bluuebunny/crossref_metadata_2025_split huggingface dataset:
Hypofractionated, dose escalation radiotherapy for high-risk prostate cancer: The primary endpoint of a group led phase III trial. (PCS5).
Authors: Niazi Tamim , Nabid Abdenour , Bettahar Redouane , Vincent Linda S. , Martin Andre-Guy , Jolicoeur Marjory , Yassa Michael , Barkati Maroie , Igidbashian Levon , Bahoric Boris , Archambault Robert , Villeneuve Hugo , Tsui James M , Mohiuddin MD 
Published: February 2018

123 Background: The low α\β ratio of prostate cancer (PCa), 1.5-2, suggests high radiation-fraction sensitivity and predicts a therapeutic advantage of hypofractionated radiation treatment (HFRT). Most available data of moderate HFRT have focused on low, intermediate and/or mixed risk groups. We therefore conducted the first randomized trial of moderately HFRT in high-risk PCa patients and present the primary safety analysis of side effects at 2 years. Methods: We conducted a Canadian multi-centric phase III trial of conventional fractionated radiation therapy (CFRT) vs. intensity-modulated HFRT in men with high-risk PCa as per NCCN definition. From February 2012 to March 2015, 329 patients were randomized in a 1:1 ratio to receive either CFRT or HFRT. All patients received neo-adjuvant, concurrent and adjuvant androgen suppression, with a median duration of 24 months. CFRT consisted of 76 Gy in 2 Gy per fraction to the prostate where 46 Gy was delivered to the pelvic lymph nodes. HFRT consisted of concomitant dose escalation of 68 Gy in 2.72 Gy per fraction to the prostate and 45 Gy, in 1.8Gy per fraction to the pelvic lymph nodes. The primary endpoint was to compare the toxicities at 6 months and at 24 months using the CTCAE v.4. Results: Of the329 patients, 164 were randomized to HFRT and 165 to CFRT. The minimum, median and maximum follow-up were 24, 40 and 60 months respectively. At 24 months, 12 patients in the CFRT arm and 15 patients in the HFRT arm had grade 2 or worse gastrointestinal (GI)-related adverse events (HR:1.32 [0.62.2.83] 95% CI; P=NS). Similarly, 11 patients in the CFRT arm and 3 patients in HFRT arm had grade 2 or higher genitourinary (GU) toxicities (HR:0.26 [0.07-0.94] 95% CI; P=0.037). In the HFRT arm, there were 3 grade 3 GI and one grade 3 GU related toxicities. In the CFRT arm there were 3 grade 3 GU and no grade 3 GI related toxicities. There were no grade 4 toxicities in either arm. Conclusions: This is the first hypofractionated dose escalated radiotherapy study in high-risk PCa patients treated with contemporary radiation and androgen suppression. Our results indicate that moderate HFRT to high risk PCa patients is equally well tolerated as CFRT at 2 years. Clinical trial information: NCT01444820.
A phase 2 study of olaparib and durvalumab in metastatic castrate-resistant prostate cancer (mCRPC) in an unselected population.
Authors: Karzai Fatima , Madan Ravi Amrit , Owens Helen , Couvillon Anna , Hankin Amy , Williams Monique , Bilusic Marijo , Cordes Lisa M. , Trepel Jane B , Killian Keith , Meltzer Paul S. , Gulley James L. , Lee Jung-min , Dahut William L. 
