Olaparib plus abiraterone significantly delays progression in frontline mCRPC

Adding olaparib (Lynparza) to standard frontline abiraterone acetate (Zytiga) significantly improved radiographic progression-free survival versus (rPFS) abiraterone alone in patients with metastatic castration-resistant prostate cancer (mCRPC), regardless of homologous recombination repair (HRR) gene mutation status, according to findings from the phase 3 PROpel trial.1

The results, which came from an interim analysis of the study, also showed a trend toward improved overall survival (OS) with the combination of the PARP inhibitor and novel hormonal agent; however the data remain immature and the OS analysis remains ongoing.

There were no new safety or tolerability signals with either agent compared to the toxicity profiles of either agent established in prior trials.

No specific data have been released yet, with the findings targeted to be presented at a future medical conference.

Overall, the double-blind, multicenter phase 3 PROpel trial assessed the efficacy and safety of frontline abiraterone plus either olaparib or placebo in patients with mCRPC who had no prior chemotherapy or treatment with a novel hormonal agent in the frontline mCRPC setting. Patients in both arms also received prednisone or prednisolone twice daily.

The study enrolled an all-comer population of patient with or without HRR gene mutations. Prior docetaxel was allowed if it was administered in a disease stage prior to the mCRPC setting. Prior novel hormonal agents (other than abiraterone) were allowed in earlier disease stages, provided that the treatment had stopped ≥1 year from the patient’s randomization in the frontline mCRPC setting. All men had an ECOG performance status of 0-1. The primary end point was rPFS.

“We are encouraged by the PROpel results and the clinical benefit Lynparza in combination with abiraterone demonstrated versus abiraterone alone as a 1st-line treatment option for men with metastatic castration-resistant prostate cancer. Today’s results build on MSD and AstraZeneca’s commitment to bring Lynparza earlier in lines of treatment and to more patients with advanced prostate cancer,” Roy Baynes, senior vice president and head of Global Clinical Development, Chief Medical Officer, Merck (MSD) Research Laboratories, stated in a press release.

FDA approval of olaparib

The FDA approved olaparib in May 2020 for the treatment of adult patients with deleterious or suspected deleterious germline or somatic HRR gene-mutated metastatic mCRPC who have progressed following prior treatment with enzalutamide or abiraterone.

The approval was based on findings from the phase 3 PROfound trial, in which there was a significant benefit in PFS with olaparib compared with abiraterone acetate or enzalutamide (Xtandi) in men with mCRPC who on progressed on a novel hormonal agent.

There were 2 cohorts in the PROfound study. In cohort A, patients had alterations in BRCA1/2 or ATM (n = 245), which are more established markers of HRR. In cohort B (n = 142), patients had an alteration in BARD1, BRIP1, CDK12, CHEK1/2, FANCL, PALB2, PPP2R2A, RAD51B/C/D, or RAD54L, which are all associated with HRR but not as established as those in cohort A. Within each cohort, patients were randomized 2:1 to olaparib or physician's choice of abiraterone plus prednisone or enzalutamide.

Results from the PROfound trial reported subsequent to the FDA approval showed that olaparib also improved OS versus abiraterone and enzalutamide.2 In cohort A the median OS was 19.1 months versus 14.7 months with olaparib versus abiraterone or enzalutamide, respectively (HR, 0.69; P = .02). In cohort B the median OS was 14.1 versus 11.5 months respectively.

Beyond the abiraterone regimen, olaparib is also being explored in other combinations, including with the immunotherapy agent pembrolizumab (Keytruda).

References

1. Lynparza in combination with abiraterone significantly delayed disease progression in all-comers in PROpel Phase III trial in 1st-line metastatic castration-resistant prostate cancer. Published online September 24, 2021. Accessed September 24m 2021. https://bit.ly/3lOzmdq.

2. M. Hussain, J. Mateo, K. Fizazi, et al. Survival with olaparib in metastatic castration-resistant prostate cancer. N Engl J Med. 2020;383:2345-2357. doi:10.1056/NEJMoa2022485.