# Presentation: 215695

## Prostate Cancer

**William Dahut, M.D.**
**Chief, Genitourinary CRS**
**MOB, CCR**
**National Cancer Institute**

## Prostate histology

## Prostate Cancer Importance

**Prostate Cancer is the most common non-cutaneous malignancy in men**
**186,320 new cases and 28,660  deaths expected in 2008**
**Despite some recent advances Castration Resistant Prostate Cancer (CRPC ) remains an incurable disease with few effective treatments**
** **

## Prognosis

**Prognosis is directly related to stage and grade of the tumor**
**The Gleason Grade is the most common grading system**
**Tumors are graded from 1-5 with the higher number indicative of a more aggressive tumor**
**In practice the two most predominant patterns are added together to give a score from 2-10 **

## Gleason Grade(3) Well-Differentiated

## Gleason grade (5) Poorly-Differentiated

## Prognosis Related to PSA, Gleason Score, Stage and Positive Biopsies

**PSA at diagnosis, percent of tumor in a biopsy specimen, number of positive biopsies, Gleason Score and clinical stage are useful prognostic factors**
**Nomograms are now available to predict the likelihood of positive surgical margins, lymph node involvement and disease recurrence after local therapy.**

## Detection

**May be detected due to symptoms, physical findings or through PSA screening**
**Most patients in the US are asymptomatic at the time of diagnosis. **

## Family History

**Men with a father or brother affected are twice as likely to develop prostate cancer.**
**Men with two or three first degree relatives have a  **_**five**_**  and**_** eleven**_**-fold increased risk of developing prostate cancer.**_** **_

## Treatment

**Patients with a life expectancy of less then 10 years and/or low grade/ low stage lesions may be candidates for active surveillance**
**Primary hormone therapy is an option for patients not suitable for definitive local therapy**

## Treatment - continued

**Eradication of the cancer is the goal of therapy in patients with a life expectancy greater than 10 years**
**Radical Prostatectomy **
**External-beam Radiation**
**Brachytherapy**

## Radical Prostatectomy

**Surgical removal of the prostate**
**May be done with a retropubic, perineal, laproscopic or robotic approach**
**Most common side effects are impotence and incontinence**

## Prostate histology

## Prostate surgery

## Randomized Trial Comparing Surgery and Watchful Waiting

**695 men with early stage prostate cancer randomized to radical prostatectomy or watchful waiting**
**Median of 8.2 years of follow-up 83 deaths in surgery group and 106 in watchful waiting group (P=0.04). **
**30 of the 347 men assigned to surgery and 50 of the 348 men assigned to watchful waiting, death was due to prostate cancer **
**More advanced clinically then current patients**

## External-beam Radiation 

**Radiation to the prostate from outside the body**
**Evidence that higher doses are associated with better efficacy**
**Newer techniques (such as 3-D conformal) hope to increase radiation delivery and to decrease toxicity**
**Most common side effects are impotence and rectal irritation**

## Prostate histology

## Prostate map

## Brachytherapy

**Radiation implants placed directly into the prostate under ultrasound or ct guidance**
**Very high dose radiation to the prostate with little radiation outside the prostatic bed**
**Acute urinary symptoms common, some patients with impotence **
**Procedure completed in one day**

## Brachytherapy seeds

## Biochemical Recurrence

**May be occult local or metastatic disease**
**Options include additional local therapy, hormonal treatment or watchful waiting**
**Little data to predict the impact of treatment on survival**

## Pound Data

**Probably the most important report on this population because of the limited use of radiation and hormonal therapy**
**Over 15 years 1,997 patients underwent a radical prostatectomy, with 304 (15%) experiencing a PSA relapse.**
**Of the 304, 103 (34 %) developed metastatic disease.**

## Pound Data (continued)

**No patients received hormonal therapy without clinically evident metastatic disease.**
**Median time from PSA elevation to metastatic disease was 8 years**
**Median time to death after metastatic disease was 5 years.**
**Prognostic factors predictive of outcome included the Gleason score on the surgical specimen, time to PSA recurrence and PSA doubling time.**