Published: February 2018

163 Background: Data suggests 25-30% of sporadic mCRPC has defects in DNA repair pathways which may confer sensitivity to PARP inhibition (PARPi). Immune checkpoint blockade may increase the proportion of patients that respond to PARPi. We hypothesize that increased DNA damage by olaparib (O) will complement anti-tumor activity of immune checkpoint blocking antibody, durvalumab (D), in mCRPC (NCT02484404). Methods: Single arm pilot study with accrual of 25 patients (pts) with mCRPC and disease that is amenable to biopsy. Prior treatment with enzalutamide and/or abiraterone is required. D is given at 1500 mg iv q28 days + O 300 mg tablets po q12 hours. The primary endpoint is PFS. Core biopsies undergo mutational analysis. Results: In the first 17 pts, median age is 66 (range 45-79 years), median baseline PSA is 79.67 ng/mL [3.93-2356 ng/mL]). Median Gleason score is 8. 6 patients have bone only disease and 11 patients have bone and soft tissue/visceral disease. Median number of cycles is 7 (2-17). Grade 3/4 adverse events include anemia 4/17 (24%), lymphopenia 2/17 (12%), infection 2/17 (12%), thrombocytopenia, leukopenia, neutropenia, nausea, vomiting, UTI, hypertension, hearing impairment, fatigue, syncope, oral mucositis, muscle weakness, and muscle cramps [1/17 each, (6%)]. 8/17 pts (47%) had PSA responses >50%. 6 of these pts had mutations in the DNA damage repair pathways (DNAdr). 2/17 pts (11%) had PSA responses >30% with no known mutations in DNAdr. 4 pts had a PR. The 12 month PFS is 51.5% (95% CI: 25.7-72.3%). Conclusions: Preliminary data shows D+O is well tolerated with activity in an unselected population. Accrual is ongoing with biomarker analysis. Clinical trial information: NCT02484404.
Phase II trial of SM 88 in non-metastatic biochemical recurrent prostate cancer.
Authors: Roach Mack , Gostout Zachary , Zawisny Patricia , Retter Avi S. , Sokol Gerald H. , Hoffman Steve , Del Priore Giuseppe 
Published: February 2018

175 Background: Despite toxicity and no clear survival benefit, non-metastatic recurrent prostate cancer (nmPC) is typically treated with androgen deprivation therapy (ADT). SM88 is a relatively non-toxic novel combination therapy (amino acid analogue, CYP3a4 inducer, mTOR inhibitor and catalyst) based on the Warburg effect, with activity in a variety of cancers including prostate (JCO 2017 35, e16567). Phase I and II results demonstrated stable or rising testosterone levels while achieving a reduction of CTCs (circulating tumor cells) and no radiographic progression events (Annal Oncol 2017, 28(5):274-5). We now report results for toxicities typically seen with ADT. Methods: Prospective ongoing Phase Ib/II of SM88 (230mg po bid) in recurrent nmPC with rising PSA (PCWG3 definition), detectable CTCs, and no radiographically identified metastases at baseline. Results: Since Sept 2016, there have been 17 consented (of 34 planned) with 10 evaluable (completed > 1 cycle) (median 7, range 1-13). Mean age was 71.2 (53-84); all had prior ADT after curative intent RT (50%) or surgery (50%); with no patient currently on ADT. Mean testosterone level was 307.6 ng/dL before SM88 and 349.2 after (p = 0.07, one-tail T test), rising in (5/10) or remained stable except for one patient who entered the trial castrate ( < 2.5). Overall 70% had some grade 1-2 adverse event (AE) but no drug related serious AE. EORTC-QLQ-C30 relating to mental function domain (Q20-28) and QLQ-PR25 intimacy domains (Q44-50) remained stable, including 9 (90%) reporting no or resolved hot flashes; 7 (70%) reporting an improved or stable “interest in sex”; and 6 (60%) having “excellent” “overall health” and “QOL”. Weight and osteoporosis (measured by Urinary NTX) did not worsen; mean EKG QTc (422 ms); mean arterial pressure (95.1 mmHg); glucose (115.2 mg/dl) and hematocrit (41.5%) were not affected. Conclusions: Toxicities typically associated with ADT were not seen with SM88, a novel non-hormonal anti-neoplastic. Despite the limited follow-up, these data suggest that ADT may be avoided or delayed without progression in selected patients with nmPC. A phase III RCT of SM88 vs patient choice of hormonal or active surveillance is planned for confirmation of these results. Clinical trial information: NCT02796898.
