Hormone Activity Suppression in Castration-resistant Prostate Cancer

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PRIORITY PRESS - 48th Annual Meeting of the American Society of Clinical Oncology

Chicago, Illinois / June 1-5, 2012

Chicago - A series of multicentre studies with agents that suppress hormone activity are expected to revise current management pathways in castration-resistant prostate cancer (CRPC). The 2 largest studies, testing different strategies in different settings, were both halted at an interim analysis due to a clear advantage for the experimental therapy over controls. The major benefits associated with suppression of hormone activity have included an improvement in overall survival, the most widely accepted criterion for changing clinical practice. Studies presented here at the 2012 ASCO validated the efficacy of hormone suppression for a broad range of indications in CRPC. These included first-line treatment in those with newly diagnosed metastatic disease and those being treated second-line after chemotherapy.

Chief Medical Editor: Dr. Léna Coïc, Montréal, Quebec

The versatility of hormone suppression for controlling castration-resistant prostate cancer (CRPC) has been demonstrated in a series of recent clinical trials with the potential to alter routine management.                                                                                 

Study Findings

The most important data presented here at ASCO 2012 were generated by the AFFIRM and COU-AA-302 trials. AFFIRM was a phase III study of enzalutamide, formerly MDV3100, in patients who had previously received docetaxel chemotherapy. While the primary results were presented several months ago at the 2012 ASCO Genitourinary Cancers Symposium, detailed secondary analyses were made available at ASCO. COU-AA-302 was a randomized, phase III study of abiraterone acetate in chemotherapy-naive patients with metastatic CRPC. The data were presented as a late-breaker. Both studies were halted at an interim analysis because of a compelling overall survival (OS) advantage in the experimental arm.

In AFFIRM, the survival data for enzalutamide were characterized by Dr. Johann S. de Bono, Royal Marsden NHS Foundation Trust, London, UK, as “the best we have seen in the post-chemotherapy setting.” The primary end point of OS, reported previously, was improved by 37% (HR 0.63; 95% CI, 0.53-0.75; P<0.0001) with enzalutamide over placebo (median 18.4 vs. 13. 6 months). The relative advantage for radiographic progression-free survival (rPFS), a secondary end point, was somewhat greater (median 8.3 vs. 2.9 months: HR 0.40; 95% CI, 0.35-0.466; P<0.0001). In the first detailed evaluation of secondary end points, Dr. de Bono reported that every response indicator was positive, typically at high levels of statistical significance. Not least of the relative advantages was a more than doubling of the proportion of patients with quality of life (QOL) improvement on the Functional Assessment of Cancer Therapy-Prostate (FACT-P) measurement tool (43.3% vs. 17.8%; P<0.0001).

A total of 1199 patients were randomized in AFFIRM in a 2:1 ratio to enzalutamide 160 mg/day or to placebo. Prednisone or other glucocorticoids were allowed but not required. All of the measured end points associated enzalutamide with substantial advantages, including time to PSA progression (median 8.3 vs. 3.0 months; P<0.0001), objective response rates (28.9% vs. 3.9%; P<0.0001) and PSA response (43.3% vs. 17.8%; P<0.0001).

AFFIRM associated enzalutamide with a placebo-like adverse-event profile. While hot flushes were more common on enzalutamide (20% vs. 10%), adverse events of grade ≥3 tended to be lower. For example, while all grades of fatigue (34% vs. 29%) and diarrhea (21% vs. 18%) were slightly higher on enzalutamide than placebo, the rate of grade ≥3 fatigue (6% vs. 7%) and liver function test abnormalities (0.4% vs. 0.8%) were slightly lower. Seizures, a side effect previously associated with androgen receptor blockers, was extremely rare in either group (0.6% vs. 0%). More telling was the large increases across FACT-P domains of QOL. The ASCO-invited discussant for these data, William K. Kelly, DO, Thomas Jefferson University, Philadelphia, Pennsylvania, called the QOL benefits “impressive” and characterized the overall risk:benefit ratio as “very favourable.”

Currently, abiraterone is indicated in combination with prednisone for the treatment of metastatic CRPC in patients who have received prior docetaxel. Its activity is attributed to inhibition of an enzymatic step in androgen biosynthesis. In late stages of clinical testing, enzalutamide inhibits androgen receptor signalling by several mechanisms including blockade of testosterone binding to androgen receptors. .