## Disseminated Disease (Hormone responsive)

**Prostate Cancer tends to spread to bone and lymph nodes**
**However metastatic lesions have been found in virtually every part of the body including brain, liver and lungs.**
**Many patients do not have measurable lesions thus traditional response criteria (RECIST) is difficult to use.**

## Bone Scan in Metastatic Prostate Cancer

## Treatment of Metastatic Disease

**Leuprolide and Goserelin are most common GnRh-agonists**
**Both agents may cause a decrease in libido, hot flashes, bone loss and increased risks of DM and CVD.**
**May initially result in an increase in testosterone**
**Orchiectomy- side effects include hot flashes , decreased libido and sexual potency**

## Hormonal changes associated with aging correlate with bone loss
Lower testosterone levels
Leads to less aromatization (conversion) of testosterone to estradiol
Estradiol protects / strengthens bone
Therefore lower levels = less protection

**Lower testosterone levels**
**Leads to less aromatization (conversion) of testosterone to estradiol**
**Estradiol protects / strengthens bone**
**Therefore lower levels = less protection**

- E2

**Osteoporosis Risk Factors for men**

**Notes:**
However, recent studies have suggested that estrogen (specifically, bioavailable estradiol) levels are better predictors of BMD in men than testosterone levels. For example, the declining levels of testosterone associated with age or hypogonadism may lead to a decrease in estrogen, since peripheral aromatisation of androgens to estrogens occurs. 67 Therefore, peripheral conversion of testosterone to estradiol may be a dominant factor in age-related osteoporosis in men, and not merely a declining testosterone level. 

## Hormonal Therapy

**BMD loss with hormonal therapy**
**Decrease T by >95%**
**Decrease E****2**** by >80%**
**With orchiectomy the BMD loss is 2.4% at 1 year and 10% at 2 years**
**With GnRH Agonist, the BMD loss is 3.4% at 1 year and 6.5% at 2 years**

|  | 1 yr | 2 yr |
| --- | --- | --- |
| Orchiectomy | 2.4% | 10% |
| GnRH Agonist | 3.4% | 6.5% |

## Hormonal Therapy

**This decrease in BMD is associated with an increase in ****fractures**
**Men without prostate cancer over the age of 65 who are not on hormonal therapy have a fracture rate of 0.5% per year**
**With hormone therapy there was a 5% incidence of osteoporotic fractures seen in a median of 22 months**
**In one series, within 7 years 28% of prostate cancer patients treated with orchiectomy had a fracture vs. 1% of patients who did not undergo orchiectomy**

## Castration Sensitive and Castration-Resistant Progression of Prostate Cancer 

## Measurement of Response

**Tremendous problem in prostate cancer**
**Often left with large trials with survival as an endpoint**
**Traditional markers such as PSA, Bone Scan and CT are all flawed**

**Notes:**
Although the recent failures in prostate cancer drug development are due in some part to the modest activity of the agents studied in a field with so little to offer patients it is possible that we are discarding drugs that may benefit some patients.  Sometimes as we evaluate new agents we forget that PCa is not acute leukemia.  In other words the first sign of progression does not always herald a rapid and catastrophic course. Secondly tumor growth leads to m and m , not the lack of tumor response.  Finally Disease Progression may not always mean a treatment should be stopped-remember this is what we do in CAD.  We don’t stop cholesterol medication after an MI.  It is possible that the drugs we will be using in the future may be more like drugs we use for CAD than drugs used to treat acute leukemia.

## Bone scan

_**Prior  to therapy**_

_**After 2 months**_

**PSA 199**

**PSA  658**

**Bone scan**

**Notes:**
This may be a little difficult to see but on the left there is a bone scan prior to treatment  with an initial PSA of 199 then  2 months after treatment there is decrease in lesions. The lesions especially in the pelvis and rib lesions have decreased. It should be noted that the PSA has risen to 658. 