A phase Ia study of safety and clinical activity of atezolizumab (atezo) in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Kim Joseph W. , Shaffer David R. , Massard Christophe , Powles Thomas , Harshman Lauren Christine , Braiteh Fadi S. , Conkling Paul R. , Sarkar Indrani , Kadel Edward E. , Mariathasan Sanjeev , O'Hear Carol , Schiff Christina , Fasso Marcella , Carroll Susheela , Petrylak Daniel Peter 
Published: February 2018

187 Background: In the past decade, several therapies have been approved for mCRPC. However, most pts develop resistance and experience disease progression. Thus, there remains a high unmet need. Atezo (anti–PD-L1) blocks the interaction between PD-L1 and its receptors, PD-1 and B7.1, thereby restoring anti-tumor immunity. Atezo has demonstrated clinical efficacy in many tumor types. Here we report the clinical safety and activity of atezo in pts with mCRPC from a Phase Ia study (PCD4989g; NCT01375842). Methods: Eligible pts previously received enzalutamide and/or sipuleucel-T for mCRPC. Pts also had PSA or radiographic progression prior to enrollment. Atezo 1200mg was administered IV q3w. CT and bone scans were performed q6w for 24w and q12w thereafter (q6w if treatment beyond disease progression). Primary objectives were safety and tolerability; OS was an exploratory objective. mCRPC cohort–specific objectives included PSA response, radiographic progression per PCWG2 criteria, soft tissue response per RECIST v1.1 and immune-related response criteria (irRC). Survival follow-up data was collected ≈ every 3 mo until death or loss to follow-up. Results: The 15 pts in the initial mCRPC cohort were evaluated (clinical cutoff: December 31, 2016). 13 pts (87%) had received ≥ 2 prior lines of therapy for mCRPC. Median survival follow-up was 15.8 mo (range, 2.3-23.0). 9 pts (60%) had a treatment-related AE (TRAE); only 1 pt (7%) experienced a Gr 3 TRAE (hyponatremia). No Gr 4-5 TRAEs were reported. The landmark 12-mo OS rate was 55.6% (95% CI: 27.4, 83.7); median OS was not reached (range, 2.3-23.0 mo). Median PFS was 3.4 mo (95% CI: 2.3, 5.7); the 6-mo PFS rate was 26.7% (95% CI: 4.3, 49.1). 1 pt (9%) had a PR per irRC (irPR); 5 pts (45%) had SD per RECIST v1.1 and irRC. 2 pts (13%) had a ≥ 50% decrease in PSA from baseline. The pt who experienced an irPR had increased CD8 expression and expansion of T-cell clones on study treatment. Conclusions: Atezo was well tolerated and demonstrated long-term disease control in pts with heavily pretreated mCRPC, with a 12-mo OS rate of 55.6%. Preliminary biomarker analyses from the pt who experienced an irPR were suggestive of an activated immune response. Clinical trial information: NCT01375842.
Randomized trial of enzalutamide versus bicalutamide in combination with androgen deprivation in metastatic hormone sensitive prostate cancer: A Prostate Cancer Clinical Trials Consortium trial.
Authors: Vaishampayan Ulka N. , Heilbrun Lance K. , Monk Paul , Tejwani Sheela , Sonpavde Guru , Smith Daryn , Jasti Pallavi , Dobson Kimberlee , Heath Elisabeth I. , Cher Michael L. , Chinni Sreenivasa , Fontana Joseph A. 
Published: February 2018

190 Background: Addition of abiraterone or docetaxel has overall survival (OS) benefit in metastatic hormone sensitive prostate cancer (mHSPC). The clinical outcomes with early enzalutamide in mHSPC are unknown. We compared the combinations of enzalutamide (Arm A) or bicalutamide (Arm B) each with LHRH analogue therapy in mHSPC. Methods: The primary endpoint was PSA nadir < 4 ng/ml after 7 months of therapy, as this has been recognized as a powerful surrogate for overall survival (OS) outcomes. A minimum of 29 African American (AA) patients were required to be enrolled to evaluate the effect of race on the primary endpoint. Secondary endpoints were toxicities, biochemical and radiologic progression free survival (PFS), and OS. Stratification was by presence of bone pain and race; AA or other. PSA was monitored monthly for first 7 months and then every 3 months. The target sample size was 82 evaluable patients but the study was stopped when early abiraterone showed OS benefit in mHSPC. Metastatic site biopsies were mandatory pretherapy and optional post therapy. Results: 71 men; 29 black, 41 white and 1 Asian were enrolled. The median age was 67 years (range 46-87 years) and median baseline PSA was 56.3 ng/ml in Arm A (4.2-10,431 ng/ml) and 60 (4.9-12,030 ng/ml) in Arm B. 27 pts (38.5%) had bone pain and 13 had visceral metastases. No seizures were noted in either arm. Grade 3+ AE’s on Arm A were: Hypertension (13%), infection (7%), and Snycope (7%) and on Arm B were: Hypertension (21%), Fatigue (7%), and Hematuria (7%). By intent to treat PSA nadir < 4ng/ml at month 7 was achieved in 96.3% pts in arm A and 66.7% pts in arm B and in 71.7% of AA men and 89.7% of Caucasians. The 6-month PSA remission duration rates after month 7 on Arms A and B were 86% and 79%, respectively. 53 (75%) biopsy samples had tumor tissue available. Tmprss2-Erg fusion gene expression and androgen biosynthetic enzyme levels were determined in metastatic biopsies and will be correlated with clinical endpoints. Conclusions: Early enzalutamide use in mHSPC has the potential to improve PSA remission rates and subsequently improve PFS and OS outcomes. Clinical trial information: NCT02058706.
