PCa Commentary | Volume 217 – September 2026

Posted by Edward Weber, MD | September 2026

PARP INHIBITORS: What Are They? How Are They used as Monotherapy or in Combinations in Prostate Cancer Management in Men with BRCA 1, 2, & ATM Mutations

About 30% of men at diagnosis have mutations (“germline”) in genes that correct mistranslation of their genome during the process of cell division. The most consequential of these germline mutations are in the genes for BRCA 1,2, and ATM. When these genes are mutated and nonfunctional in correcting genomic mistranslation, correction falls to a backup program, the PARP group (poly [ADP-ribose] polymerase), the second line of defense. Paradoxically, if the BRCA group malfunctions, the PARP group is therapeutically inhibited, and both systems are disrupted, the cell dies. This Commentary covers the various FDA approved PARP inhibitors and how to engage them.

Regarding “somatic” mutations: Later in disease progression, under pressure of multiple treatments, new gene mutations develop which can also influence cell behavior and treatment decisions. These “somatic” (acquired) mutations can be identified by genomic sequencing of blood for DNA and RNA with FoundationOne Liquid CDx to identify newly emergent BRCA1 & 2, ATM, and other mutations.

The “downside” of having acquired mutations in the BRCA group is that they confer greater aggressiveness to cancer. The “upside” is that those men with BRCA-mutated cells, when treated with PARP inhibitors, experience improved progression-free and overall survival. Hence the importance of checking for these mutations early in the disease and again later during treatment. The FDA has approved 4 PARP inhibitors: olaparib (“Lynparza”), rucaparib (“Rubraca”), talazoparib (“Talzenna”) and niraparib (“Zejula”) for selected patients with these mutations.

Detecting Germline Mutations:

In a summary article, “BRCA1, BRCA2 and Associated Cancer Risks and Management for Males: A Review” (Cheng et al., JAMA Oncol 2024), Cheng pointed out that only 1% of men diagnosed with prostate cancer undergo cancer-specific genetic testing (!). Genetic testing was recommended for men diagnosed with prostate cancer who had a family history of prostate or breast cancer, advanced local disease (Gleason Score >8, Gleason Grade >4, PSA >20 ng/mL), and metastases in lymph nodes or elsewhere. The cumulative risk estimates for men carrying mutations in BRCA1/2 (the most consequential mutation) increase with age from 2-14% at ages 50 – 60 years to 43-78% at age 80 or higher.

An earlier article, “Inherited DNA Repair Gene Mutations in Men with Metastatic Prostate Cancer (Nelson et al., NEJM 2016), reported that the total deleterious mutations reached 11.8%. The most common mutation, BRCA2,  was found in 5.3%.

How to Test for Genetic Mutations:

Early genetic testing is accomplished by submitting the initial prostate biopsy or prostatectomy specimen to a pathology department for testing. Later in disease, when additional new mutations may have accumulated, testing can be accomplished by submitting blood to a lab such as FoundationOne Liquid CDx.

Currently, PARP inhibitors are used as monotherapy or combined with other agents as first- or second-line treatment for metastatic castration-resistant prostate cancer in men with BRCA-like mutations and are under study for use in non-metastatic cancer, such as non-metastatic hormone-sensitive PC.

Example: Olaparib pills (purchased online) are 150mg. The daily dose is 300 mg. Toxicities include fatigue, anemia, nausea, and vomiting. CBC should be monitored. Talazoparib pills are dosed at 0.5 mg orally once daily.

FDA Approved PARP Inhibitors:

1. Olaparib (“Lynparza”) is FDA approved for treatment of men with BRCA-like mutations with mCRPC after progression on Xtandi or Zytiga: radiographic PFS (rPFS) was 7.4 (olaparib) vs 3.6; and median overall survival (OS) was 19.1 (olaparib) vs14.7 mo.In 2023, the FDA approved olaparib+Zytiga/prednisone first-line for men with BRCA 1&2 + ATM mutations having metastatic castration-resistant prostate cancer. Median overall survival was 68+ mo for the combination vs 26 months for olaparib alone. (BRCAway Trial)
2. Rucaparib (“Rubraca”) is FDA-approved for men with BRCA 1/2 and ATM mutations (germline or somatic) in mCRPC after initial therapy with ADT. In the TRITON3 Trial, it improved median OS to 23 months as compared to 21 months for ADT. Median rPFS and median OS: 11.2 vs 6 mo; 23.2 vs 21.2 mo.
3. Talazoparib (“Talzenna”) is FDA-approved as first-line therapy along with Xtandi for a wide range of BRCA-like mutations in men with mCRPC. Median rPFS was 31 (combination) vs 19.5 mo; and median OS was 45.8 (combination) vs 37.0 mo.
4. Niraparib (“Akeega”) is FDA-approved for first-line treatment in men in combination with Zytiga/prednisone for men with BRCA1-2 mutated metastatic castration-resistant PC; also, for BRCA2 mutated metastatic castration-resistant PC. Median rPFS – not available vs 29.5 mo. OS data not mature.
5. On July 31, 2025, the FDA approved Pluvicto in combination with an androgen receptor pathway inhibitor ( i.e., darolutamide or apalutamide) for metastatic hormone-sensitive prostate cancer at diagnosis. Data for PFS and OS suggest its effectiveness compared to an ARPI alone. (PSM Addition Clinical Trial)

BOTTOM LINE:

The take-away from this Commentary is that men with BRCA-like mutations at any stage of their disease benefit from use of PARP inhibitors alone or in combination. Therefore, early and subsequent genetic testing for BRCA-like mutations is recommended.

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