## CT scan

_**Prior  to therapy**_

**PSA 130**

**PSA  294**

**CT scan**

**Notes:**
The CT scan demonstrates a soft tissue lesion that has decreased after 2 months of therapy. Once again note the initial PSA  

## Measurement of Response-Bone Scans

**New lesions do not always represent progression**
**Can occur with healing, trauma or inflammation**
**New lesions may develop prior to adequate drug treatment and than not resolve**
**The importance of 1-2 asymptomatic new bone scan abnormalities remains unclear**

**Notes:**
Although the recent failures in prostate cancer drug development are due in some part to the modest activity of the agents studied in a field with so little to offer patients it is possible that we are discarding drugs that may benefit some patients.  Sometimes as we evaluate new agents we forget that PCa is not acute leukemia.  In other words the first sign of progression does not always herald a rapid and catastrophic course. Secondly tumor growth leads to m and m , not the lack of tumor response.  Finally Disease Progression may not always mean a treatment should be stopped-remember this is what we do in CAD.  We don’t stop cholesterol medication after an MI.  It is possible that the drugs we will be using in the future may be more like drugs we use for CAD than drugs used to treat acute leukemia.

## Measurement of Response-CT

**Improved and more frequent imaging has probably led to the discovery of more patients with measurable disease**
**However in many patients bone disease dominates the clinical course**
**RECIST response or progression may not be relevant**
**Progression in lymph nodes with stable bone scan occur**

**Notes:**
Although the recent failures in prostate cancer drug development are due in some part to the modest activity of the agents studied in a field with so little to offer patients it is possible that we are discarding drugs that may benefit some patients.  Sometimes as we evaluate new agents we forget that PCa is not acute leukemia.  In other words the first sign of progression does not always herald a rapid and catastrophic course. Secondly tumor growth leads to m and m , not the lack of tumor response.  Finally Disease Progression may not always mean a treatment should be stopped-remember this is what we do in CAD.  We don’t stop cholesterol medication after an MI.  It is possible that the drugs we will be using in the future may be more like drugs we use for CAD than drugs used to treat acute leukemia.

## TAX327; A Multicenter, Randomized Phase III Study of Intermittent Docetaxel + Prednisone vs. Weekly Docetaxel + Prednisone vs. Mitoxantrone + Prednisone in Patients with Hormone-Refractory Prostate Cancer ●Docetaxel 75mg/m2 Q3 + Prednisone 10mg orally given daily● Docetaxel 30mg/m2 Wkly + Prednisone 10mg orally given daily ●Mitoxantrone 12mg/m2 Q3 + Prednisone 10mg orally given daily

**TAX327; A Multicenter, Randomized Phase III Study of Intermittent Docetaxel + Prednisone vs. Weekly Docetaxel + Prednisone vs. Mitoxantrone + Prednisone in Patients with Hormone-Refractory Prostate Cancer ****●****Docetaxel 75mg/m2 Q3 + ****Prednisone 10mg orally given daily****●**** ****Docetaxel 30mg/m2 Wkly + ****Prednisone 10mg orally given daily**** ****●****Mitoxantrone 12mg/m2 Q3 + Prednisone 10mg orally given daily**

## Main Results of Study

**TAX327 study showed significantly ****longer survival**** for the ****3 weekly docetaxel (D3P)**** arm compared to mitoxantrone **
**No significant survival benefit with weekly docetaxel**
**D3P**** arm showed ****better palliation****, as recorded by pain and quality of life responses **
**Greater number of patients had significant PSA declines**** **

## Docetaxel 3-weekly

## Mitoxantrone

**Mitoxantrone**

## Docetaxel weekly

**Docetaxel weekly**

## Conclusions

**The updated survival analysis confirmed the previously reported results.**
**Similar hazard ratios among the analyzed subgroups are evidence for robust data.**

## Implications

**Three weekly docetaxel and prednisone remains the preferred treatment option for most patients with mCRPC. **

## Satraplatin in patients with advanced hormone-refractory prostate cancer (HRPC): overall survival (OS) results from the phase III Satraplatin and Prednisone Against Refractory Cancer (SPARC) trial

**Notes:**
Dr Sartor has just presented the results of the overall survival from the SPARC trial. I would like to highlight several aspects of the trial and also discuss a few other studies in PCa that failed to meet its primary endpoint.