Overall survival of patients with metastatic prostate cancer starting androgen deprivation therapy with degarelix, a gonadotropin-releasing hormone antagonist.
Authors: Freedland Stephen J. , Sørensen Per Settergren , Persson Bo-Eric 
Published: February 2018

198 Background: Morbidity and mortality amongst patients diagnosed with metastatic prostate cancer remains high and androgen deprivation therapy is the mainstay of hormonal treatments for these patients. The gonadotropin-releasing hormone (GnRH) antagonist, degarelix, has a fast and profound onset of action and compares favorably with GnRH agonists in terms of progression-free survival (PFS) and overall survival during the first year of treatment. It is of interest to assess longer term survival data in patients with very advanced disease. Methods: Data from several studies of patients treated with degarelix are available for descriptive analysis from a study repository. We analyzed data from patients with metastatic disease and prostate-specific antigen (PSA) > 50 ng/mL treated with degarelix from 17 controlled and uncontrolled trials for overall survival and PFS. Possible selection bias over time was also estimated. Results: Overall, 519 patients with metastatic disease and PSA > 50 ng/mL were included; median age was 71 (±6) years. Survival at 36 months was 83% for patients with baseline PSA > 50 to < 200 ng/mL and 72% for patients with baseline PSA > 200 ng/mL. The corresponding numbers for PSA-PFS were 29% and 15%, respectively (Table). A delayed separation of Kaplan-Meier estimates was observed between the PSA > 50 to < 200 ng/mL and > 200 ng/mL groups; 6 months for PSA-PFS and 12 months for survival. A Cox regression indicated no significant effect of age (p = 0.20) or BMI (p = 0.33). The data suggest some selection bias over time in the most advanced patients. Conclusions: The data indicate that 77% of patients with metastatic disease and PSA > 50 ng/mL who start degarelix treatment are alive after an observation period of 36 months. This is an analysis of uncontrolled data and a comparative randomized approach is required to allow potential comparison with other treatments. [Table: see text]
Immunotherapy for biochemically recurrent prostate cancer.
Authors: Madan Ravi Amrit , Karzai Fatima , Bilusic Marijo , Strauss Julius , Slovin Susan F. , Harshman Lauren Christine , Theoret Marc Robert , Arlen Philip M. , Rauckhorst Myrna , Couvillon Anna , Hankin Amy , Williams Monique , Kantoff Philip W. , Dahut William L. , Schlom Jeffrey , Gulley James L. 
