 
6 Cycles  
(Q3 weeks 
±7 days) 
 
 
 
Re-
Staging 
Visit h 
±7 days 
Surgery 
8 weeks 
from 
surgery 
±14 days 
Adjuvant 
RT to 
pelvic bed i 
SBRT to 
Oligomet. 
Sites j 
±28 
days 
±28 days 
Informed consent 
X 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
Physical assessment 
X 
X 
X 
 
x 
 
 
 
X 
Vital signs k 
X 
X 
X 
 
x 
 
 
 
X 
Weight  
X 
X 
X 
 
x 
 
 
 
X 
Height  
X 
 
 
 
x 
 
 
 
 
ECOG Performance status 
X 
X 
X 
 
x 
 
 
 
X 
Adverse Events Assessment 
X 
X 
X 
 
x 
 
 
 
X
Concomitant Medications 
X 
X 
X 
 
x 
 
 
 
X 
Quality of life l
X 
 
X 
 
 
 
 
 
 
Hematology u
X 
X w
X 
X
 
 
 
 
X 
Serum Chemistry v
X 
X 
X 
X
 
 
 
 
X 
PSA 
X 
X 
X 
X
x 
Xb
 
Q3mo 
X 
Testosterone 
X 
 
X 
X
 
 
 
Q3mo 
X 
CT/MRI m
X m
 
X m
 
 
 
 
X m 
X m
Bone Scan n
X n
 
X n
 
 
 
 
X n
X n
Chemotherapy o 
 
X 
 
 
 
 
 
 
 
Hormone therapy P 
 
X 
 
 
 
 
 
 
 
Bicalutamide q
 
 
X 
 
 
 
 
 
 
 
Prostatectomy r 
 
 
 
X x 
 
 
 
 
 


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a. 
Neoadjuvant treatment (month 1 through ~6): All patients will be treated with up to 6 months of androgen deprivation, plus up to 6 cycles of docetaxel chemotherapy 
(Docetaxel 75 mg/m2, 65mg/m2, 55mg/m2, or 35mg/m2 at physician discretion every 3 weeks as a 1hour intravenous infusion). 
b. Surgery and Radiation (month 7 though ~11): After completion of neoadjuvant therapy, men will be treated with definitive local therapy with radical prostatectomy (RP) 
+/- adjuvant radiation therapy (RT). After definitive local therapy, patients will be treated with consolidative stereotactic body radiation therapy (SBRT) to the metastatic 
sites. PSA needs to be checked within 8 weeks after surgery, prior to radiation. 
c. 
Follow up: Patients will be followed for 2 years after the last ADT treatment. 
d. PSA and Testosterone should be obtained at every 3 months and can be done at an outside facility. 
e. 
End of Study Visit will be at 36 months. 
f. 
Study Subjects may be contacted every 3 months for survival data. Other potential data such as the subjects’ follow-up treatment or care may be requested during these 
contacts. The contacts can be via telephone or correspond with disease assessment visits or other scheduled visits. 
g. Screening will be performed within 30 days of Cycle 1 Day 1. 
h. Re-staging, 4 weeks after final cycle of chemotherapy is given. 
i. 
Adjuvant radiation to pelvic bed (if indicated, given per provider’s discretion); given over 3-7 weeks. 
j. 
SBRT to oligometastatic sites per provider’s discretion. 
k. Vital sign measurements include diastolic and systolic BP, heart rate, and temperature. 
l. 
Quality of life scoring using the Functional Assessment of Cancer Therapy-Prostate (FACT-P) [REF] supplemented with the FACT-Taxane [REF]. QOL instruments 
will be administered at Screening and  Re-Staging visit. 
m. Radiographic evaluation will be performed at screening (up to 90 days before Cycle 1 Day1) and restaging visit; however subsequent radiographic assessments may be 
performed as clinically indicated. Testing will include CT with intravenous contrast or MRI of the chest, abdomen, and pelvis. The scans can be done at an outside 
facility. 
n. Bone scanning will be performed at screening (screening Bone scan may be done up to 90 days before Cycle 1 Day 1) and restaging visit. Requirements for additional 
Bone scans will be performed as clinically indicated. The scans can be done at an outside facility. 
o. Docetaxel will be given at any of the following doses (75 mg/m2, 65 mg/m2, 55 mg/m2 or 35 mg/m2 IV) on day 1 of each cycle, up to 6 cycles at physician discretion. 
p. LHRH analog (Q3 month injection). Androgen deprivation therapy may have started up to 90 days before Day 1. It is given for a total of 1 year; the clock for 1 year of 
androgen deprivation would begin at the time of therapy initiation, rather than at study enrollment. 
q. Bicalutamide (Casodex) (50mg daily) and/or or abiraterone acetate 1000 mg / day + prednisone 5mg / day) may be added to the leuprolide in the event that the 
Investigator elects to administer complete androgen blockade. No replacements are allowed for bicalutamide or abiraterone. No dose adjustments are allowed for 
bicalutamide. 
r. 
Following docetaxel therapy, patients with a PSA response of at least a 50% decrease from baseline, will proceed to maximum consolidative therapy. 
Adjuvant radiation therapy (RT) s 
 
 
 
 
 
X 
 
 
 
SBRT  
 
 
 
 
 
 
X 
 
 
MRI t 
 
 
X 
 
 
 
 
 
 
Survival Follow-Up f
 
 
 
 
 
 
 
 
X f


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s. 
Adjuvant radiation to pelvic bed (if indicated, given 3 months after prostatectomy). Radiation therapy to pelvic bed indicated if positive margins at prostatectomy and/or 
Radiation therapy to pelvic bed indicated if pT3 and/or R1 (per AUA-ASTRO guidelines) 
t. 
Optional MRI, standard of care 
u. Hematology: hemoglobin, hematocrit, RBC count, WBC count with differential, ANC and platelet count. Labs must be done within 7 days (+/-) of the specified study 
visit date unless otherwise noted. 
v. Serum Chemistry: sodium, potassium, chloride, bicarbonate, glucose, BUN, creatinine, ALT, AST, alkaline phosphatase, total bilirubin, total protein, albumin, calcium. 
Labs must be done within 7 days (+/-) of the specified study visit date unless otherwise noted. 
w. Hematology: CBC- 1-week post Docetaxel administration.  
x. CBC, CMP, PSA, testosterone- within 7 days of surgery 
y. Prior to enrollment, patients will be seen by a Medical Oncologist, Urologist, and Radiation Oncologist to ensure the patient is aware of risks and potential benefits of 
each type of treatment. 
 


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9.  Study Assessments 
Response and progression of targeted metastatic prostate cancer lesions will be evaluated 
as follows: 
 
1) CT scans (to assess lymph nodes)- Using the Response Evaluation Criteria in Solid 
Tumors (RECIST 1.1) Committee 34.  Changes in only the largest diameter 
(unidimensional measurement) of the tumor lesions are used in the RECIST criteria.   
 
2) Bone scans- Lesions by bone scan will be evaluated as positive, negative or no change. 
 
3) Serial PSA changes. 
 
4) Adverse events (AEs) will be monitored every 3 weeks during neoadjuvant therapy and 
at two-months post surgery.  Patients requiring adjuvant EBRT will be assessed as per 
standard of care during treatment and at two-months post therapy.   AEs will be 
monitored as per standard of care during treatment and at two-months post therapy. 
AEs will then be monitored 3 months (per study calendar). 
 
9.1. Definitions 
 
Oligometastases:  
Oligometastatic prostate cancer will be defined as prostate cancer with up to 5 sites of 
metastases, including bone lesions, regional and non-regional lymph nodes; men with 
visceral metastases will not be included. 
 
Undetectable PSA:  
PSA ≤ 0.2 ng/mL  
 
PSA increase/PSA recurrence:   
Surgery arm: PSA >0.2, over two time-points 
Radiation therapy arm: PSA increased 2ng/mL over nadir (nadir is determined 
after therapy) 
 
2-year undetectable PSA (time interval): 
 
2 years after completion of systemic consolidative therapy 
 
2-year PSA progression-free survival:  
(PSA<0.2 ng/ml) among men who have non-castrate testosterone levels 2 years 
after enrollment 
*for men with a baseline testosterone ≤200ng/dL, 2-year PSA PFS is defined as a 
PSA <0.2 at baseline level of testosterone, 2 years after enrollment 
 
Noncastrate testosterone level: 
 
>200 ng/dL 
 


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9.2. Imaging 
Patients should be re-evaluated for 6 months, and as clinically indicated.  
 
CT SCAN   
Spiral CT should be performed using a 5 mm contiguous reconstruction algorithm.  This 
applies to tumors of the chest, abdomen, and pelvis.  
 
Radiographic response assessed using RECIST 1.1 criteria 34.  
 
Bone SCAN  
To be performed as per standard of care to assess response of osseous lesions to therapy. 
Radiographic response assessed using the following criteria: progression, no change, and 
response.  
 9.3. Safety 
 
Safety will evaluated based on the incidence, severity, duration, causality, seriousness, and 
type of adverse events (AEs), and changes in the patient’s physical examination, vital signs, 
and clinical laboratory results.  Investigators will use the NCI CTC version 4.0 (published 14 
June 2010) to assess the severity of AEs and toxicities 
(http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf). 
For safety considerations specific to the study drugs, see section 10 of the protocol.  
 