## Satraplatin

**Satraplatin**

**Novel oral platinum compound **
**Activity against cell lines **
**	****resistant to taxanes, **
**	****anthracyclines and **
**	****other platinum compounds**
**Activity in early prostate cancer trials **

## Study Endpoints

**Study Endpoints**

- Primary Endpoints
- Progression Free Survival (PFS)
- Based on 802 events (June 2006 data cutoff)
- Composite endpoint based on first occurrence of: Tumor Progression, Skeletal Event, Symptomatic Progression, Death
- PFS assessed by an Independent Review Committee (IRC)
- PSA increase was NOT a criterion for progression
- Overall Survival (OS)
-  Based on 713 events (September 2007 data cutoff)
- Secondary Endpoint
- Time to Pain Progression (TPP)

**Notes:**
The study had 2 primary endpoints one was PFS and the second was overall survival. I would like to focus initially on the PFS endpoint.
The authors when designing the trial tried to standardize the various clinical factors one might use to determine if a drug was benefiting a patient, with the notable exception of PSA.  Thus they looked at radiographic progression, skeletal events, symptomatic progression or death to define progression. At first glance this seems reasonable and even laudable. However in a clinical trial definitions are needed and an increase in narcotics or 2 new lesions on bone scan led to the removal of  patients from the trial. Neither of these is a validated endpoint.  More problematic a “mixed response” also led to the stopping of drug.  This is perfectly reasonable in leukemia or Burkett's lymphoma but less clear with these endpoints.  For example a patient with marked improvement in pain but with 2 new small skull lesions seen on bone scan was taken off of trial.

## SPARC Progression Free SurvivalIntent-to-Treat (ITT) Population Per IRC	         Satraplatin   PlaceboMedian (wks)          11.1            9.7HR: 0.67 (95% CI: 0.57 - 0.77)Log-Rank P value <0.0001

**SPARC Progression Free Survival****Intent-to-Treat (ITT) Population Per IRC****	****         Satraplatin   Placebo****Median (wks)          11.1            9.7****HR: ****0.67 (95% CI: 0.57 - 0.77)****Log-Rank *****P***** value <0.0001**

**16%**

**30%**

**Weeks**

**17%**

**7%**

**At Risk**

**Sternberg CN et al. *****ASCO 43rd Annual Meeting (Chicago, IL),***** June 4, 2007 (abstract 5019)**** **

**Notes:**
As Dr Sternberg had presented last year there was an improvement in the PFS by independent reviewers.  The PFS was quite short in each arm, remember an increase in narcotics was progression. This is not what we would generally do in the clinic.  There did seem to be a difference between the two groups even out to a year, however the population benefiting from the drug is small.  During the initial ODAC evaluation there was concern about the utility of the composite endpoint (since it was not a response measurement), the relative small difference between experimental arm and the control arm and the concern that the myelosuppression of satraplatin might have impacted the decision making of physicians.  In other words if you suspected one was on satraplatin, due to falling counts. One might not increase narcotics because that would lead to removal from trial.  The decision was made to defer approval until the survival data was availble

## SPARC Overall SurvivalITT Population, Unstratified AnalysisMedian (wks)Satraplatin	61.3 Placebo	61.4Unstratified HR: 0.97 (95% CI: 0.83, 1.13)Log-Rank P value = 0.7011

**SPARC Overall Survival****ITT Population, Unstratified Analysis****Median (wks)Satraplatin****	****61.3 Placebo****	****61.4****Unstratified HR: 0.97 (95% CI: 0.83, 1.13)****Log-Rank *****P***** value = 0.7011**

