Is a Brighter Future Possible for PARP Inhibitor Use in Prostate Cancer?

Poly ADP-ribose polymerase (PARP) inhibitors are a cornerstone of treatment in ovarian cancer—with 3 treatments currently approved for use in this setting—and have been successfully used in patients with breast cancer. More recently, mounting evidence has supported the use of PARP inhibitors in prostate cancer, according to a new study.

Growing interest in the potential of PARP inhibitors in metastatic castration-resistant prostate cancer (mCRPC) stems from recent efforts of next-generation sequencing, which have unveiled that DNA damage repair gene defects are more common in these patients than traditionally thought.

“The introduction of PARP inhibitors for the treatment of patients with mCRPC is a milestone towards precision oncology for men with prostate cancer, where biomarkers for patient stratification have largely been missing,” emphasized the researchers. “Results of ongoing studies will show which PARP inhibitor has the best clinical efficacy and toxicity profile.”

In May, the FDA gave the nod to olaparib for patients with mCRPC and pathogenic or likely pathogenic germline or somatic homologous recombination-mediated repair (HRR) gene defects who have progressive disease under a second- generation antihormonal drug. The approval was based on the phase 3 multicenter PROfound study, which showed a survival benefit associated with olaparib compared with enzalutamide or abiraterone (progression-free survival [PFS], 7.4 vs 3.6 months, respectively) and a higher objective response rate (33% vs 2%).

Rucaparib has FDA approval for use in patients with mCRPC with confirmed deleterious germline or somatic mutations in BRCA1 or BRCA2 and who have been previously treated with an antihormonal agent and taxane-based chemotherapy after demonstrating a 47.5% objective response in preliminary results of the TRITON2 trial. More than half (53.6%) of patients also saw a prostate-specific antigen decrease of ≥50%.

A third PARP inhibitor, niraparib, is currently being studied in a phase 2 multicenter trial of patients with mCRPC who have biallelic DNA damage repair gene defects. Interim analysis data showed that patients with biallelic BRCA1/2 defects had a 41% objective response rate (ORR) and a 63% complete response (CR), whereas just 9% of non-BRCA patients had an ORR and 17%, a CR.

“While there is emerging evidence that patients with BRCA1 or BRCA2 inactivation have the most benefit from PARP inhibitor therapy, very little is currently known about genes with lower prevalence such as PALB2 or FANCA,” wrote the researchers. “Since cohort size is a limiting factor for clinical trials assessing this problem, it may therefore be of interest to use mutational signatures or functional biomarkers to identify tumors with defective HRR.”

There are also current studies assessing the benefit of combination therapies with PARP inhibitors. For example, targeting PARP inhibition and inhibition of the androgen receptor pathway. The researchers pointed to a study using olaparib in combination with abiraterone that showed significantly longer PFS for the combination compared with abiraterone and placebo (13.8 vs 8.2 months).

The researchers also predict that research will shift toward earlier stages of the disease, with several studies looking at the efficacy and safety of PARP inhibitors in metastatic hormone-sensitive prostate cancer or in the neoadjuvant setting in locally advanced prostate cancer.

Reference

Nientiedt C, Duensing A, Zschäbitz S, et al. PARP inhibition in prostate cancer. Gene Chromosome Canc. Published online October 21, 2020. doi:10.1002/gcc.22903