Adverse events (AEs) will be monitored every 3 weeks during neoadjuvant therapy and at two-
months post surgery.  Patients requiring adjuvant EBRT will be assessed as per standard of care 
during treatment and at two-months post therapy.   AEs will be monitored as per standard of care 
and at two-months post SBRT. AEs will then be monitored 3 months (per study calendar). 
 
Please see Section 13.1, Early Stopping Boundaries for Toxicity 
 
10. Pharmaceutical Information 
 
10.1. Drug Name: leuprolide acetate  
[Adapted from FDA prescribing information] 
[Note: for leuprolide replacements, following FDA prescribing information] 


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 Chemical Name: 5-oxo-L-prolyl-L-histidyl-L-tryptophyl-L-seryl-L-tyrosyl-D-leucyl-L-
leucyl-L-arginyl-N-ethyl-L-prolinamide acetate (salt) 
 Molecular Formula: C59H84N16O12.C2H4O2 
  Molecular Weight: 1269.45 
 
Description 
Leuprolide acetate is a synthetic nonapeptide analog of naturally occurring gonadotropin 
releasing hormone (GnRH or LH-RH). The analog possesses greater potency than the natural 
hormone. 
Leuprolide acetate injection is a sterile, aqueous solution intended for subcutaneous injection. It 
is available in a 2.8 mL multiple-dose vial containing 5 mg/mL of Leuprolide acetate, 6.3 mg/mL 
sodium chloride, USP for tonicity adjustment, 9 mg/mL of benzyl alcohol as a preservative and 
water for injection, USP. The pH may have been adjusted with sodium hydroxide, NF and/or 
acetic acid, NF. 
 
Clinical Pharmacology 
Leuprolide acetate, an LH-RH agonist, acts as a potent inhibitor of gonadotropin 
secretion when given continuously and in therapeutic doses. Animal and human studies 
indicate that following an initial stimulation of gonadotropins, chronic administration of 
Leuprolide acetate results in suppression of ovarian and testicular steroidogenesis. This 
effect is reversible upon discontinuation of drug therapy. Administration of Leuprolide 
acetate has resulted in inhibition of the growth of certain hormone dependent tumors 
(prostatic tumors in Noble and Dunning male rats and DMBA-induced mammary tumors 
in female rats) as well as atrophy of the reproductive organs. 
 
In humans, subcutaneous administration of single daily doses of Leuprolide acetate 
results in an initial increase in circulating levels of luteinizing hormone (LH) and follicle 
stimulating hormone (FSH), leading to a transient increase in levels of the gonadal 
steroids (testosterone and dihydrotestosterone in males, and estrone and estradiol in pre-
menopausal females). However, continuous daily administration of Leuprolide acetate 
results in decreased levels of LH and FSH. In males, testosterone is reduced to castrate 
levels. In pre-menopausal females, estrogens are reduced to post-menopausal levels. 
These decreases occur within two to four weeks after initiation of treatment, and castrate 
levels of testosterone in prostatic cancer patients have been demonstrated for periods of 
up to five years. 
 


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Leuprolide acetate is not active when given orally. 
 
Safety/Precautions 
 Tumor Flare 
Initially, Lupron Depot, like other GnRH agonists, causes increases in serum levels of 
testosterone to approximately 50% above baseline during the first weeks of treatment. 
Isolated cases of ureteral obstruction and spinal cord compression have been 
observed, which may contribute to paralysis with or without fatal complications. 
Transient worsening of symptoms may develop. A small number of patients may 
experience a temporary increase in bone pain, which can be managed 
symptomatically. 
 
Patients with metastatic vertebral lesions and/or with urinary tract obstruction should 
be closely observed during the first few weeks of therapy. 
 
 Hyperglycemia and Diabetes 
Hyperglycemia and an increased risk of developing diabetes have been reported in 
men receiving GnRH agonists. Hyperglycemia may represent development of 
diabetes mellitus or worsening of glycemic control in patients with diabetes. Monitor 
blood glucose and/or glycosylated hemoglobin (HbA1c) periodically in patients 
receiving a GnRH agonist and manage with current practice for treatment of 
hyperglycemia or diabetes. 
 
 Cardiovascular Diseases 
Increased risk of developing myocardial infarction, sudden cardiac death and stroke 
has been reported in association with use of GnRH agonists in men. The risk appears 
low based on the reported odds ratios, and should be evaluated carefully along with 
cardiovascular risk factors when determining a treatment for patients with prostate 
cancer. Patients receiving a GnRH agonist should be monitored for symptoms and 
signs suggestive of development of cardiovascular disease and be managed according 
to current clinical practice. 
 
 Effect on QT/QTc Interval 
Androgen deprivation therapy may prolong the QT/QTc interval. Providers should 
consider whether the benefits of androgen deprivation therapy outweigh the potential 
risks in patients with congenital long QT syndrome, congestive heart failure, frequent 
electrolyte abnormalities, and in patients taking drugs known to prolong the QT 
interval. Electrolyte abnormalities should be corrected. Consider periodic monitoring 
of electrocardiograms and electrolytes. 
 
 Convulsions 
Postmarketing reports of convulsions have been observed in patients on leuprolide 
acetate therapy. These included patients with a history of seizures, epilepsy, 
cerebrovascular disorders, central nervous system anomalies or tumors, and in 
patients on concomitant medications that have been associated with convulsions such 
as bupropion and SSRIs. Convulsions have also been reported in patients in the 


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absence of any of the conditions mentioned above. Patients receiving a GnRH agonist 
who experience convulsion should be managed according to current clinical practice. 
 
Information for Patients 
Patients should be informed that:  
 The most common side effects associated with Lupron Depot are hot flashes, pain 
(especially joint pain and back pain), injection site pain and fatigue. 
 If they have had an allergic reaction to other drugs like Lupron Depot, they should 
not use this drug. 
 Lupron Depot may cause impotence. 
 The increase in testosterone that occurs during the first weeks of therapy can 
cause an increase in urinary symptoms or pain. 
 If they have metastatic cancer to the spine or urinary tract, they need close 
medical attention during the first weeks of therapy. 
 
Laboratory tests 
Response to Leuprolide acetate should be monitored by measuring serum levels of 
testosterone and prostate-specific antigen (PSA). In the majority of patients, testosterone 
levels increased above baseline during the first week, declining thereafter to baseline 
levels or below by the end of the second week of treatment. Castrate levels were reached 
within two to four weeks and once attained were maintained for as long as drug 
administration continued. 
 
Drug Interactions 
No pharmacokinetic-based drug-drug interaction studies have been conducted with 
Leuprolide acetate. However, because Leuprolide acetate is a peptide that is primarily 
degraded by peptidase and the drug is only about 46% bound to plasma proteins, drug 
interactions would not be expected to occur. 
 
Adverse Reactions 
In the majority of patients testosterone levels increased above baseline during the first 
week, declining thereafter to baseline levels or below by the end of the second week of 
treatment. This transient increase was occasionally associated with a temporary 
worsening of signs and symptoms, usually manifested by an increase in bone pain. In a 
few cases a temporary worsening of existing hematuria and urinary tract 
obstruction occurred during the first week. Temporary weakness and paresthesia of the 
lower limbs have been reported in a few cases. 
 
Potential exacerbations of signs and symptoms during the first few weeks of treatment 
is a concern in patients with vertebral metastases and/or urinary obstruction which, if 
aggravated, may lead to neurological problems or increase the obstruction. 
 
Administration, Supply and Storage 
 
Administration 
The recommended dose is 1 mg (0.2 mL or 20 unit mark) administered as a single daily 


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subcutaneous injection. As with other drugs administered chronically by subcutaneous 
injection, the injection site should be varied periodically. Each 0.2 mL contains 1 mg of 
Leuprolide acetate, sodium chloride for tonicity adjustment, 1.8 mg of benzyl alcohol as 
preservative and water for injection. The pH may have been adjusted with sodium 
hydroxide and/or acetic acid. 
 
Supply 
Leuprolide Acetate Injection is a sterile solution, supplied as follows: 
 
 2.8mL multiple dose vial 
 one multiple-dose vial per one 14-day patient 
 1 mg/0.2 mL 
 administration kit with 14 disposable syringes and 28 alcohol swabs 
 NDC number: 0703-4014-18 
 
 
Storage 
Store below 25°C (77° F). DO NOT FREEZE. Protect from light. Store vial in carton 
until contents are used. 
10.2. Drug Name: bicalutamide  
[Adapted from FDA prescribing information] 
 
 
 Chemical Name: ropanamide, (+-)-N-[4-cyano-3-(trifluoromethyl)phenyl]-3-[(4- 
fluorophenyl)sulfonyl]-2-hydroxy-2-methylpropanamide. 
 Molecular Formula: C18H14F4N2O4S 
 Molecular Weight: 430.37 
 
Description 
Bicalutamide tablets, USP contain 50 mg of Bicalutamide, a non-steroidal androgen receptor 
inhibitor with no other known endocrine activity. 
 
Clinical Pharmacology 
Bicalutamide tablets are a non-steroidal androgen receptor inhibitor. It competitively 
inhibits the action of androgens by binding to cytosol androgen receptors in the target 
tissue. Prostatic carcinoma is known to be androgen sensitive and responds to treatment 


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that counteracts the effect of androgen and/or removes the source of androgen. 
 