**Proportion Event Free****  ****(%)**

**Weeks**

**0**

**10**

**20**

**30**

**40**

**50**

**60**

**70**

**80**

**90**

**100**

**0**

**10**

**20**

**30**

**40**

**50**

**60**

**70**

**80**

**90**

**100**

**110**

**120**

**130**

**140**

**150**

**160**

**170**

**180**

**190**

**Weeks**

**0**

**10**

**20**

**30**

**40**

**50**

**60**

**70**

**80**

**90**

**100**

**0**

**10**

**20**

**30**

**40**

**50**

**60**

**70**

**80**

**90**

**100**

**110**

**120**

**130**

**140**

**150**

**160**

**170**

**180**

**190**

**Notes:**
Not surprisingly in a trial in which PFS in the experimental arm was only 11.1 weeks (although patents may have taken the drug somewhat longer since this is based on independent review) and only 10 days longer than control would there be no impact on survival.

## Conclusions

**Conclusions**

- SPARC was the largest phase 3 trial in this patient population
- The question remains what is a meaningful measure of clinical benefit in second line HRPC
- Could better imaging (bone ?) help to define if there was a population of patients that actually might benefit from an agent such as this ?

**Notes:**
These are Dr Sartor’s conclusions The first and third are factual but have little impact on the field.  The second and fourth are somewhat contradictory.  If satraplatin has an important clinical benefit it implies that one knows what the meaningful measures of benefit should be in this population. My interpretation is that satraplatin may benefit a portion of this population-but do to the design of the trial which nobly tried to mimic clinical practice but unfortunately fell short we can’t yet say that has an important benefit.  Also unfortunately there is no genotyping obtained that might detect a population of patients that genetically would be more likely to respond to a platinum based agent.

## Study M00-244 Design Objective: To evaluate the safety and efficacy of 10 mg atrasentan vs placebo in patient with non=metastatic HRPC

**Notes:**
The work done on atrasentin provided a clue that perhaps trial design and not surprisingly duration of tx could have an impact on outcome .  In this trial pts were randomized to atrasentin or placebo with the primary endpoint being development of clinical disease

## Study M00-244Efficacy – Progression Free Survival

- Study M00-244Efficacy – Progression Free Survival

|  | Placebo | Atrasentan |
| --- | --- | --- |
| Events N(%) | 285(60.1) | 243(52.0) |
| Median PFS(days) | 645 | 722 |
| HR = 0.917 (95% CI 0.773 – 1.089) |  |  |
| P = 0.227 |  |  |

**Notes:**
This trial failed to meet its primary efficacy endpoint of PFS

## Patient Accountability● 494 Patients had disease progression, 56% Placebo and 49% Atrasentan ●160 Patients were active at the end of study ● 278 Patients Discontinued Without Disease Progression

|  | Placebon(%) | Atrasentann(%) | Total n(%) |
| --- | --- | --- | --- |
|  |  |  |  |
|  |  |  |  |
|  |  |  |  |
| Confirmed Progression | 267 (56.3) | 227 (48.6) | 494 (52.5) |
| Active at study end | 80 (16.9) | 80 (17.1) | 160 (17.0) |
| Discontinued without Disease Progression | 123 (25.9) | 155 (33.2) | 278 (29.5) |
|  |  |  |  |
|  |  |  |  |
|  |  |  |  |
|  |  |  |  |
|  |  |  |  |
|  |  |  |  |

**Notes:**
However despite an endpoint with clear clinical significance about 30 % of the patients withdrew from the trial prematurely 

