The novel drug enzalutamide (formerly MDV3100) significantly improved overall survival in men with metastatic castrate-resistant prostate cancer (mCRPC), according to the results of a phase III study that were published in the New England Journal of Medicine
The study demonstrated the largest overall survival benefit ever recorded in a post-chemotherapy setting for mCRPC, confirmed Howard I. Scher, MD, chief of the Genitourinary Oncology Service at Memorial-Sloan Kettering Cancer Center in New York and co-principal investigator and lead author of the AFFIRM study.
If approved, he said, enzalutamide will treat patients in the final stages of prostate cancer whose disease has progressed after treatment with hormones and chemotherapy, and for whom there is currently no standard of care.
“It does not have the side effects of chemotherapy, and it can benefit them in many ways: pain, function, and preventing some of the complications of cancer—in the bone, in particular—as well as enabling them to live longer,” Scher said. “Another advantage is that patients don’t need to take enzalutamide with steroids, which have their own side effects: potential bleeding and loss of muscle mass and bone.”
The international, randomized, double-blinded AFFIRM trial tested the novel oral androgen receptor signaling inhibitor in mCRPC patients previously treated with docetaxel-based chemotherapy.
The trial randomized 1199 men in a 2:1 ratio to receive either once-daily, oral enzalutamide monotherapy or placebo. Participants treated with enzalutamide had a median overall survival of 18.4 months (95% confidence interval [CI], 17.3 to not yet reached), compared to 13.6 months (95% CI, 11.3 -15.8) for those treated with placebo (hazard ratio 0.63; 95% CI, 0.53-0.75; P=< .0001). That translates into a 37% reduction in the risk of death for men in the study’s enzalutamide arm.
Because it met its primary endpoint of overall survival, the study was stopped early, in November 2011, after a planned interim analysis.
While men in the enzalutamide group had higher rates of fatigue, diarrhea, and hot flashes, and seizures were reported in five patients receiving enzalutamide, serious adverse events were lower in the experimental group than in the placebo group. Furthermore, the study’s authors reported, those in the enzalutamide group gained a median of 8.4 months, as compared to men in the placebo group, before experiencing an initial adverse event of grade 3 or higher, due to better control of their disease-related symptoms.
In addition to demonstrating prolonged survival, Scher said, the trial was significant because it validated the concept that the androgen receptor remains active in mCRPC patients who have castrate levels of testosterone, meaning that their tumors are not refractory to hormone therapy.
“It shows the importance of the molecular profiling of cancers, because that’s what led to the discovery that there was too much of the receptor,” the doctor said. “It shows that, if you have a rationally designed drug against a target that drives the cancer, patients will benefit.”
Scher, who was also a lead investigator in the phase III trial of the recently approved hormonal prostate-cancer treatment abiraterone (Zytiga), said he anticipates that a large study considering that drug in combination with enzalutamide will be performed in the near future.
“One lowers the amount of testosterone and the other blocks binding of testosterone to the receptor itself, so you’d postulate that there will by synergy,” he said. “Whether one is better than the other we don’t know.”
A trial of enzalutamide in the first-line setting in patients who are hormone-therapy naïve has begun in Europe, Scher added.
“A drug like this will ultimately be used earlier in the treatment of prostate cancer,” he said. “That is where, ultimately, it will find its true home.”
Medivation, Inc. and Astellas Pharma Inc., which are collaborating in the development of enzalutamide, announced on July 24 that the FDA had accepted a new drug application for review of the drug, and granted the application priority review designation. The FDA expects to return its decision on the application by Nov. 22, Scher said.
Scher HI, Fizazi K, Saad F, et al. Increased Survival with Enzalutamide in Prostate Cancer after Chemotherapy [Published online ahead of print August 15, 2012]. N Engl J Med. 2012. DOI: 10.1056/NEJMoa1207506.