When Bicalutamide tablets are combined with luteinizing hormone releasing hormone 
(LHRH) analog therapy, the suppression of serum testosterone induced by the LHRH 
analog is not affected. However, in clinical trials with Bicalutamide tablets as a single 
agent for prostate cancer, rises in serum testosterone and estradiol have been noted. 
 
In a subset of patients who have been treated with Bicalutamide tablets and an LHRH cv                           
agonist, and who discontinue Bicalutamide tablets therapy due to progressive advanced 
prostate cancer, a reduction in Prostate Specific Antigen (PSA) and/or clinical 
improvement (antiandrogen withdrawal phenomenon) may be observed. 
 
Safety/Precautions 
 Hepatitis Cases of death or hospitalization due to severe liver injury (hepatic failure) 
have been reported post-marketing in association with the use of Bicalutamide tablets. 
Hepatotoxicity in these reports generally occurred within the first 3 to 4 months of 
treatment. Hepatitis or marked increases in liver enzymes leading to drug 
discontinuation occurred in approximately 1% of Bicalutamide tablets patients in 
controlled clinical trials. 
Serum transaminase levels should be measured prior to starting treatment with 
Bicalutamide tablets, at regular intervals for the first 4 months of treatment, and 
periodically thereafter. If clinical symptoms or signs suggestive of liver dysfunction 
occur (e.g., nausea, vomiting, abdominal pain, fatigue, anorexia, “flu-like” symptoms, 
dark urine, jaundice, or right upper quadrant tenderness), the serum transaminases, in 
particular the serum ALT, should be measured immediately. If at any time a patient 
has jaundice, or their ALT rises above two times the upper limit of normal, 
Bicalutamide tablets should be immediately discontinued with close follow-up of 
liver function. 
 
 Gynecomastia and Breast Pain In clinical trials with Bicalutamide tablets 150 mg as 
a single agent for prostate cancer, gynecomastia and breast pain have been reported in 
up to 38% and 39% of patients, respectively. 
 
 Glucose Tolerance A reduction in glucose tolerance has been observed in males 
receiving LHRH agonists. This may manifest as diabetes or loss of glycemic control 
in those with preexisting diabetes. Consideration should therefore be given to 
monitoring blood glucose in patients receiving Bicalutamide tablets in combination 
with LHRH agonists. 
 
Information for Patients 
 Patients should be informed that therapy with Bicalutamide tablets and the LHRH 
analog should be started at the same time and that they should not interrupt or stop 
taking these medications without consulting their physician. 
 
 During treatment with Bicalutamide tablets, somnolence has been reported, and those 
patients who experience this symptom should observe caution when driving or 


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operating machines. 
 
 Patients should be informed that diabetes, or loss of glycemic control in patients with 
preexisting diabetes has been reported during treatment with LHRH agonists. 
Consideration should therefore be given to monitoring blood glucose in patients 
receiving Bicalutamide tablets in combination with LHRH agonists. 
 
Laboratory tests 
 Regular assessments of serum Prostate Specific Antigen (PSA) may be helpful in 
monitoring the patient’s response. 
 
 If PSA levels rise during Bicalutamide tablets therapy, the patient should be evaluated 
for clinical progression. For patients who have objective progression of disease 
together with an elevated PSA, a treatment-free period of antiandrogen, while 
continuing the LHRH analog, may be considered. 
 
 
 
Drug Interactions 
Clinical studies have not shown any drug interactions between Bicalutamide and LHRH 
analogs (goserelin or leuprolide). There is no evidence that Bicalutamide induces hepatic 
enzymes. 
 
In vitro studies have shown that R-Bicalutamide is an inhibitor of CYP 3A4 with lesser 
inhibitory effects on CYP 2C9, 2C19 and 2D6 activity. Clinical studies have shown that 
with coadministration of Bicalutamide tablets, mean midazolam (a CYP 3A4 substrate) 
levels may be increased 1.5 fold (for Cmax) and 1.9 fold (for AUC). Hence, caution 
should be exercised when Bicalutamide tablets are coadministered with CYP 3A4 
substrates. 
 
In vitro protein-binding studies have shown that Bicalutamide can displace coumarin 
anticoagulants from binding sites. Prothrombin times should be closely monitored in 
patients already receiving coumarin anticoagulants who are started on Bicalutamide 
tablets and adjustment of the anticoagulant dose may be necessary. 
 
Adverse Reactions 
In patients with advanced prostate cancer treated with Bicalutamide tablets in 
combination with an LHRH analog, the most frequent adverse reaction was hot flashes 
(53%). 
In the multicenter, double-blind, controlled clinical trial comparing Casodex 50 mg once 
daily with flutamide 250 mg three times a day, each in combination with an LHRH 
analog, the following adverse reactions with an incidence of 5% or greater, regardless of 
causality, have been reported: pain (general), back pain, asthenia, pelvic pain, infection, 
abdominal pain, chest pain, headache, fly syndrome, hot flashes, hypertension, 
constipation, nausea, diarrhea, increased liver enzyme, dyspepsia, flatulence, anorexia, 
vomiting, anemia, peripheral edema, weight loss, hyperglycemia, AP increased, weight 


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gain, bone pain, myasthenia, arthritis, pathological fracture, dizziness, paresthesia, 
insomnia, anxiety, depression, dyspnea, increased cough, pharyngitis, bronchitis, 
pneumonia, rhinitis, rash, sweating, nocturia, hematuria, urinary tract infection, 
gynecomastia, breast pain, urinary frequency, urinary retention, urinary impaired, and 
urinary incontinence. 
 
 
Administration, Supply and Storage 
Administration 
The recommended dose for Bicalutamide tablets therapy in combination with an 
LHRH analog is one 50 mg tablet once daily (morning or evening), with or 
without food. It is recommended that Bicalutamide tablets be taken at the same 
time each day. Treatment with Bicalutamide tablets should be started at the same 
time as treatment with an LHRH analog. 
 
Supply 
Bicalutamide Tablets, USP are available containing 50 mg of Bicalutamide, USP. 
 
The 50 mg tablets are white film-coated, round, unscored tablets debossed with M 
on one side of the tablet and C17 on the other side. They are available as follows: 
 
NDC 0378-7017-93 
bottles of 30 tablets 
 
NDC 0378-7017-05 
bottles of 500 tablets 
 
Storage 
Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.] 
 
 
10.3. Drug name: abiraterone 
[Adapted from FDA prescribing information] 
 
 
 Chemical Name: Abiraterone acetate; 154229-18-2; Zytiga; CB7630; CB-7630 
 Molecular Formula: C26H33NO2 


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 Molecular Weight: 391.555 g/mol 
 
Description 
Abiraterone acetate, the active ingredient of ZYTIGA is the acetyl ester of abiraterone. 
Abiraterone is an inhibitor of CYP17 (17α-hydroxylase/C17,20-lyase). Each ZYTIGA tablet 
contains 250 mg of abiraterone acetate. Abiraterone acetate is designated chemically as (3β)- 
17-(3-pyridinyl)androsta-5,16-dien-3-yl acetate. 
Abiraterone acetate is a white to off-white, non-hygroscopic, crystalline powder. Abiraterone 
acetate is a lipophilic compound with an octanol-water partition coefficient of 5.12 (Log P) 
and is practically insoluble in water. The pKa of the aromatic nitrogen is 5.19. 
Inactive ingredients in the tablets are lactose monohydrate, microcrystalline cellulose, 
croscarmellose sodium, povidone, sodium lauryl sulfate, magnesium stearate, and colloidal 
silicon dioxide. 
 
Clinical Pharmacology 
Abiraterone acetate (ZYTIGA) is converted in vivo to abiraterone, an androgen biosynthesis 
inhibitor, that inhibits 17 α-hydroxylase/C17,20-lyase (CYP17). This enzyme is expressed 
in testicular, adrenal, and prostatic tumor tissues and is required for androgen biosynthesis. 
CYP17 catalyzes two sequential reactions: 1) the conversion of pregnenolone and 
progesterone to their 17α-hydroxy derivatives by 17α-hydroxylase activity and 2) the 
subsequent formation of dehydroepiandrosterone (DHEA) and androstenedione, 
respectively, by C17, 20 lyase activity. DHEA and androstenedione are androgens and are 
precursors of testosterone. Inhibition of CYP17 by abiraterone can also result in increased 
mineralocorticoid production by the adrenals. 
Androgen sensitive prostatic carcinoma responds to treatment that decreases androgen 
levels. Androgen deprivation therapies, such as treatment with GnRH agonists or 
orchiectomy, decrease androgen production in the testes but do not affect androgen 
production by the adrenals or in the tumor. 
ZYTIGA decreased serum testosterone and other androgens in patients in the placebo controlled 
phase 3 clinical trial. It is not necessary to monitor the effect of ZYTIGA on 
serum testosterone levels. 
Changes in serum prostate specific antigen (PSA) levels may be observed but have not been 
shown to correlate with clinical benefit in individual patients. 
 
