Prostate cancer in 2014 - 2015: Advances and ongoing challenges in therapeutics, biomarkers, and precision medicine

ORLANDO, FL, USA ( - Looking back at her “Year in Review” presentation at the 2015 American Society of Clinical Oncology (ASCO) Genitourinary Cancers Symposium, Dr. Mary-Ellen Taplin describes a landscape of medical progress amid continuing Federal-funding challenges. Following are excerpts from Dr. Taplin's remarks which were compiled exclusively for UroToday readers.

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UroToday: Stories have been published in the mainstream press about the impact of reduced investigator and institutional funding on progress against any number of serious and deadly illnesses. In your presentation, you provided specific figures for prostate cancer.

Dr. Taplin: According to the Prostate Cancer Foundation, which provided these figures for 2015, prostate cancer research will receive $255 million from the National Institutes of Health, and $80 million from the Department of Defense. We all know the exorbitant cost of drug development from pre-clinical to phase III studies, and this amount of funding surely limits opportunities for promising research and trial opportunities for patients.

gucancerssympaltUroToday: A couple of important trials in particular, you said, have been instrumental in informing, even changing, standards of care in prostate cancer.

Dr. Taplin: The Chemohormonal Therapy vs Androgen Ablation Randomized Trial for Extensive Disease (CHAARTED) trial (results) changed the standard of care for men with hormone-sensitive metastatic prostate cancer. This ECOG intergroup trial evaluated the addition of 6 cycles of docetaxel to androgen deprivation therapy. The primary endpoint was overall survival.

UroToday: In its recruitment phase, you mentioned that the CHAARTED investigators were concerned about possible slow patient accrual.

Dr. Taplin: At the time the trial was developed, it was presumed that this stage of prostate cancer (metastatic hormone sensitive) was uncommon enough that a phase 3 trial could suffer from low accrual. (Instead, the trial enrolled) nearly 800 men over (a period of) 6.5 years. Data reached maturity in about 7.25 years from the (time) the first man was enrolled.

The primary endpoint of the CHAARTED trial was overall survival. With a hazard ratio of 0.61, the overall survival was 57.6 months for the cohort receiving docetaxel compared to 44 months for the ADT-only cohort.

UroToday: You said the analysis was stratified by baseline disease burden. What did these results show?

Dr. Taplin: The CHAARTED results showed that the survival improvement was greatest for the subset of men with high-volume disease—(showing) an observed 17-month difference in favor of the docetaxel cohort.

The median survival has not yet been reached in the low-volume patients. This trial provides the clearest demonstration of the difference in survival according to disease burden, and this information is helpful in guiding patient expectations and in clinical decision-making.

There is much more data to be mined from this Federally-funded trial over the coming years.

UroToday: COUGAR 302 was another recent trial that delivered important and instructive information about treatment and trial design.

Dr. Taplin: The COUGAR 302 trial compared abiraterone and prednisone to a prednisone and placebo control in men with metastatic castrate-resistant prostate cancer who were naïve to chemotherapy. Over a period of one year, 1 088 men were accrued. The study was powered to measure two co-primary endpoints: radiographic progression-free survival and overall survival.

The study was unblinded on the recommendation of the date safety monitoring committee after the second interim analysis, based on (a finding of) a significant difference in rPFS as well as an emerging trend in overall survival favoring treatment with abiraterone.

(At the 2014 ESMO meeting), Dr. Chuck Ryan presented the updated survival analysis. The analysis incorporated data following the observation of 741 deaths, which represented 96% of the deaths required for completion of the final statistical analysis.

UroToday: Dr. Taplin, you explained that this trial provided a lesson in trial design. You referred to an “evolution of statistical significance” over the course of sequential analyses, and commented on the potential impact of this on ultimate trial results.

Dr. Taplin: (Yes), after a median follow-up of more than 4 years and at the fourth and final analysis, improvement in overall survival with abiraterone was statistically significant. (It was notable that), 44% of men in the prednisone arm subsequently received abiraterone, and the post-protocol abiraterone did not dilute the survival benefit.

The primary lesson from this experience is that, despite an early unblinding for positive rPFS, -- the co-primary endpoint in this case -- the final survival analysis required continued data collection. Early trial termination with a distant time-to-event endpoint, such as survival, should be avoided.

UroToday: The PREVAIL study established that enzalutamide is a great advance to the field, you said, allowing men with castrate-resistant prostate cancer to live longer and to delay chemotherapy.