## Study M00-244Efficacy – Progression Free Survival By Region

- Study M00-244Efficacy – Progression Free Survival By Region

| Non-US | Placebo | Atrasentan |
| --- | --- | --- |
| Median PFS(days) | 652 | 839 |
| HR = 0.792 (95% CI 0.637 – 0.985) |  |  |
| P = 0.012 |  |  |

| US | Placebo | Atrasentan |
| --- | --- | --- |
| Median PFS(days) | 640 | 531 |
| HR = 1.170 (95% CI 0.885 – 1.547) |  |  |
| P = 0.189 |  |  |

**Non-US****N=561**

**US****N=380**

**Notes:**
There was a dramatic difference in compliance by geographic region and in addition a dramatic difference in  outcome.  In the subset of patients from outside the US where discontinuation was less common PFS appeared to be better with atrasentin

## ●Report PSA changes using waterfall plots.●Confirmation of bone scan findings with a second scan.●Eliminate overall response as an outcome measure. ●Insure a drug is no longer working before stopping therapy.

## Anti-angiogenesis, prostate cancer cell, chemotherapy

**Anti-angiogenesis, prostate cancer cell, chemotherapy**

## Docetaxel + Thalidomide Survival

**Dahut et al *****J Clin Oncol*****, 2004**

- Thalidomide + Docetaxel
-       median 26.9 months

- Docetaxel
- Median 14 months

- P=0.0407

**Notes:**
I had previously shown in a randomized phase II trial that thalidomide added to the clinical activity of docetaxel

## Rationale

**Tumor angiogenesis **
**Blocking one pathway may be inadequate for anti-tumor activity**
**Anti-angiogenic targets**
**Thalidomide: bFGF, endothelial cells and TNF**
**Bevacizumab: VEGF **
**Complex interplay of multiple angiogenic factors**

**Notes:**
I hypothesized that the combination of more than one anti-angiogenic agent may have greater anti-tumor activity.  My rationale was that tumor angiogenesis is a complex interplay of many factors and that blocking one pathway may be easily overcome by the tumor. Thalidomide and bev have different targets with thal targeting bFGF, endo and TNF and bdv VEGF

## Single-arm Phase II trial (n = 60)

Metastatic CRPC

No prior chemotherapy for metastatic disease

- Metastatic CRPC
- No prior chemotherapy for metastatic disease

**Docetaxel, Bevacizumab, & Thalidomide**

**Notes:**
I recently completed accrual to this study testing this hypothesis.  60 pts with met CRPC have been accrued to this trial of ATT. Pt’s have had no chemo  for met disease, but several had had docetaxel for adjuvant therpy. In general pts with aggressive disease with on study dt of about 35 days and many with visceral disease.

## Results

- PSA 50% decline rate: 	90%
- RECIST Response rate: 	63 %
- TTP 			18.2 months

**Notes:**
The response rate has been outstanding.  The PSA decline rate is 90 %. Rr 63  % and the TTP 18 months.  This is one of the most active regimens ever seen in this disease. Almost like in lymphoma when I enrolled a patient on this trial I expected him to respond

## Best Response in PSA

**Best Response in PSA**

**Notes:**
This is the waterfall plot of PSA declines.  As you can almost all patients have had dramatic falls in PSA.

## CEC in PC3 Xenografts after Docetaxel and Thalidomide

**CEC in PC3 Xenografts after Docetaxel and Thalidomide**

**Notes:**
Correlative studies are difficult in PCA because of the lack of easily biopsiable tumor. Using circulating endothelial cells as marker of anti-angiogenis is an attractive option.  Preclinical studies done in collaboration with Doug Figg in PC3 xenografts showed that the combination of docetaxel and thalidomide led to an increase in apoptotic endothelial cells

## CEC changes at 6 weeks

**CEC (6 wks - pre)**

**PSA Decrease**

**0**

*p* = 0.02

**>75% **

**<75% **

**CEC changes at 6 weeks**

**Notes:**
We looked @ circulating endothelial cells @ baseline and again @ 6 weeks in patients on ATT. . Patients with a 75 % decline in PSA had a significant increase in CEC’s as compared to those with less than a 75 % PSA decline, indicating that our agents may be hitting the presumed target.