 
Safety/Precautions 
Hypertension, Hypokalemia and Fluid Retention Due to Mineralocorticoid 
Excess. Use ZYTIGA with caution in patients with a history of cardiovascular disease. ZYTIGA 
may cause hypertension, hypokalemia, and fluid retention as a consequence of increased 
mineralocorticoid levels resulting from CYP17 inhibition. Co-administration of a corticosteroid 
suppresses adrenocorticotropic hormone (ACTH) drive, resulting in a reduction in the incidence 
and severity of these adverse reactions. 


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Adrenocortical Insufficiency. Adrenocortical insufficiency has been reported in clinical trials in 
patients receiving ZYTIGA in combination with prednisone, following interruption of daily 
steroids and/or with concurrent infection or stress. Use caution and monitor for symptoms and 
signs of adrenocortical insufficiency, particularly if patients are withdrawn from prednisone, 
have prednisone dose reductions, or experience unusual stress. 
 
Hepatotoxicity.  Marked increases in liver enzymes leading to drug discontinuation or dosage 
modification have occurred. Measure serum transaminases (ALT and AST) and bilirubin levels 
prior to starting treatment with ZYTIGA, every two weeks for the first three months of treatment 
and monthly thereafter. 
 
Food effect. ZYTIGA must be taken on an empty stomach. No food should be consumed for at 
least two hours before the dose of ZYTIGA is taken and for at least one hour after the dose of 
ZYTIGA is taken. Abiraterone Cmax and AUC0-∞ (exposure) were increased up to 17- and 10-
fold higher, respectively, when a single dose of abiraterone acetate was administered with a meal 
compared to a fasted state. 
 
 
Information for Patients 
•Patients should be informed that ZYTIGA and prednisone are used together and that 
they should not interrupt or stop either of these medications without consulting their 
physician. 
 
•Patients receiving GnRH agonists should be informed that they need to maintain this 
treatment during the course of treatment with ZYTIGA and prednisone. 
 
•Patients should be informed that ZYTIGA must not be taken with food and that no food 
should be consumed for at least two hours before the dose of ZYTIGA is taken and for at 
least one hour after the dose of ZYTIGA is taken. They should be informed that the 
tablets should be swallowed whole with water. Patients should be informed that taking 
ZYTIGA with food causes increased exposure and this may result in adverse reactions. 
 
•Patients should be informed that ZYTIGA is taken once daily and prednisone is taken 
twice daily according to their physician’s instructions. 
 
•Patients should be informed that in the event of a missed daily dose of ZYTIGA or 
prednisone, they should take their normal dose the following day. If more than one daily 
dose is skipped, patients should be told to inform their physician. 
 
•Patients should be apprised of the common side effects associated with ZYTIGA, 
including peripheral edema, hypokalemia, hypertension and urinary tract infection. 
 
• Patients should be advised that their liver function will be monitored using blood tests. 
 
•Patients should be informed that ZYTIGA may harm a developing fetus; thus, women 


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who are pregnant or women who may be pregnant should not handle ZYTIGA without 
protection, e.g., gloves. Patients should also be informed that it is not known whether 
abiraterone or its metabolites are present in semen and they should use a condom if 
having sex with a pregnant woman. The patient should use a condom and another 
effective method of birth control if he is having sex with a woman of child-bearing 
potential. These measures are required during and for one week after treatment with 
ZYTIGA. 
 
 
Laboratory tests 
Monitor patients for hypertension, hypokalemia, and fluid retention at least once a month. 
Control hypertension and correct hypokalemia before and during treatment with 
ZYTIGA®. 
Use caution and monitor for symptoms and signs of adrenocortical insufficiency, 
particularly if patients are withdrawn from prednisone, have prednisone dose reductions, 
or experience unusual stress. 
Permanently discontinue ZYTIGA® for patients who develop a concurrent elevation of 
ALT greater than 3 x ULN and total bilirubin greater than 2 x ULN in the absence of 
biliary obstruction or other causes responsible for the concurrent elevation. 
Promptly measure serum total bilirubin, AST, and ALT if clinical symptoms or 
signs suggestive of hepatotoxicity develop. Elevations of AST, ALT, or bilirubin from 
the patient’s baseline should prompt more frequent monitoring. If at any time AST 
or ALT rise above five times the ULN, or the bilirubin rises above three  times the ULN, 
interrupt ZYTIGA® treatment and closely monitor liver function. 
Assess for hypertension, hypokalemia, and fluid retention: Baseline and at least once per 
month. 
 
Assess liver function tests (AST, ALT, bilirubin): baseline, every 2 weeks for first 3 
months of treatment and monthly thereafter. 
 
Drug Interactions 
Effects of Abiraterone on Drug Metabolizing Enzymes 
ZYTIGA is an inhibitor of the hepatic drug-metabolizing enzyme CYP2D6. In a 
CYP2D6 drug-drug interaction trial, the Cmax and AUC of dextromethorphan (CYP2D6 
substrate) were increased 2.8- and 2.9-fold, respectively, when dextromethorphan was 
given with abiraterone acetate 1,000 mg daily and prednisone 5 mg twice daily. Avoid 
coadministration of abiraterone acetate with substrates of CYP2D6 with a narrow 
therapeutic index (e.g., thioridazine). If alternative treatments cannot be used, exercise 
caution and consider a dose reduction of the concomitant CYP2D6 substrate drug. 
 
Drugs that Inhibit or Induce CYP3A4 Enzymes 
Based on in vitro data, ZYTIGA is a substrate of CYP3A4. The effects of strong 
CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, 
nefazodone, saquinavir, telithromycin, ritonavir, indinavir, nelfinavir, voriconazole) or 


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inducers (e.g., phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital) 
on the pharmacokinetics of abiraterone have not been evaluated, in vivo. Avoid or use 
with caution, strong inhibitors and inducers of CYP3A4 during ZYTIGA treatment. 
 
 
Adverse Reactions 
In a placebo-controlled, multicenter phase 3 clinical trial of patients with metastatic 
castration-resistant prostate cancer who were using a gonadotropin-releasing hormone 
(GnRH) agonist or were previously treated with orchiectomy, ZYTIGA was administered 
at a dose of 1,000 mg daily in combination with prednisone 5 mg twice daily in the active 
treatment arm (N = 791). Placebo plus prednisone 5 mg twice daily was given to control 
patients (N = 394). The median duration of treatment with ZYTIGA was 8 months. The 
most common adverse drug reactions (≥5%) reported in clinical studies were joint 
swelling or discomfort, hypokalemia, edema, muscle discomfort, hot flush, diarrhea, 
urinary tract infection, cough, hypertension, arrhythmia, urinary frequency, nocturia, 
dyspepsia, and upper respiratory tract infection. The most common adverse drug 
reactions that resulted in drug discontinuation were aspartate aminotransferase increased, 
alanine aminotransferase increased, urosepsis and cardiac failure (each in <1% of patient 
taking zytiga. 
Adverse reactions and laboratory abnormalities related to mineralocorticoid effects were 
reported more commonly in patients treated with ZYTIGA than in patients treated with 
placebo: hypokalemia 28% versus 20%, hypertension 9% versus 7% and fluid retention 
(edema) 27% versus 18%, respectively. In patients treated with ZYTIGA, grades 3 to 4 
hypokalemia occurred in 5% of patients and grades 3 to 4 hypertension was reported in 
1% of patients. 
 
 
Cardiovascular Adverse Reactions: 
The majority of arrhythmias in the phase 3 trial were grade 1 or 2. Grade 3-4 arrhythmias 
occurred at similar rates in the two arms. There was one death associated with arrhythmia 
and one patient with sudden death in the ZYTIGA arm. No patients had sudden death or 
arrhythmia associated with death in the placebo arm. Cardiac ischemia or myocardial 
infarction led to death in 2 patients in the placebo arm and 1 death in the ZYTIGA arm. 
Cardiac failure resulting in death occurred in 1 patient on both arms. 
 
Hepatotoxicity: 
Drug-associated hepatotoxicity with elevated ALT, AST, and total bilirubin has been 
reported in patients treated with ZYTIGA. Across all clinical trials, liver function test 
elevations (ALT or AST increases of > 5X ULN) were reported in 2.3% of patients who 
received ZYTIGA, typically during the first 3 months after starting treatment. In the 
phase 3 trial, patients whose baseline ALT or AST were elevated were more likely to 
experience liver function test elevations than those beginning with normal values. When 
elevations of either ALT or AST > 5X ULN, or elevations in bilirubin > 3X ULN were 
observed, ZYTIGA was withheld or discontinued. In two instances marked increases in 


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liver function tests occurred. These two patients with normal baseline hepatic function, 
experienced ALT or AST elevations 15 to 40X ULN and bilirubin elevations 2 to 6 X 
ULN. Upon discontinuation of ZYTIGA, both patients had normalization of their liver 
function tests and one patient was re-treated with ZYTIGA without recurrence of the 
elevations. 
 
Other Adverse Reactions: 
Adrenal insufficiency occurred in two patients on the abiraterone arm of the phase 3 
clinical trial (< 1%). 
 
 
Administration, Supply and Storage 
Administration 
The recommended dose of ZYTIGA is 1,000 mg administered orally once daily in 
combination with prednisone 5 mg administered orally twice daily. ZYTIGA 
must be taken on an empty stomach. No food should be consumed for at least two 
hours before the dose of ZYTIGA is taken and for at least one hour after the dose 
of ZYTIGA is taken.  The tablets should be swallowed whole with water. 
 