Published: February 2018

215 Background: Annually about 30-50,000 men are diagnosed with biochemically recurrent prostate cancer (BCRpc), defined by a rising PSA after radical prostatectomy (RP) or definitive radiation therapy (RT) with negative conventional imaging (CT and bone scan). Standard treatments include salvage therapies, androgen deprivation or surveillance. The role of immunotherapy in BCRpc is undefined. Methods: This study evaluates PROSTVAC, a pox-viral based therapeutic cancer vaccine targeting PSA, in BCRpc. Key eligibility criteria include PSA > 0.8 after RP or > 2.0 after RT with a maximum PSA of 30, PSA doubling time (DT): 5-15 months; testosterone > 100, negative CT and bone scan. Patients (pts) are randomized to vaccine for 6 months or 6 months surveillance followed by 6 months of vaccine. In a post hoc analysis delayed PSA declines were characterized as a confirmed PSA decline after an intra-study apex PSA (ISAP) defined by a peak PSA affirmed by a contiguous PSA within 10% (to exclude lab variations). 80 pts will be enrolled at NCI, Dana-Farber Cancer Institute and Memorial Sloan Kettering Cancer Center. Results: Of the 26 pts enrolled thus far, 22 have been followed for > 9 months after vaccine and are evaluable. On-study median values were age 66.8 years (54-78), PSA 2.67 ng/ml (0.83-28.5), PSA DT 7.5 months (5.1-14.9). 8 pts (38%) had delayed PSA declines after ISAP (-12% to -99%). Of 13 pts on surveillance for 6 months, only one pt had a similar decline lasting only 56 days. Conclusions: Preliminary data from this study suggests that PROSTVAC may be associated with delayed, but sustained PSA declines in BCRpc which are rarely seen in surveillance alone. Additional data will be acquired from this study, but this provides rationale to develop immunotherapy combinations in BCRpc. Clinical trial information: NCT02649439. [Table: see text]
Phase II trial of carfilzomib for metastatic castration-resistant prostate cancer (mCRPC) following androgen pathway inhibitors.
Authors: Naik Gurudatta , Bae Sejong , De Shazo Mollie R. , Dixon Pam , Merritt Lynn , Sartor A. Oliver , Schnell Frederick M. , Sonpavde Guru 
Published: February 2018

224 Background: mCRPC is an incurable disease with suboptimal outcomes following prior therapy. Bortezomib, a proteasome inhibitor, has exhibited activity in a subset of patients. Carfilzomib is a second-generation selective and irreversible proteasome inhibitor and is approved for refractory myeloma. Methods: A non-randomized phase II trial (NCT02047253) was designed to evaluate carfilzomib for mCRPC following abiraterone acetate (AA) and/or enzalutamide (enza); prior docetaxel (D) was allowed. A 6-month progression-free survival (PFS) rate ≥30% defined by Prostate Cancer Working Group (PCWG) guidelines was considered important, while PFS < 10% was not. History and physical exam, and prostate specific antigen (PSA) was performed every 4 weeks. Circulating tumor cells (CTCs) were measured at baseline and 12 weeks later. Radiographic evaluation was performed every 12 weeks. Carfilzomib was administered on days 1,2,8,9,15,16 every 28 days. The starting dose was 20 mg/m2 during the first week followed by dose escalation to 56 mg/m2 if no serious toxicities occurred. Daily oral acyclovir was administered for herpes zoster prophylaxis. Therapy continue until PCWG or symptomatic progression or severe toxicities. Results: Twenty-eight patients were recruited and prior AA, enza or D had been received by 21 pts each and 20 pts received > 1 of these agents. The median age was 70 (range 55-88). One patient attained 6-month PFS; 2 other patients progressed at 6 months. Minor PSA declines and CTC declines were observed in 3 patients each, and one patient exhibited both PSA and CTC declines. The major toxicities of any grade were: anemia (n = 13, 46%), Fatigue (n = 7, 25%), and Constipation (n = 5, 18%), with anorexia, cough, fever, headache and thrombocytopenia in 4 patients each (14%). The major toxicities of grade ≥3 in > 1 patient were: anemia (n = 3, 11%) and hypertension (n = 2, 7%). Conclusions: Carfilzomib is not active as salvage therapy following AA and/or enza in unselected patients with mCRPC. Minor and transient activity may be present in a small subset of patients. Clinical trial information: NCT02047253.
Impact of statins on outcomes in patients (pts) with metastatic castration resistant prostate cancer (mCRPC): Post-hoc analysis of data from COU-AA-301 and COU-AA-302 trials.
Authors: de Velasco Guillermo , Lora David , Lorente David , Choueiri Toni K. , Sweeney Christopher , Castellano Daniel E. 
