Alicia Morgans, MD, MPH: Nonmetastatic castration-resistant prostate cancer [CRPC] is an entity that we’ve actually created clinically by treating patients with hormonal deprivation when they don’t have metastatic disease. They just have biochemical recurrence. Nonmetastatic CRPC occurs when we continue to treat patients with hormonal deprivation and PSA [prostate-specific antigen] levels start to rise despite a castrate level of testosterone. These patients, on reimaging, don’t have metastatic disease. Reimaging, importantly, is a standard bone scan and CT [computed tomography] scan.
There are about 50,000 to 60,000 patients in the United States estimated to have new, nonmetastatic CRPC each year. This estimate is actually changing over time, as imaging becomes more nuanced and more sensitive and capable of detecting metastatic disease. We think about the risk assessment of nonmetastatic CRPC by really considering the PSA doubling time. As the PSA doubling time gets shorter and shorter, these patients become higher risk of developing metastatic disease and, ultimately, dying from their prostate cancer.
Matthew R. Smith, MD, PhD: In February 2018, apalutamide was approved by the US Food and Drug Administration for the treatment of men with nonmetastatic castration-resistant prostate cancer. That approval was based on the results of the pivotal SPARTAN trial. SPARTAN is an international, randomized phase III study to compare the effects of apalutamide versus placebo with ongoing androgen deprivation therapy in men with nonmetastatic castration-resistant prostate cancer.
The study enrolled a total of 1207 patients. Patients were randomized 2:1 to apalutamide versus placebo. The primary endpoint was metastasis-free survival [MFS]. There were a variety of other important secondary endpoints. Compared with placebo, apalutamide significantly improved median metastasis-free survival by more than 2 years and reduced the risk of metastasis or death by 72%. Apalutamide also significantly improved time to symptomatic progression, 1 of the key secondary endpoints. Collectively, this information led to the regulatory approval of apalutamide in this setting.
The final analysis for overall survival in SPARTAN is event driven and will occur after a total of 427 deaths. At the time of the primary analysis for metastasis-free survival, the overall survival data were immature—with only 104 events, or about a quarter of events acquired for the final overall survival analysis. So we performed a prespecified interim analysis, interim analysis 2, and reported at this meeting to get a better understanding of the impact of apalutamide on survival in this patient population.
The second interim analysis reported at this meeting was prespecified and event driven. It occurred after a total of 285 events, or about 67% of the number of events required for the final survival analysis. At the time of this analysis, we had much longer follow up—41 months’ follow-up compared with only 20 months follow up at the primary MFS analysis. We found that compared with placebo, apalutamide reduced the risk of death by 25%. The hazard ratio was 0.075, with confidence intervals that did not cross 1. Although close, the study didn’t quite reach statistical significance because it had very strict P value boundary for sequential testing. So the study follow-up will continue per protocol, and the final analysis for overall survival will occur after 427 events have been observe
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