In COU-AA-302, 1088 patients were randomized at 151 centres in 12 countries to abiraterone 1 g plus prednisone 5 mg twice daily or to placebo plus the same dose of prednisone. OS and rPFS were the co-primary end points. At a preplanned interim analysis in February of this year, the data monitoring committee recommended unblinding the study because of the large and consistent advantage for the abiraterone/prednisone arm.

“This is the first randomized trial to demonstrate both OS and rPFS in chemotherapy-naive patients with metastatic CRPC,” reported the presenting author of the COU-AA-302 results, Dr. Charles J. Ryan, University of California, San Francisco.

With a median follow-up of 22.2 months, the median rPFS was 8.3 months for the control but not reached for the active treatment arm, producing a hazard ratio (HR) of 0.43 (95% CI, 0.35-0.52; P<0.0001). The median OS was 23.7 months in the control arm but it was not reached in the abiraterone arm (HR 0.75; 95% CI, 0.61-0.93; P=0.0097). The secondary end points that favoured abiraterone included a longer time to prostate-specific antigen (PSA) progression (11.1 vs. 5.6 months; P<0.0001).

The COU-AA-032 study was stopped after 40% of the anticipated events had occurred on the basis of the co-primary end point of OS and rPFS. The invited discussant, Dr. Susan Halabi, Duke University, noted that although the reduction in the mortality hazard was significantly reduced, the improvement in OS did not reach prespecified definition of significance, particularly because of a termination that was based on the co-primary end points. She suggested that the early termination will confound and perhaps bias the final analyses.

Evaluating Appropriate Treatment Sequences

The results of COU-AA-302 and AFFIRM answer important questions about the value of effective hormone suppression to improve outcomes in CRPC. They will also provide the framework for pursuing new strategies to further expand on the activity of hormone suppression. Here at the 2012 ASCO, several studies pointed to new directions. For example, a multicentre team that included Canadian investigators provided an outline of a study that will test a neoadjuvant combination of leuprolide, dutasteride and enzalutamide after prostatectomy for intermediate- and high-risk cancer. In another study, a comparison of bicalutamide and enzalutamide is underway for control of metastatic CRPC.

In addition, studies evaluating the appropriate sequence of therapies are also underway. For example, a small study has tested the activity of abiraterone in metastatic CRPC patients already exposed to both docetaxel and enzalutamide. In this study of 24 patients taking abiraterone 1 g plus prednisone 10 mg/day, 5 patients had a PSA reduction while 3 patients had a PSA reduction >50%. The duration of the PSA response ranged from 2 to 4.5 months. Moreover, 6 patients had a symptomatic response. While 1 patient discontinued abiraterone due to edema and hypokalemia, the treatment was generally well tolerated.

“This study provides preliminary evidence that abiraterone can exert activity even in patients with metastatic CRPC who have received both docetaxel and enzalutamide,” reported Dr. Ecaterina Ileana, Institut Gustave Roussy, Villejuif, France. The differences in the underlying mechanism of action may explain how loss of efficacy with one hormonal treatment does not necessarily eliminate the potential for benefit from another. More studies to define the optimal sequence of such therapies are needed.

At a much earlier stage of disease, combination neoadjuvant hormone therapy with leuprolide/abiraterone was found to be well tolerated in localized high-risk prostate cancer. In a phase II study, outcomes were compared in 28 men on leuprolide acetate alone and in 30 men who received the combination. In results provided by Dr. Mary-Ellen Taplin, Dana Farber Cancer Institute, Boston, Massachusetts, those who received the combination were far more likely at 12 weeks to have a nadir PSA of <0.2 ng/Ml (90% vs. 4%; P<0.0001) although the difference was no longer significant at 24 weeks. Dr. Taplin also noted that the proportion of patients with a total or near pathologic complete response (34% vs. 15%; P=0.089) approached statistical significance. “These results support further evaluation of aggressive androgen deprivation as a neoadjuvant/adjuvant therapy for localized high-risk prostate cancer,” stated Dr. Taplin.


The ASCO organizers used the term “paradigm shift” in the title of the scientific session that featured the COU-AA-302 and AFFIRM trials. The title reflects the anticipated impact of these data. While the magnitude of the clinical benefit achieved in metastatic prostate cancer and docetaxel-experienced patients with abiraterone and enzalutamide, respectively, has been uncommon in modern cancer therapy trials, the data define an opportunity to control disease and improve QOL with well-tolerated and relatively simple regimens. The activity of these agents encourages further testing to refine algorithms most likely to suppress symptoms over extended periods of survival.   

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