Published: February 2018

230 Background: Retrospective database studies have suggested that statins may have a positive impact on some mCRPC pts treated with prednisone (P)/abiraterone (AA) Methods: We conducted a post-hoc analysis of individual pt data of mCRPC pts treated with AA and/or P on randomized phase III clinical trials COU -AA-301 and COU-AA-302 to analyze the impact of statins on overall survival (OS). Statistical analyses were performed using the Kaplan Meier method and Cox regression adjusted for known prognostic factors. This study, was carried out under YODA Project #2016-1136 Results: 458 (41%) prechemotherapy pts and 348 (29%) postchemotherapy pts were statins users (Table). Improved OS was observed for mCPRC pts who were statins users in the postdocetaxel setting [HR: 0.82 (95% CI: 0.71 to 0.94); p = 0.006], and there was a trend towards a prolonged OS in the predocetaxel setting [HR: 0.89 (95% CI: 0.77 to 1.03); p = 0.13] adjusted by interventional treatment (AA and/or P). In the predocetaxel setting there were no significant differences in OS between the groups AA/P/non-statin users and placebo/P/statin users (p=0.3). In the multivariate analysis, patients randomized to AA/P who were statins users and presenting ECOG <2 had superior OS in the postdocetaxel setting. Similarly, age, ECOG and statin use were the strongest prognostic factors in the predocetaxel setting. Conclusions: In a post-hoc analysis of two prospective randomized clinical trials statin use was associated with superior OS in mCPRC pts treated with P or AA/P. Further studies are needed to confirm these results and guide use of statins as adjunct to P and A. [Table: see text]
Abiraterone acetate plus prednisone (AAP) in chemotherapy-naïve patients with metastatic castration-resistant prostate cancer (mCRPC) and prior diethylstilbestrol (DES) therapy: Preliminary results.
Authors: Bastos Diogo Assed , Machado Marcos Tobias , Panhoca Renato , Pioner Giovani Thomaz , Werutsky Gustavo , Grings Mariana , Lopes Lizis , Gonzalez Francisco , Santos Telma Murias , Gidekel Rosemarie ,   On Behalf of the ABIRA DES Investigators
Published: February 2018

235 Background: AAP is approved for patients with chemotherapy-naïve mCRPC, but the population with previous use of DES was not studied before. DES is a commonly used hormone therapy for mCRPC in second and plus lines, especially in developing countries, due to lack of access to novel and efficacious therapies. The objective of this trial is to describe the efficacy and safety of AAP after DES treatment in patients who are chemotherapy-naïve, potentially affecting chemotherapy onset. This is the first and only prospective trial to show this data. Methods: This phase 2 multicenter, open-label single-arm study evaluated 46 patients receiving AA (1000 mg daily) + low-dose prednisone (P; 10 mg daily) and androgen deprivation therapy in patients with DES–refractory mCRPC enrolled from Oct 2014 to Oct 2015. The primary efficacy endpoint was time to prostate-specific antigen progression (PSAP) by Prostate Cancer Working Group (PCWG2) criteria. Secondary endpoints included PSA response (≥50% reduction), overall survival, and safety. Results: At baseline, median age was 69 years, median PSA was 40 ng/mL, there were no visceral metastases, 98% of patients had Eastern Cooperative Oncology Group Performance Status 0-1, and 44% had Gleason scores ≥7. Thirty two subjects (71.1%) had PSAP. PSA response was achieved by 47% of patients at week 12 and 56% at any time. Three patients remain on study drug and 4 are in follow-up. AA treatment continued until PSAP, clinical progression, consent withdrawal, or unacceptable toxicity. The median duration of study treatment was 8.6 months. The median time to PSAP was 7.4 months (95% CI = 5.6-9.4) and the median overall survival was 25.6 months (95% CI = 15.7-NE). Treatment-related adverse events included hypertension (19.6%), hyperglycemia (19.6%), fatigue (17.4%), and hypokalemia (4.5%); most grade 1-2. Conclusions: The present study confirmed that AAP provides PSA responses even in heavily treated patients, showing clinical benefit post-DES in chemotherapy-naive mCRPC patients. It also confirmed tolerability of AAP, with an easily manageable toxicity profile. Clinical trial information: NCT02217566.