Supply 
ZYTIGA (abiraterone acetate) 250 mg tablets are white to off-white, oval-shaped 
tablets debossed with AA250 on one side. ZYTIGA 250 mg tablets are available 
in high-density polyethylene bottles of 120 tablets. NDC Number 57894-150-12 
 
Storage 
ZYTIGA 250 mg tablets are available in high-density polyethylene bottles of 120 
tablets. NDC Number 57894-150-12 
 
 
 
10.4. Drug Name: docetaxel  
[Adapted from FDA prescribing information] 


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 Chemical Name: (2R,3S)-N-carboxy-3-phenylisoserine,N-tert-butyl ester, 13-ester with 
5β-20epoxy-1,2α,4,7β,10β,13α-hexahydroxytax-11-en-9-one 4-acetate 2-benzoate, 
trihydrate 
 Molecular Formula: C43H53NO14• 3H2O 
 Molecular Weight: 861.9 
 
Description 
Docetaxel is an antineoplastic agent belonging to the taxoid family. It is prepared by 
semisynthesis beginning with a precursor extracted from the renewable needle biomass of yew 
plants. Docetaxel is a white to almost-white powder with an empirical formula of C43H53NO14• 
3H2O, and a molecular weight of 861.9. It is highly lipophilic and practically insoluble in water. 
 
Clinical Pharmacology 
Docetaxel is an antineoplastic agent that acts by disrupting the microtubular network in 
cells that is essential for mitotic and interphase cellular functions. Docetaxel binds to free 
tubulin and promotes the assembly of tubulin into stable microtubules while 
simultaneously inhibiting their disassembly. This leads to the production of microtubule 
bundles without normal function and to the stabilization of microtubules, which results in 
the inhibition of mitosis in cells. Docetaxel’s binding to microtubules does not alter the 
number of protofilaments in the bound microtubules, a feature which differs from most 
spindle poisons currently in clinical use.  
 
 
Safety/Precautions 
Acute myeloid leukemia: In patients who received TAXOTERE, doxorubicin and 
cyclophosphamide, monitor for delayed myelodysplasia or myeloid leukemia  
 
Cutaneous reactions: Reactions including erythema of the extremities with edema 
followed by desquamation may occur. Severe skin toxicity may require dose adjustment  
 
Neurologic reactions: Reactions including. paresthesia, dysesthesia, and pain may occur. 
Severe neurosensory symptoms require dose adjustment or discontinuation if persistent.  
 
Asthenia: Severe asthenia may occur and may require treatment discontinuation.  
 
Pregnancy: Fetal harm can occur when administered to a pregnant woman. Women of 
childbearing potential should be advised not to become pregnant when receiving 
TAXOTERE  
 
Information for Patients 
The patient should be informed that: 
 TAXOTERE may cause fetal harm. Patients to avoid becoming pregnant while 
receiving this drug. 


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 
It is important that they provide a detailed allergy and concomitant drug information 
history prior to TAXOTERE administration.  
 
It is important that they report if they were not compliant in taking the oral 
corticosteroids prior to taxotere 
 
Instruct patients to immediately report signs of a hypersensitivity reaction.  
 
Tell patients to watch for signs of fluid retention such as peripheral edema in the 
lower extremities, weight gain and dyspnea.  
 
Explain the significance of routine blood cell counts. Instruct patients to monitor their  
temperature frequently and immediately report any occurrence of fever.  
 
Instruct patients to report myalgia, cutaneous, or neurologic reactions.  
 
Explain to patients that side effects such as nausea, vomiting, diarrhea, constipation, 
fatigue, excessive tearing, infusion site reactions, and hair loss are associated with 
docetaxel administration.  
 
Laboratory tests 
Perform frequent peripheral blood cell counts on all patients receiving TAXOTERE. 
Patients should not be retreated with subsequent cycles of TAXOTERE until neutrophils 
recover to a level >1500 cells/mm3 
and platelets recover to a level > 100,000 cells/mm3.  
A 25% reduction in the dose of TAXOTERE is recommended during subsequent cycles 
following severe neutropenia (<500 cells/mm3) lasting 7 days or more, febrile 
neutropenia, or a grade 4 infection in a TAXOTERE cycle.  
Neutropenia (<2000 neutrophils/mm3) occurs in virtually all patients given 60 mg/m2 to 
100 mg/m2 
of TAXOTERE and grade 4 neutropenia (<500 cells/mm3) occurs in 85% of 
patients given 100 mg/m2 and 75% of patients given 60 mg/m2. Frequent monitoring of 
blood counts is, therefore, essential so that dose can be adjusted. TAXOTERE should not 
be administered to patients with neutrophils <1500 cells/mm3.  
Febrile neutropenia occurred in about 12% of patients given 100 mg/m2 
but was very 
uncommon in patients given 60 mg/m2. Hematologic responses, febrile reactions and 
infections, and rates of septic death for different regimens are dose related  
 
 
Drug Interactions 
Docetaxel is a CYP3A4 substrate. In vitro studies have shown that the metabolism of 
docetaxel may be modified by the concomitant administration of compounds that induce, 
inhibit, or are metabolized by cytochrome P450 3A4.  
In vivo studies showed that the exposure of docetaxel increased 2.2-fold when it was 
coadministered with ketoconazole, a potent inhibitor of CYP3A4. Protease inhibitors, 
particularly ritonavir, may increase the exposure of docetaxel. Concomitant use of 
TAXOTERE and drugs that inhibit CYP3A4 may increase exposure to docetaxel and 
should be avoided. In patients receiving treatment with TAXOTERE, close monitoring 
for toxicity and a TAXOTERE dose reduction could be considered if systemic 
administration of a potent CYP3A4 inhibitor cannot be avoided  
 
 
Adverse Reactions 
The most serious adverse reactions from TAXOTERE are:  


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Toxic Deaths-  
Breast Cancer 
TAXOTERE administered at 100 mg/m2 was associated with deaths considered possibly 
or probably related to treatment in 2.0% (19/965) of metastatic breast cancer patients, 
both previously treated and untreated, with normal baseline liver function and in 11.5% 
(7/61) of patients with various tumor types who had abnormal baseline liver function 
(AST and/or ALT >1.5 times ULN together with AP >2.5 times ULN). Among patients 
dosed at 60 mg/m2, mortality related to treatment occurred in 0.6% (3/481) of patients 
with normal liver function, and in 3 of 7 patients with abnormal liver function. 
Approximately half of these deaths occurred during the first cycle. Sepsis accounted for 
the majority of the deaths.  
 
Non-Small Cell Lung Cancer 
TAXOTERE administered at a dose of 100 mg/m2 in patients with locally advanced or 
metastatic non-small cell lung cancer who had a history of prior platinum-based 
chemotherapy was associated with increased treatment-related mortality (14% and 5% in 
two randomized, controlled studies). There were 2.8% treatment-related deaths among 
the 176 patients treated at the 75 mg/m2 dose in the randomized trials. Among patients 
who experienced treatment-related mortality at the 75 mg/m2 dose level, 3 of 5 patients 
had an ECOG PS of 2 at study entry. 
 
Hepatotoxicity- Patients with combined abnormalities of transaminases and alkaline 
phosphatase should not be treated with TAXOTERE. 
 
Neutropenia- Perform frequent peripheral blood cell counts on all patients receiving 
TAXOTERE. Patients should not be retreated with subsequent cycles of TAXOTERE 
until neutrophils recover to a level >1500 cells/mm3 and platelets recover to a level > 
100,000 cells/mm3.  
A 25% reduction in the dose of TAXOTERE is recommended during subsequent cycles 
following severe neutropenia (<500 cells/mm3) lasting 7 days or more, febrile 
neutropenia, or a grade 4 infection in a TAXOTERE cycle. 
 
Hypersensitivity- Patients should be observed closely for hypersensitivity reactions, 
especially during the first and second infusions. Severe hypersensitivity reactions 
characterized by generalized rash/erythema, hypotension and/or bronchospasm, or very 
rarely fatal anaphylaxis, have been reported in patients premedicated with 3 days of 
corticosteroids. Severe hypersensitivity reactions require immediate discontinuation of 
the TAXOTERE infusion and aggressive therapy. Patients with a history of severe 
hypersensitivity reactions should not be rechallenged with TAXOTERE.  
 
Fluid Retention - Severe fluid retention has been reported following TAXOTERE 
therapy. Patients should be premedicated with oral corticosteroids prior to each 
TAXOTERE administration to reduce the incidence and severity of fluid retention. 


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Patients with pre-existing effusions should be closely monitored from the first dose for 
the possible exacerbation of the effusions.  
When fluid retention occurs, peripheral edema usually starts in the lower extremities and 
may become generalized with a median weight gain of 2 kg.  
 
Most common adverse reactions across all TAXOTERE indications are infections, 
neutropenia, anemia, febrile neutropenia, hypersensitivity, thrombocytopenia, 
neuropathy, dysgeusia, dyspnea, constipation, anorexia, nail disorders, fluid retention, 
asthenia, pain, nausea, diarrhea, vomiting, mucositis, alopecia, skin reactions, myalgia. 
 
