PARP Inhibitors for Prostate Cancer: 5 Things to Know

 Prostate cancer is the second most common cancer in men worldwide, with nearly 1.4 million new cases diagnosed each year. PARP inhibitors have transformed the treatment landscape for biomarker‑selected metastatic disease, moving from experimental agents to a core option for a subset of men with advanced prostate cancer. By exploiting defects in DNA repair — particularly homologous recombination repair (HRR) alterations such as BRCA1 and BRCA2 — these drugs can deliver meaningful survival gains after progression on standard hormone‑directed therapies. But their use is not one size fits all: benefit depends on tumor genomics, indications remain restricted to metastatic settings, and class‑specific toxicities such as anemia demand close monitoring and dose adjustment.

Here are five things to know about currently approved PARP inhibitors for prostate cancer and the next‑generation agents now in clinical trials.

1. The FDA has approved four PARP inhibitors to treat metastatic castration-resistant prostate cancer (mCRPC) or metastatic castration-sensitive prostate cancer (mCSPC) with homologous recombination repair (HRR) gene alterations.

In May 2020, olaparib was approved by the FDA for patients with HRR gene-mutated mCRPC. In May 2023, the FDA approved olaparib with abiraterone and prednisone (or prednisolone) for adult patients with deleterious or suspected deleterious BRCA-mutated (BRCAm) mCRPC. 

In December 2025, the FDA granted regular approval to rucaparib for adults with a deleterious BRCA mutation (BRCAm) (germline and/or somatic)-associated mCRPC previously treated with an androgen receptor-directed therapy. Rucaparib was granted accelerated approval in 2020 for a similar indication. In June 2023, the FDA approved talazoparib with enzalutamide for HRR gene-mutated mCRPC.

In December 2025, the FDA approved niraparib and abiraterone acetate with prednisone for adults with deleterious or suspected deleterious BRCA2-mutated (BRCA2m) mCSPC.

2. PARP inhibitors block the PARP enzyme, which normally repairs single-strand DNA breaks, and the result is synthetic lethality.

When the PARP repair mechanism is blocked in cancer cells that already have faulty DNA repair pathways (such as BRCA1 or BRCA2 mutations), the cancer cells accumulate fatal DNA damage and die. 

Given the importance of PARP to repairing DNA, PARP inhibitors were originally designed to sensitize tumor cells to DNA-damaging agents. Later, single-agent cytotoxicity was demonstrated in cell lines with deleterious germline mutations in DNA repair genes including BRCA1 and BRCA2. This situation, where two genetic defects which by themselves pose little consequence to cell survival are exploited synergistically and pharmacologically to promote cell death, is termed synthetic lethality.

3. Although PARP inhibitors extend progression-free survival and sometimes overall survival in patients with prostate cancer, side effects, especially anemia, are prevalent and can lead to treatment discontinuation. 

For example, in the phase 3 TALAPRO-2 prostate cancer study, the most common severe or life-threatening treatment-emergent side effect during treatment with talazoparib/enzalutamide was anemia at 65.8%. Anemia caused 8.3% of patients to discontinue treatment and 43.2% of patients to receive a dose reduction.

In a review of 14 relevant studies involving 2066 patients with mCRPC treated with PARP inhibitors, the most common hematological toxicity was anemia, reported in 42% of patients. In the same review, the three most common nonhematological toxicities reported were nausea (43%), fatigue (34%), and anorexia (27%).

4. Several investigational PARP inhibitors are being studied. Among these are saruparib and senaparib.

Saruparib is a new-generation PARP inhibitor that selectively inhibits and traps PARP1. It is designed to selectively target cancer cells while sparing normal bone marrow, and thus, may offer a safer toxicity profile compared to earlier generation PARP inhibitors.

Senaparib is a novel, highly selective PARP1/2 inhibitor being studied for the treatment of mCRPC, specifically in patients with HRR gene alterations (such as BRCA1 and BRCA2 mutations). The drug has been reported to demonstrate promising antitumor activity and is well tolerated. 

5. In a study that assessed homologous recombination repair mutation (HRRm) testing patterns in mCRPC in the USA, Europe, and Japan, testing rates were low. 

In an international survey conducted from January to August 2020, three quarters of physicians (oncologists, urologists, specialist surgeons) globally reported access to genetic/genomic testing, but just over half were HRRm testers. Surveyed physicians reported HRRm testing and positivity rates for 1913 patients, which were 18.1% and 33.7%, respectively. Of patients tested (n = 347), the most common HRR genes tested were BRCA (91.6%) and ATM (47.3%).

PARP inhibitors are the first targeted therapies approved for the treatment of advanced prostate cancer, but studies show their use is limited by the low testing rates of tumors. Increased awareness and education are needed to encourage testing but also broader access to somatic genomic profiling to ensure all patients with advanced disease have their tumors tested.

https://www.medscape.com/viewarticle/parp-inhibitors-prostate-cancer-5-things-know-2026a1000ocr