COMMENTARY

Apalutamide's Approval for Prostate Cancer Beneficial but Raises New Questions

Gerald Chodak, MD

Disclosures

March 15, 2018

Hello. I'm Dr Gerald Chodak for Medscape. Today's topic is a new antiandrogen for the treatment of men with nonmetastatic, castration-resistant prostate cancer.

Smith and colleagues[1] reported results of a clinical trial comparing apalutamide with placebo in the New England Journal of Medicine. This randomized study involved a large group of patients with negative bone scan and CT scan at enrollment. In addition, they had to have a high risk of developing metastatic disease based on a prostate-specific antigen (PSA) doubling time of < 10 months [during continuous androgen-deprivation therapy]. Patients were randomized 2:1 to apalutamide 240 mg or placebo. If patients progressed, they could receive secondary treatment with abiraterone acetate and prednisone.

The study reported a statistically significant reduction in the development of metastatic disease or prolongation of time to metastases associated with apalutamide compared with placebo (40.5 months vs 16.2 months, respectively). Other secondary endpoints also were significantly favorable for the apalutamide group. Significant side effects included hypothyroidism, fracture, and rash. However, this only resulted in about a 3.5% greater risk of discontinuing the study.

This appears to be an excellent study in favor of this new antiandrogen. Perhaps the most significant problem to the study, however, is that we now know that CT scan and bone scan will miss a significant number of metastatic sites that can be identified using a PET scan. One has to wonder what would have happened if the men had been screened with a PET scan, either in addition to or instead of using the CT scan and the bone scan. The authors acknowledged this problem. They think that it still would result in a significant benefit in favor of the apalutamide because all of the secondary outcomes were in favor of the apalutamide group and all of the subgroups benefited.

A secondary problem, however, is that another study,[2] using enzalutamide in the same group of patients, also found a statistically significant benefit and is likely to get approval in the near future. If some of the men being treated did indeed have metastatic disease, we have to consider whether they would benefit best from apalutamide or enzalutamide, or if giving them chemotherapy would be a better approach. Without doing additional randomized trials, that answer won't be known.

Another interesting factor is that the US Food and Drug Administration has given approval without [research] proving an overall survival benefit. If that is going to be the new paradigm, it may result in other drugs getting approved at an earlier point in time and coming to market before proving overall survival.

The bottom line is that this is a significant improvement and opportunity for men who have nonmetastatic disease with a rising PSA. Until we have more data, there will still be some unanswered questions. I look forward to your comments. Thank you.

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