Dr. Taplin: The PREVAIL phase III trial was larger than COUGAR 302. A total of 1 714 men with castrate-resistant prostate cancer were accrued over a period of one year, and randomized either to enzalutamide or placebo. Co-primary endpoints were radiographic progression-free survival and overall survival. Positive results were found for both endpoints. In fact, the hazard ratio for rPFS is the lowest ever observed in a phase 3 castration-resistant prostate cancer trial.

For the enzalutamide cohort, the median time on therapy was a respectable 16.6 months. As much as 42% of participants remained on enzalutamide at the time of analysis.

We look forward to updated performance metrics as they emerge.

UroToday: You commented that one unusual side effect emerged with enzalutamide treatment. That was hypertension.

Dr. Taplin: The most common all-grade adverse event was fatigue, but hypertension was observed in 13% of patients receiving enzalutamide, primarily after an extended time on therapy. The etiology of hypertension is not clear, and calls for clinical awareness and appropriate management. On the other hand, seizures were not observed in this large cohort. This finding relieves concern about increased seizure risk with standard-dose enzalutamide.

Important areas of ongoing investigation of enzalutamide include optimal sequencing of secondary androgen-receptor-directed approaches, combination approaches, biomarkers of response and resistance, and exploration of efficacy in earlier disease settings.

UroToday: There were several negative phase 3 trials in 2014. You pointed out that much is to be learned from these studies.

Dr. Taplin: Several rationally-designed trials (that produced negative results in phase 3 investigation) were preceded by favorable pre-clinical and phase 2 data supportive of further development.

In post-chemotherapy castrate-resistant prostate cancer patients, (the trial comparing) orteronel vs prednisone demonstrated a positive rPFS but negative overall survival.

In the same patient group, cabozaninib, ipilimumab, and sunitinib also had negative overall survival results.

In pre-chemotherapy mCRPC patients, custirsen and dasatinib produced negative overall survival when combined with docetaxel, and compared to docetaxel alone.

Separate phase 3 trials of ipilimumab (prechemotherapy), that are pending, hold promise for approval of these agents for CRPC patients.

These negative trials accrued 6 275 men at a significant cost in both human and financial resources. I would submit that more routine human in vivo tissue correlative work in phase 1 and 2 would be worth the investment before embarking on phase 3 for most drugs in development.

UroToday: Some excitement has been generated, including at this meeting, by a report by investigators from Johns Hopkins regarding the value of the androgen receptor slice variant, ARV7, as a predictive and prognostic biomarker, and its planned role in the first biomarker-directed phase 3 trial in advanced prostate cancer patients.

Dr. Taplin: The hypothesis the Hopkins team investigated was that detection of ARV7 in circulating tumor cells from men with castrate-resistant prostate cancer is associated with resistance to enzalutamide and abiraterone.

The first phase 3 trial in men with metastatic castrate-resistant prostate cancer who are also ARV7 positive will shortly be launched.

UroToday: Personalized targeted therapy in prostate cancer is in the early stages of development and validation, you said, with the notable exception of the Stand Up to Cancer (SU2C) program. What are the goals of this program?

Dr. Taplin: The Stand Up to Cancer program has funded an East and West coast dream team, with goals that include sampling hundreds of prostate cancer metastases and performing whole genome and whole transcription analyses. Results are presented at a tumor board and patient and physician are given the information. If targetable mutations are identified, recommendations for clinical trials follow. A total of 363 patients are enrolled in the program to date.

Examples of pathway-directed therapy from observed mutations in this cohort include trials of PARP inhibitors for BRCA-mutated tumors, and increased intensity of ADT in AR-amplified tumors.

gu cancers taplin mePresented by Mary-Ellen Taplin, MD at the 2015 Genitourinary Cancers Symposium - "Integrating Biology Into Patient-Centric Care" - February 26 - 28, 2015 - Rosen Shingle Creek - Orlando, Florida USA

Director of Clinical Research, Lank Center for Genitourinary Oncology Institute Physician, Dana-Farber Cancer Institute, Boston, MA USA

Written by UroToday contributor, Barbara Jones


CHAARTED: Chemohormonal Therapy versus Androgen Ablation Randomized Trial for Extensive Disease in Prostate Cancer

Final Overall Survival Analysis of COU-AA-302, a Randomized Phase 3 Study of Abiraterone Acetate in Metastatic Castration-resistant Prostate Cancer Patients without Prior Chemotherapy

Radiographic Progression-free Survival as a Response Biomarker in Metastatic Castration-resistant Prostate Cancer: COU-AA-302 Result



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