The OBR Blog

June 02, 2012 - 02:06 pm Posted in Featured comments3 Comments

By Stephanie Hawthorne, PhD, Director, Commercial Development, Kantar Health

The most anticipated data in prostate cancer at ASCO 2012, and one of the most anticipated data overall at the conference, is that of the COU-302 trial of Zytiga (abiraterone acetate; Johnson & Johnson) in chemotherapy-naïve metastatic castrate-resistant prostate cancer (mCRPC). Zytiga quickly established itself as standard of care in second-line CRPC following its approval in 2011, but its favorable safety profile and high level of efficacy have prompted a wide desire to move the drug into earlier lines of therapy, specifically prior to chemotherapy. The data presented in this morning’s Clinical Science Symposium (“New Paradigms for Hormone Therapy in Prostate Cancer”) didn’t disappoint.

The randomized Phase III COU-AA-302 trial was designed to investigate the use of Zytiga in chemotherapy-naïve mCRPC patients. Asymptomatic or minimally symptomatic (defined as not requiring opiate analgesics for > 1 month prior to the trial) patients (n=1098) were randomized to Zytiga + prednisone or placebo + prednisone. The co-primary endpoints of the trial are radiographic progression-free survival (rPFS) and overall survival (OS). The trial was halted at its second interim analysis in February 2012, and the data presented represent approximately 40% of the expected OS events. The rPFS was significantly improved in the Zytiga arm (median rPFS: placebo = 8.3 months; Zytiga = not reached; HR = 0.43; p<0.0001), with early and sustained separation of the Kaplan-Meier curves. There was a statistical trend towards an increased OS, although the median has not yet been reached in the Zytiga-prednisone arm (median OS: placebo = 27.2 months; Zytiga = not reached; HR = 0.75; p=0.0097 – did not reach the specified a level). There were also significant improvements in the Zytiga arm in all secondary endpoints (time to opiate use, time to chemotherapy, time to ECOG Performance Status deterioration, and time to PSA progression). Zytiga was well-tolerated in patients, although patients in the Zytiga arm have a greater incidence of Grade 3/4 adverse events related to mineralocorticoid excess (ALT increased: 0.8% vs 5.4%; AST increased: 0.9% vs 3.0%).

Although the rPFS results are exciting, this is the first time that rPFS has been used as one of the primary endpoints in a Phase III study in prostate cancer, and the clinical benefit of this endpoint is still a subject of investigation. Does a rPFS provide meaningful benefit to a patient, compared to observation alone, Provenge (sipuleucel-T, Dendreon; already approved in this same setting), or immediate chemotherapy? The answer is currently being debated in the scientific community, but if development of pain and need for chemotherapy can be significantly delayed this adds greater weight to rPFS as a surrogate endpoint. Because the FDA has historically approved new agents in this setting based on OS, the OS results at the final analysis will be critical. Because the trial has been unblinded and patient crossover is now allowed, it is possible that the OS effect will become diluted during the remainder of the trial. However, statistical analysis conducted by discussant Dr. Halabi looks very promising for the trial to eventually demonstrate a significant OS benefit. Physicians in this morning’s session appear uniformly excited about the establishing Zytiga as a new standard of care in the chemotherapy-naïve setting.

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