## Conclusion 

**High durable response in PSA **
**Prolonged TTP**
**High ORR**
**Increased apoptotic CEC**

**Notes:**
In conclusion this is a very active regimen with a 

## Castration Sensitive and Castration-Resistant Progression of Prostate Cancer 

## Phase 1-2 Study of MDV3100 in Patients with Progressive Castration-Resistant Prostate Cancer

## MDV3100

**1.****	****Small molecule AR antagonist with a novel mechanism of action that blocks nuclear translocation of AR, DNA binding, with no agonist activity when AR is overexpressed.**
**2.****	****Identified from a cell-based screen that mimics castration-resistant tumors with overexpressed AR.**
**3.****	****Active in bicalutamide-resistant prostate cancer models.**
**4.****	****Currently under investigation in a Phase 1-2 trial in patients with CRPC.**

**Notes:**
MDV3100 is an analogue of RD162 and is currently in clinical investigation for the treatment of CRPC.  It is a novel AR antagonist which was rationally designed to retain its antagonism against the AR and not act as an agonist in the setting of AR overexpression.
It is active in bicalutamide-resistant models of prostate cancer.
MDV3100 has a novel mechanism of action.  Unlike bicalutamide, it blocks the nuclear translocation of AR and DNA binding. 

## Waterfall Plot of PSA Change from Baseline to 12 Weeks for Chemotherapy-Naïve Patients Treated at 60, 150, and 240 mg/day

_**>**_**50% Decline:  23/42 (55%)**

**N=42  Chemo-naïve **

**7 pt off study **
**<12 weeks**

## Waterfall Plot of PSA Change from Baseline to 12 Weeks for Post-Chemotherapy Patients Treated at 60, 150, and 240 mg/day

_**>**_**50% Decline:  13/31 (42%)**

**N=31  Post-chemo**

**5 pt off study **
**<12 weeks**

## FDG and FDHT PET Scans Identify Areas of ActiveProstate Cancer Spread

- FDHT

- AR expression by
- immunohistochemistry

- 18F-DHT

- FDG and FDHT PET Scans Identify Areas of ActiveProstate Cancer Spread

## PRE- and POST-MDV3100 PET Imaging of Biopsy Proven Metastatic Disease in a Lymph Node

**PRE- and POST-MDV3100 PET Imaging of Biopsy Proven Metastatic Disease in a Lymph Node**

## Circulating Tumor Cell (CTC) in MDV3100

**Baseline:****	****	****	****CTC <5****	**** n=25 (58%)**
**	****	****	****	****CTC **_**>**_**5****	**** n=18 (42%)**
**92% in both dose levels have retained favorable cell counts (4 or less) pre- and post-treatment**
**33% and 56% at 60 and 150 mg/day, respectively, converted from a pre-treatment unfavorable to a post-treatment favorable cell counts.**
**Associations with clinical outcomes are ongoing.**

**CellSearch Platform from Veridex, LLC**

## Abiraterone Acetate

## Oral irreversible inhibitor of CYP17 (P450c17)17α –hydroxylase C17,20-lyaseInhibits testosterone production in testis, adrenal glands and prostate

**Oral irreversible inhibitor of CYP17 (P450c17)****17****α**** –****hydroxylase ****C****17,20****-lyase****Inhibits testosterone production in testis, adrenal glands and prostate**

## CYP17 blockade inhibits androgen synthesis

*Attard et al, submitted for publication*

## COU-AA-001in chemotherapy-naïve CRPC 

**First-in-human, first-in-class continuous dosing proof-of-concept study**
**Phase I/II open-label, single-centre, dose- escalation clinical trial**
**Capsules (250mg) administered once daily continuously**
**Dose levels:**
**250mg, 500mg, 750mg, 1000mg, 2000mg**
**28 days defined as 1 treatment course **

