Sternberg Showcases Promising PROSPER Data With Enzalutamide in Nonmetastatic CRPC

Cora N. Sternberg, M.D.

Enzalutamide (Xtandi) resulted in prolonged overall survival (OS) in patients with metastatic castration-resistant prostate cancer (CRPC) and a rapidly rising prostate-specific antigen in the phase 3 PROSPER trial, according to Cora N. Sternberg, MD, who added that the safety profile of the agent proved to be consistent with what has previously been reported.

Results of the final OS analysis from the randomized, double-blind, placebo-controlled study reported during the 2020 ASCO Virtual Scientific Program showed that treatment with enzalutamide resulted in a 27% reduction in the risk of death, which was found to be statistically significant. Specifically, the median OS in the enzalutamide arm (n = 933) was 67.0 months versus 56.3 months in the placebo arm (n = 468; HR, 0.73; 95% CI, 0.61-0.89; P = .001). Additionally, the time to first use of subsequent antineoplastic therapy was a median 66.7 months with enzalutamide/ADT versus 19.1 months with placebo/ADT (HR, 0.29; 95% CI, 0.25-0.34; P <.001).

“When we had the [updated] OS data for the analysis, we actually saw a 27% reduction in the risk of death in patients with nonmetastatic CRPC who received early enzalutamide as opposed to those who had subsequent therapies or subsequent enzalutamide after crossover,” said Sternberg. “This [translates] to an 11-month difference, an almost 1-year difference, in OS for those who received early enzalutamide.”

With regard to safety, all-grade adverse effects (AE) were reported in 94% of patients who received enzalutamide/ADT versus 82% of those who received placebo/ADT; grade 3 or higher AEs were reported in 48% versus 27%, respectively. Serious AEs were reported in 40% and 22% of those on the enzalutamide and placebo arms, respectively. Toxicities that resulted in treatment discontinuation were reported in 17% of those on the experimental arm versus 9% on the comparator arm.

In an interview with OncLive, Sternberg, Clinical Director of the Englander Institute for Precision Medicine, a Medical Oncologist and Professor of Medicine at Weill Cornell Medical College and an attending physician at NewYork-Presbyterian Hospital, discusses the data seen with enzalutamide in CRPC, and the updated survival results from the phase 3 PROSPER trial, and how she chooses among the agents available in the space.

OncLive: What are some of data that have been reported with enzalutamide thus far in prostate cancer? Could you provide some background to the PROSPER trial?

Sternberg: We first studied enzalutamide in the AFFIRM trial, in patients with metastatic CRPC, who had already [progressed on] docetaxel chemotherapy; these patients were pretty ill. The trial examined enzalutamide versus placebo in this population, and the agent was then approved for use in that setting. We then did a trial called PREVAIL, which was also for metastatic CRPC in patients who had no pain and were asymptomatic but did have metastatic disease. [Patients with] visceral disease were permitted [to enroll on] this trial, as opposed to the COU-AA-302 trial with abiraterone acetate (Zytiga). In PREVAIL, we also saw an improvement in OS in the patients who received enzalutamide as compared with placebo.

Two other trials, ARCHES and ENZAMET, have reported on [the use of this agent in] patients with metastatic hormone-sensitive prostate cancer. [Based on these data], enzalutamide has also become a standard of care in this space, as well.

[The PROSPER] trial was designed quite a while ago, and many companies have since been involved, but I was one of the initial investigators who helped design the trial. Essentially, it was designed for patients with nonmetastatic CRPC and a PSA doubling time of 10 months or less; they had to be rapidly progressing in terms of PSA. A total of 1401 patients were randomized 2:1 to receive ADT in combination with either enzalutamide 160 mg daily or placebo.

An open-label extension trial was then done, after we had the data on metastasis-free survival (MFS) that were presented at the 2018 Genitourinary Cancers Symposium. Patients who were on the placebo arm were able to cross over to the enzalutamide therapy and this occurred in 87 patients. There was some confusion as to how many patients actually received subsequent therapies. At least 1 subsequent therapy was received by 84% of patients when including the patients who crossed over to active enzalutamide.

In 2018, we presented the primary end point, which was MFS, and we saw a 71% reduction; that was why the amendment was instituted and cross over occurred for patients who were still on placebo to active enzalutamide. That was the major end point, but even though we saw [a good] MFS, a very long time to subsequent chemotherapy, and a much better PSA response, people were anxious to see the OS data. These OS data showed a 27% reduction in the risk of death in patients who were given early enzalutamide.

In terms of safety, were any changes noted with the longer follow-up?

No new data were reported; what we saw was similar to what has been reported in the many trials that have examined enzalutamide. You have to remember that when you look at safety, for instance in the PROSPER study, the median duration of treatment on the enzalutamide arm was 33.9 months; in the placebo arm, it was only 14.2 months. You are almost comparing apples with oranges in terms of length of treatment in evaluating safety. The incidence of AEs within the first 3-6 months was higher in the enzalutamide group, but when you adjust for 100 patient-years, the incidence is very similar.

Given all of the agents available in this setting, how do you choose among them?

It is not easy to do comparisons among the different trials. There's definitely less experience with darolutamide (Nubeqa) than there is with enzalutamide. Apalutamide is very similar to enzalutamide but there's less experience than with the former. Darolutamide, has only been approved for use in patients with nonmetastatic CRPC.

[These agents] all have pretty similar results in terms of MFS. All 3 trials—SPARTAN, PROSPER, and ARAMIS—have shown similar results in terms of OS. The patient populations are not exactly identical [between the trials], and neither are the placebo arms. That's why it's so dangerous to look between trials. The reporting of adverse events, in the way they were reported, or the time that patients are on the study, may not be identical either. You have to be very cautious when looking across different trials.

However, darolutamide is definitely different and the claim is that it doesn't cross the blood–brain barrier, which can be important in these elderly patients. As such, we need more data and more time to understand whether the agent really is better or not. Ongoing trials in which patients are randomized between darolutamide and enzalutamide were designed to answer this question.

Reference

Sternberg CN, Fizazi K, Saad F, et al. Final overall survival (OS) from PROSPER: a phase III, randomized, double-blind, placebo (PBO)-controlled study of enzalutamide (ENZA) in men with nonmetastatic castration-resistant prostate cancer (nmCRPC). J Clin Oncol. 2020;38(suppl 15):5515. doi:10.1200/JCO.2020.38.15_suppl.5515