Men who have metastatic castration-resistant prostate cancer (mCRPC) and certain altered DNA repair genes may benefit more from olaparib, a drug that inhibits an enzyme involved in DNA repair, than from newer antiandrogen medications, according to study findings presented at the European Society for Medical Oncology (ESMO) 2019 Congress in Barcelona, Spain.

Data from the phase 3 PROfound trial showed that olaparib, an inhibitor of poly-ADP ribose polymerase (PARP), slowed cancer progression by about 4 months compared with enzalutamide or abiraterone, lead investigator Maha Hussain, MD, of Robert H. Lurie Comprehensive Cancer Center at Northwestern University in Chicago, reported. In addition, olaparib-treated patients experienced decreased time to pain progression and a higher objective response rate (ORR) compared with enzalutamide or abiraterone recipients.

The open-label trial included 387 mCRPC patients whose cancer progressed while on prior treatment with the novel antiandrogens or chemotherapy. Investigators divided the men into 2 cohorts (A and B) based on their alterations in DNA repair genes. Cohort A included 245 men with alterations in BRCA1, BRCA2, and ATM genes, and Cohort B included 142 men with alterations in other genes known to be involved with DNA repair. Of the patients in Cohort B, 65.6% received prior taxane treatment. Investigators randomly assigned patients in both cohorts to receive olaparib or a physician’s choice of either enzalutamide or abiraterone. The primary end point was radiographic progression-free survival (rPFS) in Cohort A.

In Cohort A and in the overall study population (both cohorts), olaparib recipients experienced significantly improved rPFS compared with the antiandrogen-treated patients. In Cohort A, median rPFS was 7.39 months in the group treated with olaparib compared with 3.55 months among NHA recipients. Olaparib recipients had a significant 66% decreased risk of radiographic progression compared with antiandrogen-treated patients. The proportion of patients free of radiographic progression at 12 months was 28.11% and 9.40%, respectively.

Median rPFS in the overall study population was 5.82 months for olaparib recipients compared with 3.52 months for antiandrogen-treated patients. Olaparib-treated patients had a significant 51% decreased risk of radiographic progression compared with antiandrogen recipients. The 12-month rate of freedom from radiographic progression was 22.13% and 13.47%, respectively.

“To see such a significant effect on disease progression and other clinically relevant effects such as pain progression and object response rate is a remarkable achievement in such heavily pre-treated patients with prostate cancer,” Dr Hussain said in an ESMO news release.

An interim overall survival analysis showed that median OS was significantly longer with olaparib than with antiandrogens in Cohort A (18.5 vs 15.1 months) and the overall study population (17.51 vs 14.26 months).

In Cohort A, the median time to pain progression was nearly 10 months in the antiandrogen-treated patients and not reached among olaparib recipients. In the overall study population, the median time to progression was not reached in patients who received either treatment.

The confirmed ORR was significantly higher among olaparib than antiandrogen recipients in Cohort A (33.3% vs 2.3%) and the overall study population (21.7% vs 4.5%).

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According to Dr Hussain and her colleagues, adverse events (AEs), including anemia, nausea, decreased appetite, and fatigue, occurred more frequently with olaparib than with the antiandrogens, although median treatment duration was longer with olaparib than the antiandrogen (7.4 vs 3.9 months). The olaparib group had more treatment discontinuations due to AEs than the antiandrogen-treated patients (16.4% vs 8.5%).

Reference

Hussain M, Mateo J, Fizazi K, et al. PROfound: Phase III study of olaparib versu enzalutamide or abiraterone for metastatic castration-resistant prostate cancer (mCRPC) with homologous recombination repair (HRR) gene alterations. Presented at the European Society for Medical Oncology annual congress held September 27 to October 1 in Barcelona, Spain. Abstract LBA12_PR.

https://oncologypro.esmo.org/Meeting-Resources/ESMO-2019-Congress/PROfound-Phase-3-study-of-olaparib-versus-enzalutamide-or-abiraterone-for-metastatic-castration-resistant-prostate-cancer-mCRPC-with-homologous-recombination-repair-HRR-gene-alterations