 
 
Administration, Supply and Storage 
Administration 
For hormone-refractory metastatic prostate cancer, the recommended dose of 
TAXOTERE is 75 mg/m
2 every 3 weeks as a 1hour intravenous infusion.  
All patients should be premedicated with oral corticosteroids (see below for prostate 
cancer) such as dexamethasone 16 mg per day (e.g., 8 mg BID) for 3 days starting 1 day 
prior to TAXOTERE administration in order to reduce the incidence and severity of fluid 
retention as well as the severity of hypersensitivity reactions  
 
Supply 
TAXOTERE (docetaxel) Injection Concentrate is a sterile, non-pyrogenic, pale yellow to 
brownish-yellow solution at 20 mg/mL concentration. 
Each mL contains 20 mg docetaxel (anhydrous) in 0.54 grams polysorbate 80 and 0.395 
grams dehydrated alcohol solution. 
TAXOTERE is available in single use vials containing 20 mg (1 mL) or 80 mg (4 mL) 
docetaxel (anhydrous). 
TAXOTERE Injection Concentrate requires NO prior dilution with a diluent and is ready 
to add to the infusion solution. 
 
Storage 
TAXOTERE final dilution for infusion, if stored between 2°C and 25°C (36°F and 77°F) 
is stable for 4 hours. TAXOTERE final dilution for infusion (in either 0.9% Sodium 
Chloride solution or 5% Dextrose solution) should be used within 4 hours (including the 
1 hour intravenous administration).  
 
11. Study Treatments 
11.1. Hormone Therapy 
Each drug will be dosed at its respective FDA approved dose. The dosages are as follows: 
leuprolide (Lupron Depot-3 Month) 22.5mg by intramuscular (IM) injection on day 1 and then 
every three months thereafter. 
 


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Patients will receive androgen deprivation for a total of 1 year, and will be monitored clinically 
and with serum PSAs and testosterone until the 3-year endpoint.  
 
Leuprolide may be replaced with any LHRH analog. No dose adjustments are allowed for the 
LHRH analog. 
 
*In the event that the Investigator elects to administer complete androgen blockade, bicalutamide 
(Casodex) (50mg daily) and/or abiraterone acetate 1000 mg / day) may be added to the 
leuprolide. No replacements are allowed for bicalutamide. No dose adjustments are allowed for 
bicalutamide. 
Pharmaceutical information is located in Section 10.1 (leuprolide) and Section 10.2 
(bicalutamide). 
 
11.2  Chemotherapy 
Docetaxel (Taxotere) will be given at any of the following doses (75 mg/m2, 65 mg/m2, 55 mg/m2 
or 35 mg/m2 IV) on day 1 of each cycle, up to 6 cycles at physician discretion. 
 
Docetaxel will be given as neoadjuvant therapy for up to 6 months, along with androgen 
deprivation. Following up to 6 cycles of docetaxel therapy, patients with a PSA response of 
at least a 50% decrease from baseline, will proceed to maximum consolidative therapy.  
 
Docetaxel may not be replaced with another drug.  Docetaxel may be dose adjusted 
downward, at physician discretion, in response to, or to mitigate, toxicity. The dose may 
decreased in the following intervals: 65mg/M2, 55mg/M2, 35mg/M2. 
 
Pharmaceutical information is located in Section 10.3 (docetaxel).  
 
11.3   SBRT 
SBRT treatment planning 
A CT scan or MRI will be performed for tumor localization using rigid immobilization 
appropriate for stereotactic treatment. A separate PET-CT may be performed (all are 
optional) for diagnostic purposes and can be used for treatment planning with fusion -- this 
study would be done identically if the patient were having standard moderate dose radiation. 
 
CT simulation will then be performed with fabrication of a radiation therapy immobilization 
device (such as the Alpha Cradle) which will be custom made for each patient. The treating 
radiation oncologist will identify the location of the tumor.  Gross tumor volume (GTV) 
delineation will be performed with a diagnostic radiologist on sequential axial computed 
tomography images. A radiosurgical treatment plan will be developed based on tumor 
geometry and location.  The dose will be prescribed to the minimal isodose line that completely 
covers the GTV plus a 5 mm margin.  Adjacent normal structures including but not limited to 
the heart, esophagus, aorta, spinal cord, kidneys, rectum, bowel, liver, and stomach within 5 


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cm of the GTV will be identified for the purpose of limiting incidental radiation to these 
structures. [adapted from Johns Hopkins Oncology Clinical protocol J12137, NA_00069585] 
 
In addition, prior to treatment delivery, a four-dimensional cone beam CT study will be 
performed on individual patients to assess respiration in these patients and to determine tumor 
targeting accuracy for those tumors that may be subject to respiratory motion such as those in 
the bones of the thorax. If tumor motion is greater than 5 mm, the planning target volume 
(PTV) will be expanded to account for respiration. [adapted from Johns Hopkins Oncology 
Clinical protocol J12137, NA_00069585] 
 
SBRT procedure 
Within three weeks of the initial treatment planning imaging study, SBRT will be administered 
using image-guidance. An Alpha Cradle (or equivalent immobilization device) will be used to 
minimize movement of the chest, spine, and abdomen during treatment. During treatment, real 
time cone beam CT images of the patient’s body site of interest will be obtained. Cone beam 
CT scan will be obtained immediately prior to treatment and will be repeated until the treatment 
shift, required to align the CT planning scan and the cone beam CT scan performed on the day 
of treatment cone beam CT, is within tolerance for the body site.  [adapted from Johns Hopkins 
Oncology Clinical protocol J12137, NA_00069585] 
 
Within three weeks of the initial treatment planning imaging study, SBRT will be 
administered in a single dose to each treated lesion.   
If scheduling or safety prevents all lesions from being irradiated within one day, participants 
may return within 30 days to complete SBRT to all metastatic sites. [adapted from Johns 
Hopkins Oncology Clinical protocol J12137, NA_00069585] 
 
SBRT will be delivered in 1 to 5 fractions, and the dose and fractionation schedule will depend 
on the size and location of the lesion and the surrounding normal tissue constraints in 
accordance with AAPM Task Group 101 recommendations. Typical doses include 16 – 24 Gy 
in 1 fraction, 48 – 50 Gy in 4 fractions, and 50 – 60 Gy in 5 fractions. For example, isolated 
osseous lesions will be treated in a single fraction, lesions close to the lung and liver lesions 
will be treated in 3 to 5 fractions depending on their size (5 fractions for ≥ 3 cm or central 
tumors in close proximity to the mediastinum), and bone lesions will be treated in 5 fractions 
if small-bowel constrains fewer doses. [adapted from Johns Hopkins Oncology Clinical 
protocol J12137, NA_00069585] 
 
 
The dose limits for surrounding critical structures are as follows: 
 
Spinal Cord: maximal allowable dose should be = 1000 cGy in 1 fraction  
 
Lung: 2/3 of the lung volume should be kept under 500 cGy.  
 
Heart: 50 % of the heart volume should be kept under 1000 cGy.   
Esophagus: 50 % of the esophagus volume should be kept under 1000 cGy  and no 
single point dose in the esophagus should exceed 2000 cGy.  
 
Brachial Plexus: maximal allowable point dose = 1000 cGy  


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Liver: One third of the uninvolved liver or approximately 700 cc <15 Gy.  
 
Kidneys: 75% of volume of each kidney <5 Gy.  
 
Small Bowel: <5% of bowel limited to <20 Gy.  
[adapted from Johns Hopkins Oncology Clinical protocol J12137, NA_00069585] 
SBRT potential toxicities 
It is difficult at this time to predict with confidence the complication rate from the proposed 
SBRT; however, it is reasonable to extrapolate from the current experience with SBRT to the 
lung and pancreas.  One significant toxicity is radiation pneumonitis, which can be 
manifested as fever, increased excertional dypsnea, pleuritic chest pain, and peritumoral 
infiltrate on chest imaging.  It generally occurs between 1 to 3 months of completion of 
radiotherapy.  The risk of grade 2-4 radiation pneumonitis is aproximately 10-15% in patients 
treated with standard fractionated large field radiotherapy and higher in patients treated with 
combined chemoradiotherapy.  It is highly dependent on the volume of the lung treated to 
high dose and the mean lung dose.  At this point, the incidence of RT pneumonitis from 
stereotactic radiosurgery for small pulmonary tumors is unknown.  However, if the treated 
tumor volume is kept ≤ 65 cc, the risk should be < 10-15% with the proposed dose level. 
[adapted from Johns Hopkins Oncology Clinical protocol J12137, NA_00069585] 
 
 
Other toxicities commonly associated with such treatment includes dysphagia, odynophagia, 
nausea, vomiting, anorexia, and weight loss.  Some of these symptoms can also be due to 
tumor progression.  Clinical and radiographic assessments will be performed as indicated to 
identify all adverse effects, ascertain their etiology, and provide the most appropriate 
palliative measures.  Complications orther than radiation pneumonitis, if any, will be graded 
according to the Common Toxicity Criteria, National Cancer Institute, version 4.0. [adapted 
from Johns Hopkins Oncology Clinical protocol J12137, NA_00069585] 
 
 11.4. Prostatectomy  
(As per standard of care) 
 11.5. Adjuvant Radiation Therapy to Pelvic Bed  
(If indicated) 
 
Adjuvant radiation therapy treatment planning 
A CT scan or MRI will be performed for tumor localization using rigid immobilization 
appropriate for stereotactic treatment. A separate PET-CT may be performed (all are 
optional) for diagnostic purposes and can be used for treatment planning with fusion. 
 
