Emerging Treatment for nmCRPC

Matthew R. Smith, MD, PhD:Androgen pathway inhibitors have an established role in the management of patients with metastatic CRPC. Abiraterone acetate and enzalutamide, for example, are both approved based on increases in progression-free and overall survival in men with metastatic CRPC both in the pre- and postchemotherapy disease states. We believe that the biology of nonmetastatic CRPC and CRPC is largely overlapping, and there are very strong phase II data that androgen pathway inhibitors—including abiraterone, enzalutamide, and apalutamide—have high PSA response rates and durable responses in that setting.

The SPARTAN study is a phase III global, placebo-controlled randomized trial in men with nonmetastatic CRPC who are at high risk for disease progression based on a PSA doubling time of less than 10 months. The study enrolled more than 1200 men throughout the world. They were randomized in a 2:1 fashion to either apalutamide or placebo. All men continued standard androgen deprivation therapy.

The primary study endpoint was metastasis-free survival, or MFS. MFS was defined as time from randomization to development of detectable metastasis or death from any cause.

Compared to placebo, treatment with apalutamide was associated with a marked improvement in the primary study outcome. Apalutamide decreased the risk of metastasis or death by 72% and improved the median metastasis-free survival from 16 months to more than 40 months, a greater than 2-year improvement in metastasis-free survival. That striking improvement and primary outcome was also supported by evidence from a variety of supporting secondary and exploratory analyses. Apalutamide improved time to symptomatic progression. It delayed time to a second progression-free survival. And it was also associated with a longer overall survival and time to chemotherapy, although the latter 2 outcomes were an interim analysis, and we’ll await the final results based on additional events with the future analysis of the study.

Apalutamide was well tolerated in the SPARTAN study. There were very few treatment discontinuations due to adverse effects. Compared to placebo, the important differences associated with apalutamide were greater rates of rash, hypothyroidism, and falls and fractures.

In total, I think this evidence from the SPARTAN study makes apalutamide a new standard of care for nonmetastatic CRPC. This is a meaningful improvement in metastasis-free survival with strong supportive evidence from time to symptomatic progression, PFS2, and a trend towards better overall survival, and this is an oral drug that was generally very well tolerated.

Transcript edited for clarity.