Dr. Dorff on the Investigation of PARP Inhibitors in mCRPC

Tanya Dorff, MD, medical oncologist, associate clinical professor, Department of Medical Oncology & Therapeutics Research, City of Hope, discusses the investigation of PARP inhibitors in metastatic castration-resistant prostate cancer (mCRPC).

New data have presented clinicians with the idea of utilizing PARP inhibitors in combination with androgen receptor (AR) inhibitors in patients with mCRPC, irrespective of homologous recombination repair (HRR) mutation status, Dorff says. Updated data from the phase 3 PROpel trial (NCT03732820) presented at the 2022 ESMO Congress showed that patients treated with olaparib (Lynparza) plus abiraterone acetate (Zytiga) and prednisone or prednisolone experienced a median radiologic progression-free survival (rPFS) of 25.0 months, compared with 16.4 months for those given abiraterone acetate and prednisone or prednisolone alone.

Although the phase 3 MAGNITUDE trial (NCT03748641) of niraparib (Zejula) plus abiraterone acetate vs abiraterone acetate alone was positive for patients with HRR gene alterations, the study did not demonstrate a benefit in the biomarker unselected population. However, the phase 3 TALAPRO-2 trial (NCT03395197) evaluating talazoparib (Talzenna) combined with enzalutamide (Xtandi) in patients with mCRPC with or without HRR gene mutations met its primary end point of rPFS. Detailed data from the trial are expected in the near future.

Notably, these trials have largely been conducted in patients who have not been exposed to AR targeted agents, according to Dorff, who adds that patients who receive AR inhibition as part of up-front intensification are not the same population patients who were enrolled on these trials. Therefore, clinicians will have to better understand how to work these regimens into practice and if patients who have received prior treatment with an AR inhibitor will derive a similar benefit from a PARP inhibitor, Dorff notes.

Future investigations could explore PARP inhibitor–based combinations in the up-front setting, either in patients with HRR gene mutations or biomarker unselected populations, Dorff concludes.