Adjuvant radiation therapy procedure 
(As per standard of care) 
 


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12. Data Monitoring and Reporting Requirements 
Data and safety monitoring will follow Level I under the SKCCC Data and Safety 
Monitoring Plan (DSMP, 12/6/2012). Additionally, scheduled meetings will take place 
monthly and will include the protocol principal investigator, research nurse, data 
manager, and, when appropriate, the collaborators, sub-investigators, and biostatistician 
involved with the conduct of the protocol. 
 
During these meetings the investigators will discuss matters related to: safety of protocol 
participants, validity and integrity of the data, enrollment rate relative to expectation, 
characteristics of participants, retention of participants, adherence to protocol (potential 
or real protocol violations), data completeness, and progress of data for secondary 
objectives.   
 
 12.1. Principal Investigator 
The Principal Investigator, Kenneth Pienta, MD, is responsible for performing the 
following tasks: 
 Coordinating, developing, submitting, and obtaining approval for the 
protocol as well as its subsequent amendments 
 Assuring that all participating institutions are using the correct version of 
the protocol 
 Taking responsibility for the overall conduct of the study at all 
participating institutions and for monitoring the progress of the study 
 Reviewing and ensuring reporting of Serious Adverse Events (SAEs) 
 Reviewing data from all sites 
 
 12.2. Adverse Event Monitoring and Reporting 
 
An Adverse Event is defined as any unfavorable and unintended sign (including 
an abnormal laboratory finding), symptom or disease temporally associated with 
the use of a medical treatment or procedure regardless of whether it is considered 
related to the medical treatment or procedure (attribution of unrelated, unlikely, 
possible, probable, or definite). The PI and/or the research nurse will monitor 
each patient closely for the development of adverse events and toxicities and 
record all such events. Patients will be evaluated for toxicity if they have received 
one dose of leuprolide or bicalutamide, on study, or one dose of docetaxel. The 
timely reporting of adverse events (including toxic deaths) is required by the Food 
and Drug Administration (FDA). 
 
 12.3. Evaluating Adverse Events 
The grade and severity of the event will be determined using the DCT/NCI 
Common Terminology Criteria, CTCAE v.4.0. A copy of the CTCAE version 4.0 
can be downloaded from the CTEP home page (http://ctep.cancer.gov). All 


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appropriate treatment areas should have access to a copy of the CTCAE version 
4.0. Study staff must use one of the CTCAE criteria to define the event. Adverse 
events not included in the CTCAE v.4.0 should be reported and graded under the 
“Other” adverse event within the appropriate category and grade 1 to 5 according 
to the general grade definitions, mild, moderate, severe, life-threatening, fatal or 
disabling, as provided in the CTCAE. 
 
The event will be determined to be expected or unexpected. 
The determination of whether an AE is expected is based on agent-specific 
adverse event information provided in Section 8: Pharmaceutical Information. 
Unexpected AEs are those not listed in the agent-specific adverse event 
information provided in Section 8: Pharmaceutical Information.  
The event will be evaluated for relationship to the medical treatment or procedure. 
The investigator should document his/her opinion of the relationship of the event 
to study medication as follows: 
 
 Unrelated- The adverse event is clearly not related to the investigational 
agent(s). 
 Unlikely- The adverse event is doubtfully related to the investigational 
agent(s). 
 Possible- The adverse event may be related to the investigational agent(s). 
 Probable- The adverse event is most likely related to the investigational 
agent(s). 
 Definite- The adverse event is clearly related to the investigational agent(s). 
 
Based on this information, a decision will be made whether an adverse event 
should be reported as an expedited report (Serious Adverse Event, section 3.0) in 
addition to the routinely reported clinical data. All expedited adverse event reports 
should be submitted to the JHM Institutional Review Board (IRB) and to the 
FDA. 
 
Documenting Adverse Events 
Each individual sign or symptom must be documented separately. 
Worksheets must be signed and dated by person conducting evaluation to 
be used as source documentation. The attribution of all adverse events 
must be verified by an investigator. Evaluation of laboratory toxicities 
may be documented directly on a printed laboratory report or CRF 
provided it is signed by the investigator. However, if an action was 
conducted due to this abnormality (e.g., RBC transfusion due to low Hgb) 
this would be recorded on the AE form also. 
 
 12.4. Serious Adverse Events 


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A SAE is any sign, symptom or medical condition that emerges during treatment 
or during a post-treatment follow-up period that (1) was not present at the start of 
treatment and is not a chronic condition that was part of the patient’s medical 
history OR (2) was present at the start of treatment or as part of the patient’s 
medical history but worsened in severity and/or frequency during therapy, AND 
that meets any of the following regulatory criteria: 
 
 is fatal (i.e., results in death from any cause at any time) or life-threatening 
(i.e., the patient was, in the view of the investigator, at immediate risk of 
death from the reaction as it occurred) 
 required or prolonged hospitalization (see exclusions below) 
 results in persistent or significant disability/incapacity 
 constitutes a congenital anomaly or a birth defect 
 is medically significant, may jeopardize the subject and may require 
medical or surgical intervention to prevent one of the outcomes listed 
above. 
 
 
 
Events not considered to be serious adverse event are hospitalizations for the: 
 Routine treatment or monitoring of the studied indication, not associated 
with any deterioration in condition 
 Treatment, which was elective or pre-planned, for a pre-existing condition 
that did not worsen 
 
Any serious adverse event occurring in a patient from the first day of treatment 
and until 4 weeks after the last dose of treatment must be reported. The period 
after discontinuing study drug may be extended if there is a strong suspicion that 
the drug has not yet been eliminated. 
All serious adverse events must be followed to resolution (≤ 1 or baseline) or until  
considered stable or irreversible. 
 
 12.5. Expedited Reporting 
 
JHM IRB reporting: 
Serious adverse events and protocol problems will be reported in compliance with 
JHM IRB guideline, “Organization Policy on Reports of Unanticipated 
Problems Involving Risks to Participants or Others” [Policy No. 103.6(b)] 
(most current version).  A copy of this document is located at 
http://www.hopkinsmedicine.org/institutional_review_board/guidelines_policies/
guidelines/unanticipatedflowchart.pdf All deaths on study regardless of attribution 
must be reported to the JHM IRB. 
 
 12.6. Data Entry 


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Data collected during this study will be entered into a secure database. Staff at 
SKCCC will be responsible for the initial study configuration and setup in the 
database and for any future changes. 
 12.7. Case Report Forms 
Case report forms (e-crf) will be generated by Staff at SKCCC for the collection 
of all study data. Investigators will be responsible for ensuring that the CRFs are 
kept up-to-date. 
 
 
 
 12.8. Source documents 
Study personnel will record clinical data in each patient’s source documents (ie, 
the patient’s medical record). Source documentation will be made available to 
support the patient research record.  
 
 12.9. Record Retention 
The investigator will maintain adequate and accurate records to enable the 
conduct of the study to be fully documented and the study data to be subsequently 
verified. After study closure, the investigator will maintain all source documents, 
study-related documents, and the CRFs. Because the length of time required for 
retaining records depends upon a number of regulatory and legal factors, 
documents should be stored until the investigator is notified that the documents 
may be destroyed. In this study, records are to be retained and securely stored for 
a minimum of 7 years after the completion of all study activities. 
 
 12.10. Protocol Amendments 
Any changes to the protocol will be made in the form of an amendment and must 
be approved by the IRB before implementation. 
 
 12.11. Informed consent 
Written informed consent will be obtained by a study investigator or study 
research nurse working on this study. An explanation of the nature of study, its 
purpose, procedures involved, expected duration, potential risks, and benefits will 
be provided to each participant by the investigator or the research nurse. Each 
participant will be informed that participation in the study is voluntary and that he 
may withdraw from the study at any time, and that withdrawal of consent will not 
affect his subsequent medical treatment. Participants will be allowed time needed 
to make an informed decision. Participants will be encouraged to ask questions 
about the study and the consent before signing the consent form. Original signed 
consent forms will be filed in each patient’s research chart, while each patient will 


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receive a copy of the consent document. No patient will enter the study before his 
informed consent has been obtained. 
 
13. Statistical Methods 
This open label single arm phase II study of treatment for oligometastatic disease will evaluate 
consolidation with prostatectomy (RP) + adjuvant radiotherapy (RT) after systemic neoadjuvant 
chemo-hormonal therapy (C-ADT), followed by stereotactic body radiation to metastatic sites.  
60 patients will be enrolled.  If neutropenic toxicity is acceptable, RP+RT will be offered to 
patients who achieve at least a 50% decrease in PSA following C-ADT.  We expect at least 90% 
of patients to achieve that PSA endpoint.  The primary endpoint is efficacy, defined as the 2-year 
PSA progression-free (PSA<0.2 ng/ml) survival rate.  However, we will also evaluate safety, and 
the trial can be stopped early if toxicity exceeds acceptable limits, as described below. 
 
 13.1. Early Stopping Boundaries for Toxicity 
 
We are concerned with 2 very different types of adverse event (AE):  (1) Grade 3-4 neutropenia, 
and (2) Grade 3-4 acute toxicities from surgery or radiation. Because the management and 
sequelae of these AEs differ we have defined separate stopping boundaries for neutropenic AEs 
and for acute surgical -or radiation -induced AEs.  The study design incorporates safety 
monitoring after each patient, starting with the third patient.  
 