*De Bono, et al, Prostate Cancer Foundation, 2007*

## Anti-tumor Activity

**PSA decline rate**
**≥ ****50% PSA declines in ****27/44**** patients (61%) **
**≥ ****75% PSA declines in ****22/44 ****patients (50%)**
**≥ ****90% PSA declines in ****11/44**** patients (25%)**
**One PSA rise but PR on CT scan**
**Median TTP by PSAWGC: 252 days**

*Prior Phase II study of pertuzumab in this population at our institution had a *
*median TTP by PSAWGC of 43 days (de Bono et al JCO 2007)*

*De Bono, et al, Prostate Cancer Foundation, 2007*

## Abiraterone Suppresses Steroids Downstream of C17,20-lyase

**Abiraterone Suppresses Steroids Downstream of C17,20-lyase**

**1**

**60**

**Testosterone (by LC-MS/MS)**

**0**

**1**

**2**

**3**

**4**

**5**

**6**

**ng/dl**

**10**

**   ****20**

**Start of treatment**

**At**
** ****progression**

**70**

**Days**

**No rise at progression**

**Lower limit of sensitivity**

**nmol/l**

**DHEA**

**Start of treatment**

**28**

**56**

**At progression**

**Days**

**No rise at progression**

**0**

**2.5**

**5.0**

**7.5**

**10.0**

**12.5**

**2**

**1**

**0.07**

**28**

**56**

**At progression**

**Days**

**Start of treatment**

**Androstenedione**

**No rise at progression**

**nmol/l**

**Oestradiol**

**10**

**20**

**30**

**40**

**50**

**60**

**Days post treatment**

**2.5**

**5.0**

**7.5**

**10.0**

**12.5**

**0**

**ρ****mol/l**

*Attard, et al, submitted for publication*

## Abiraterone Treatment Results in a Rise in C-21 Steroids Upstream of CYP17

**ACTH**

**ng/dl**

**Deoxycorticosterone**

**10**

**20**

**30**

**40**

**50**

**60**

**Days post treatment**

**0**

**50**

**100**

**150**

**Corticosterone**

**Notes:**
By inhibiting 17alpha hydroxylase, abiraterone suppresses cortisol and this causes a rise in adrenocorticotrophic hormone that drives a rise in deoxycorticosterone – shown here- and corticosterone – shown here- . I shall discuss this in more detail in my next slides but I here show these changes graphically.

## Hormonal Impact of Abiraterone Alone or with Low Dose Corticosteroids

*Attard, et al, submitted for publication*

**Hormonal Impact of Abiraterone Alone or with Low Dose Corticosteroids**

## Exploratory Study-Dexamethasone Salvage

*Attard, et al, submitted for publication*

## COU-AA-003Phase II trial in post-docetaxel patients

- Status
**28 evaluable patients recruited to date **
- Patient disease characteristics
**Median baseline PSA: 523 (range: 33.3-10325)**
**Presence of bone mets on bone scan:  22/28 pts**
**Presence of measurable disease by RECIST: 18/28 pts**

*De Bono et al, Prostate Cancer Foundation 2007*

**Notes:**
2 PRs and 1 minor response

## PSA decline rate

**≥ ****50% PSA declines in ****14/28**** (50%) patients**
**≥****75% PSA declines in ****9/28 ****patients (32%)**
**≥ ****90% PSA declines in ****5/28**** patients (18%)**

*De Bono et al, Prostate Cancer Foundation 2007*

## Phase III Trial in Post-docetaxel Chemotherapy Placebo daily ● Abiraterone 1000 mg daily● Prednisone 10 mg daily Prednisone 10 mg daily

**Randomization 2:1**

**Abiraterone 1000 mg daily**
**Prednisone 10 mg daily**

**Placebo daily**
**Prednisone 10 mg daily**

## General Conclusions

**Docetaxel and Prednisone (q3w) remains the standard **
**Several promising combinations are under investigation **
**Response criteria remains a problem in phase II trials**
**Insure a drug is no longer working before stopping therapy**
**Hormonal treatment can be active even post chemotherapy**