Enzalutamide edges out abiraterone in mCRPC

In the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC), the use of enzalutamide yields small improvements in outcomes when compared with abiraterone acetate, according to a retrospective study from the US.

Analysis of data from 5,779 mCRPC patients (median age 74.42 years), with a median follow-up of 38–60 months, showed that overall survival (OS) was slightly longer among those who initiated enzalutamide than among those who started abiraterone acetate, with the restricted mean survival time (RMST) at 4 years being 24.29 and 23.38 months (difference, 0.90 months, 95 percent confidence interval [CI], 0.02–1.79), respectively. [JAMA Netw Open 2024;7:e2428444]

For prostate cancer–specific survival (PCS), the RMST in the enzalutamide group was longer by 0.25 months (95 percent CI, 0.09–0.42) at 1 year and by 0.48 months (95 percent CI, 0.01–0.95) at 2 years after treatment initiation than in the abiraterone group. No significant difference in the RMST at 3 or 4 years was observed. 

According to the investigators, the difference between enzalutamide and abiraterone acetate was more prominent for short-term outcomes and in patient subgroups with less aggressive prostate cancer (without prior docetaxel or with PSA doubling time ≥3 months).

Specifically, the RMST at 4 years was longer by 1.95 months (95 percent CI, 0.92–2.99) for time to next treatment switching or death (TTS) and was shorter by 3.57 months (95 percent CI, 1.76–5.38) for time to prostate-specific antigen (PSA) response (TTR) in the enzalutamide vs abiraterone group.

In the subgroup of patients with less aggressive disease, results for OS, TTS, and TTR at 4 years were more favourable with enzalutamide than with abiraterone. For instance, the RMST for OS at the said time point was longer by 1.14 months (95 percent CI, 0.19–2.10) among patients without prior docetaxel treatment and by 2.23 months (95 percent CI, 0.81–3.66) among those with PSA doubling time of 3 months or longer.

The reason for the slightly improved mCRPC outcomes with enzalutamide vs abiraterone acetate may lie in the differing mechanisms of action of the drugs, according to the investigators.

“Abiraterone acetate intensifies testosterone suppression and works upstream in the pathway, whereas enzalutamide blocks multiple downstream events, including AR nuclear translocation and transcription… [I]n some prostate cancers, AR is overactive or mutated independent of abiraterone acetate–targeted upstream events. The AR sequence variant may be resistant to upstream therapeutic targeting but still sensitive to enzalutamide,” they explained. [Nat Med 2004;10:33-39; N Engl J Med 1995;332:1393-1398; Nat Rev Cancer 2015;15:701-711]

Despite each drug’s unique mechanism of action, using the combination of enzalutamide plus abiraterone acetate in the first-line setting did not confer significant improvements in OS in a phase III trial. [J Clin Oncol 2023;41:3352-3362]”

“Our study reported results consistent with these earlier studies for shorter-term survival but added substantially longer follow-up, inclusion of individuals initiating treatment after 2017, evaluation of both chemotherapy-naive and nonchemotherapy-naive patients, and/or careful control of confounding through inverse probability of treatment weighting,” the investigators said.

“In addition to OS, we examined PCS, TTR, and TTS. This provided a holistic picture of disease trajectory and patient journey, with results suggesting the superiority of enzalutamide initiation over abiraterone acetate across different outcomes among patients with mCRPC,” they pointed out, adding that the findings may aid decisions about mCRPC treatment strategies.