Neutropenic AEs.  We will say that the treatment is feasible and safe if risk of G3/4 neutropenia 
<50%.  Before the study starts, we assume that the average risk of G3/4 neutropenia is around 
30-40%, so we take 35% as our prior probability (95% CI: 22-78%), corresponding to a 
Beta(3.5,6.5) prior distribution for the risk.  Using Bayes rule, we apply the accumulating data 
after each patient to generate posterior probability as a Beta(3.5+a, 6.5+b) distribution, where 
a=number of neutropenic AE, b=number of non-SAEs (Rosner 2016)(30).  As we become more 
certain that the underlying risk exceeds 50%, we want to consider stopping the study.  If the data 
suggest that there are at least 2:1 odds that the risk of neutropenic AEs exceeds 50%, the 
stopping boundary will be crossed, and we will consider that as enough certainty that the true 
rate exceeds 50% to stop the trial.   
 
The following table indicates the number of events that will cross the stopping boundary for each 
sample size up to 54 patients: 
 
Number of patients 
(inclusive) 
Trial stops if neutropenic 
AEs reach this value 
5 
5 
6-7 
6 
8-9 
7 
10-11 
8 
12 
9 
13-14 
10 


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15-16 
11 
17-18 
12 
19-20 
13 
21-22 
14 
23-4 
15 
25-26 
16 
27-28 
17 
29-30 
18 
31-32 
19 
33-34 
20 
35-36 
21 
37-38 
22 
39 
23 
40-41 
24 
42-43 
25 
44-45 
26 
46-47 
27 
48-49 
28 
50-51 
29 
52-53 
30 
54 
31 
 
 
Non-neutropenic acute surgical –or radiation-induced AEs.  We will say that the treatment is 
feasible and safe if risk of G3/4 acute non-neutropenic AEs<20%.  Before the study starts, we 
assume that the average risk of such AEs is around 10% (95% CI: 2-38%), corresponding to a 
Beta(1,9) prior distribution for the risk.  Again, we apply the accumulating data after each patient 
to generate posterior probability as a Beta(1+a, 9+b) distribution, where a=number of non-
neutropenic AE, b=number of non-AEs.  As we become more certain that the risk exceeds 20%, 
we want to consider stopping the study.  If the data suggest that there are at least 2:1 odds that 
the underlying risk of non-neutropenic AEs exceeds 20%, the stopping boundary will be crossed, 
and we will consider that as enough certainty that the true rate exceeds 20% to stop the trial.   
 
The following table indicates the number of events that will cross the stopping boundary for each 
sample size up to 43 patients: 
 
Number of patients 
(inclusive) 
Trial stops if non-neutropenic 
AEs reach this value 
3-5 
3 
6-10 
4 
11-14 
5 
15-19 
6 
20-23 
7 
24-28 
8 
29-33 
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34-38 
10 
39-42 
11 
43 
12 
 
The table below provides operating characteristics for both the neutropenic AE and non-
neutropenic AE stopping rules based on 5000 simulations with the above sample sizes, assuming 
varying underlying toxicity risks. For neutropenic AE the the probability of early stopping 
exceeds 50% if the true risk is >50% and is relatively unlikely for true risk <45%, while for non-
neutropenic AE the probability of early stopping exceeds 50% for true risk >20%, but is 
relatively unlikely for true risk <15%.  
 
Neutropenic AE stopping rule 
Non-neutropenic AE stopping rule 
 
Toxicity risk 
Probability of 
early stopping (%) 
Average 
sample size 
 
Toxicity Risk 
Probability of 
early stopping (%) 
Average 
sample size 
0.30 
1.2 
53.5 
0.10 
2.5 
42.2 
0.35 
3.6 
52.5 
0.15 
14.1 
39.3 
0.40 
8.3 
50.9 
0.20 
35.8 
34.1 
0.45 
20.1 
47.2 
0.25 
62.8 
27.0 
0.50 
40.0 
40.8 
0.30 
83.5 
20.4 
0.55 
65.8 
32.7 
0.35 
94.8 
15.1 
0.60 
85.1 
25.2 
n/a 
n/a 
n/a 
 
 13.2. Data Analysis 
Neutropenic and non-neutropenic toxicity rates will be calculated with 95% confidence intervals.  
If the trial enrolls the full sample size of 60 patients with acceptable neutropenic toxicity, we 
expect > 90% of patients to achieve at least a 50% decrease in PSA following C-ADT and go on 
to RP+adjuvant RT, followed by SBRT.  If the trial is not halted for non-neutropenic toxicity, the 
primary study endpoint of efficacy will be evaluated, defined as the 2 year PSA progression-free 
(PSA<0.2 ng/ml) survival rate among men who have non-castrate testosterone levels 2 years 
after enrollment.  Since there  is no direct comparator trial in this population, this will be 
compared to the historical rate from a randomized trial of men with biochemically-recurrent 
(non-metastatic) prostate cancer after prostatectomy and (for most men) after salvage 
radiotherapy, with PSADT <9 months.  In that trial, at month 18, men with non-castrate 
testosterone blood levels who received abiraterone and degarelix had an undetectable PSA rate 
of 16% 18.  Based on these data we will set the null hypothesis at 15% PSA progression-free 
survival at 2 years in men with non-castrate testosterone.   
 
Power for the efficacy endpoint is based on a 1-sample logrank test for comparing an observed 
survival to a historical control rate 19.  The table below shows PSA progression-free survival, P1, 
ranging from 30-50% compared to a historical rate of 15% (P0). We assume that 60 men will be 


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enrolled in the trial, at least 54 will achieve PSA decrease >50% and go on to RP and 
consolidative therapy, and that 80% (n=43) will have non-castrate testosterone at 2 years. For all 
comparisons α=0.05 and a 2-sided test is used.  Power is calculated using PASS v15 (NCSS 
Software, Kaysville, UT). 
 
The table shows that with N=43, PSA progression-free survival of >0.32 can be detected with 
power >82%.  These estimates may be conservative since the historical control progression-free 
rate is based on men without detectable metastases, whereas the current trial includes only men 
with oligometastatic disease, who may have lower progression-free survival under standard of 
care, i.e. ADT alone. 
 
 
Power (%) 
N 
P0 
P1 
74 
43 
.15 
.30 
82 
43 
.15 
.32 
91 
43 
.15 
.35 
97 
43 
.15 
.40 
>99 
43 
.15 
.50 
 
 
 
To conduct the safety analysis, the rates of AEs will be calculated with 95% confidence 
intervals.  Secondary time-to-event endpoints will be estimated with Kaplan-Meier methods, 
mean and median quality of life scores will be calculated with 95% confidence intervals, and chi-
square test will be used for comparison of first metastatic sites,  We will also compare secondary 
endpoints such as 2 year PSA failure-free survival to expected rates of 10-20% (based on data 
reported by CHAARTED (ASCO 2014) of 23% at 1 year for combined chemo-hormonal 
therapy) using a one-sample chi-square test.  Although power is likely to be suboptimal we will 
also perform exploratory analyses to compare the above endpoints among subgroups such as by 
age, number of initial metastatic sites, and between RP alone vs. RP+adjuvant radiation. 
 
13.3. Multicenter Guidelines 
The Protocol Chair 
The Protocol Chair, Kenneth Pienta, MD, is responsible for performing the following Tasks: 
 
Coordinating, developing, submitting, and obtaining approval for the protocol as well as 
its subsequent amendments 
 
Assuring that all participating institutions are using the current IRB approved version of 
the protocol 
 
Taking responsibility for the overall conduct of the study at all participating institutions 
and for monitoring the progress of the study 
 
Reviewing and ensuring reporting of Serious Adverse Events (SAEs) from all sites  
 
Reviewing all study data from all sites 
 
 
 


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Coordinating Center Responsibilities (SKCCC) 
Coordinating Centers must: 
 
Verify that each participating institution has a Federal Wide Assurance (FWA) number. 
 
Confirm that IRB approval has been obtained at each participating site prior to their first 
patient registration 
 
Maintain copies of IRB approvals from each site 
 
Implement central patient registration 
 
Prepare all submitted data for review by the Protocol Chair (Kenneth Pienta, MD) 
 
Establish procedures for documentation, reporting, and submitting of adverse events to 
the Protocol Chair (Kenneth Pienta, MD) and all applicable parties 
 
Facilitate audits by securing selected source documents and research records from 
participating sites for audit, or by conducting audits at participating sites. 
 
Participating Sites 
Participating sites are responsible for performing the following tasks: 
 
Follow the protocol as written and conduct the study within the guidelines of Good 
Clinical Practice. 
 
Collect and submit data, and report adverse events according to the schedule specified 
by the protocol. 
 
Register all patients with the Lead Center (SKCCC) by submitting patient registration 
forms, and signed informed consents promptly. 
 
Provide sufficient experienced clinical and administrative staff; as well as adequate 
facilities and equipment to conduct a collaborative trial according to the protocol. 
 
Maintain regulatory binders on site, and provide copies of all required documents to the 
Lead Center (SKCCC) 
 
 
 
 
 
 
 
 
 
 
                            
       


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Appendix A: 


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