Are new antiandrogens the gold standard for treatment of nonmetastatic castration-resistant prostate cancer (nmCRPC)? Three novel androgen receptor inhibitors provide an embarrassment of riches when it comes to treatment options for nmCRPC patients, but there are still questions to be answered—including the extent of these drugs’ clinical benefit.
The approvals of apalutamide (Erleada) in February 2018, enzalutamide (XTANDI) in July 2018, and darolutamide (Nubeqa) in July 2019 for the nmCRPC indication were the first moves away from a “watch-and-wait” approach for managing patients with nmCRPC.
Prior to the availability of these antiandrogens for nmCRPC, “It was a dealer’s choice approach of what to do, with no clear guidelines,” said Leonard G. Gomella, MD, professor and chair of urology at Thomas Jefferson University and senior director for clinical affairs at the Sidney Kimmel Cancer Center, Philadelphia.
“We didn’t really have a good option for treatment, which meant physicians waited for something bad to happen. We’d wait for patients’ PSA to shoot up; we’d image them; and the minute we saw signs of metastasis, we would begin metastatic castration-resistant prostate cancer treatment.”
One-third of patients with nmCRPC develop metastases within 2 years.
Now, phase III clinical trials including the SPARTAN study, a trial of apalutamide; PROSPER, a study of enzalutamide; and ARAMIS, a study of darolutamide, are changing the landscape for nmCRPC by presenting options for prolonging metastasis-free survival—the endpoint that formed the basis for FDA approval of these three agents for nmCRPC.
“These drugs fulfill an unmet need for treatment of nonmetastatic castration-resistant prostate cancer,” Dr. Gomella said.
The use of metastasis-free survival as a study endpoint has drawn questions. “There’s no proven clinical benefit associated with an improvement in metastasis-free survival per se,” said Philip Kantoff, MD, chairman of medicine at Memorial Sloan Kettering Cancer Center, New York. “The clinical benefits for this subset of patients should be measured in delayed symptoms referable to their cancer or an improvement in overall survival.”
And while data from recent studies are very encouraging, “We don’t have the long-term data to say definitively that prolonged metastasis-free survival significantly increases overall survival,” Dr. Gomella said.
As a result, there is still a need to exercise caution in using these drugs in the context of treating nmCRPC patients, Dr. Kantoff said.
“You’re treating patients who are asymptomatic, sometimes elderly, with drugs that have side effects. They’re going to feel less well than they did before they were treated with the hope that it eventually leads to clinical benefit,” Dr. Kantoff said.
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