Advanced Prostate Cancer in 2018: A Look Ahead/Part 2—Nonmetastatic Castrate-Resistant Prostate Cancer
This year, 2018, has already been quite an eventful year in castrate-resistant prostate cancer (CRPC). New data presented at the GU ASCO meeting last month demonstrated two impactful agents in the nonmetastatic (M0) CRPC patient. The M0 space had previously been an empty space in advanced prostate cancer clinics—these men were limited to repeat evaluation with imaging or clinical trial enrollment. A certain subset had adverse-risk features—rapid PSA doubling times and/or rapid emergence of the castrate-resistant phenotype—but still were unable to be treated given negative imaging. Based on this, emphasis over the last few years has turned to novel imaging markers (NaF, fluciclovine [Axumin], choline, PSMA) to “convert” some of these patients into treatable M1 patients. These agents, especially fluciclovine and PSMA, have improved the sensitivity of documenting metastases at lower PSA levels, but they have been slow to garner widespread approval and insurance coverage. These limitations have precluded their use in some areas of the country.
Progress in the M0 space has been slow because of limited clinical trial focus. The FDA emphasis on overall survival as an endpoint for cancer therapies makes approval of systemic drugs in earlier stages of prostate cancer difficult. The investment in time and financial resources for a pharmaceutical sponsor have been prohibitive given the average patent lifespan of a new drug. The international Intermediate Clinical Endpoints in Cancer of the Prostate (ICECaP) Working Group was assembled to determine new endpoints that could clear the path for less burdensome clinical trials to be performed. Indeed, the ICECaP group found in assessing trial data in over 28,000 patients with localized prostate cancer that metastasis-free survival was a strong surrogate for overall survival in 2017.1 The net result has been an accelerated look into newer agents that may be applied earlier in the disease course (a concept which has both pros and cons, as have been well-documented by recent mainstream medical commentaries).
This year at GU ASCO, two studies—SPARTAN (apalutamide) and PROSPER (enzalutamide)—demonstrated a significant delay in metastasis for men with early (M0) CRPC. Apalutamide, a competitive antagonist of the androgen receptor (similar to enzalutamide) has been anticipated due to possible lower central nervous system side effects secondary to its pharmacology. SPARTAN showed a 72% decrease in the risk of metastasis or death compared with placebo, and prolonged median metastasis-free survival by 2 years. Enzalutamide, approved for men with metastatic CRPC, showed very similar results in the M0 population during PROSPER. Importantly, men in these trials were higher risk based on PSA doubling times less than 10 months. A few days after the ASCO meeting concluded, apalutamide was approved for M0 CRPC under the trade name Erleada by the FDA. This approval was based on the SPARTAN study results, and, according to an FDA representative, “demonstrates the agency’s commitment to using novel endpoints to expedite important therapies to the American public.” Clearly, things are moving fast, and an enzalutamide approval in this space will likely be coming soon based on PROSPER. Long-term analyses will hopefully confirm that delaying metastasis in these men can lead to an improvement in overall survival. At this interval analysis, the overall survival data for both drugs were not mature and were only trending toward significance.
Successful application of these new M0 treatments will hinge on physician understanding and counseling based on the endpoint of metastasis-free survival. Even the best therapies we have in the metastatic CRPC setting prolong survival by 1 year, and it is unclear if these newer endpoints translate to similar efficacy. The marketing around these drugs will focus on an “unmet need” or “an absence of current therapies in this space,” but there is some skepticism of earlier treatment with these agents. As with abiraterone use for men with hormone-sensitive metastatic cancer (recently approved by the FDA, but overshadowed by the apalutamide approval), clinical concerns exist and will focus on morbidity and overtreatment. In both PROSPER and SPARTAN, drug discontinuation was about 10% and serious adverse effects were seen in 20% to 25% of men. This is a substantial rate of side effects in a patient population that is largely asymptomatic. Is this therapy best for men with rapid PSA doubling times or should it be given to all men with M0 disease? Will M0 treatment compromise therapies shown to prolong survival once a man has progressed to M1? Lastly, will the M0 space even be significant in a few years given anticipated changes in novel imaging markers? Those answers are coming, probably faster than we think. For now, physicians treating advanced prostate cancer have a labeled treatment for M0 disease for the first time.
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