For patients with advanced prostate cancer, germline and somatic profiling have enabled new treatment strategies. DNA damage repair mechanisms have been a specific focus of precision medicine, with one potential target being homologous recombination repair (HRR) genes including BRCA1, BRCA2, and ATM.¹ Poly (ADP-ribose) polymerase (PARP) inhibitors are a class of drugs that work by targeting cancer cells that already have deficient HRR genes. PARP enzymes also play a role in repairing DNA. One mechanism by which PARP inhibitors work is synthetic lethality. Cancer cells with HRR deficiencies (such as a BRCA-mutated cell) rely heavily on PARP-mediated repair mechanisms to survive. When a PARP inhibitor is added, there is simultaneous loss of PARP activity along with the defective HRR, leading to lethal DNA damage and cell death.

Currently, several PARP inhibitors have shown efficacy, as monotherapy or in combination with androgen receptor (AR) blockers, in treating patients with HRR genetic alterations who have castrate-resistant metastatic prostate cancer (mCRPC).

The phase 3 PROfound trial randomized olaparib vs abiraterone or enzalutamide in patients with mCRPC with progression on at least 1 novel hormonal agent (abiraterone or enzalutamide). One prior taxane agent was permitted but not required.² Patients were required to have somatic or germline HRR gene mutations. The patients were divided into cohort A (BRCA1/2 or ATM mutations) and cohort B (12 other HRR genes). The final overall survival analysis of PROfound showed a survival benefit with olaparib vs abiraterone/enzalutamide in cohort A (HR 0.69, 95% CI, 0.50-0.97).³

TRITON3 compared rucaparib or physician’s choice in patients with mCRPC.⁴ Eligible patients had mCRPC with a BRCA1, BRCA2, or ATM alteration and disease progression after treatment with a second-generation androgen-receptor pathway inhibitor. They received rucaparib or a physician’s choice control (docetaxel or a second-generation androgen receptor pathway inhibitor). The primary outcome was median duration of imaging-based progression-free survival. In the intention-to-treat analysis, imaging-based progression-free survival was improved in the rucaparib group compared to the control group (HR 0.50, 95% CI 0.36-0.69). Interestingly, the benefit for imaging-based survival was specifically seen in the BRCA subgroup; in the exploratory data analysis of patients with an ATM alteration, the duration of imaging-based progression-free survival was similar in the rucaparib and control groups. The AUA recommends that clinicians offer a PARP inhibitor to patients with deleterious or suspected deleterious germline or somatic recombination repair gene-mutated mCRPC following treatment with enzalutamide or abiraterone acetate and/or a taxane-based chemotherapy.

Further, combination therapy with PARP inhibitors and AR blockers has emerged as a management option in the treatment of mCRPC. The androgen receptor pathway has been shown to regulate the expression of DNA repair genes, and inhibiting signaling can impair the DNA repair mechanism in prostate cancer cells. As discussed above, PARP inhibitors already exploit deficiencies in DNA repair pathways. The combination of the two has a synergistic effect.⁵

Multiple studies have shown benefit in improving progression-free survival with this combination therapy, including PROPel (olaparib + abiraterone), MAGNITUDE (niraparib + abiraterone), and TALAPRO-2 (talazoparib + enzalutamide).

PROpel is a double-blind randomized phase 3 trial of abiraterone and olaparib vs abiraterone and placebo in the first-line treatment of patients with mCRPC.⁶ The primary end point was imaging-based progression-free survival. The median imaging-based progression-free survival was significantly longer for abiraterone and olaparib than in the abiraterone and placebo arm (HR 0.66, 95% CI, 0.54-0.81). In May 2023, the Food and Drug Administration (FDA) approved the combination of olaparib with abiraterone for patients with BRCA-mutated mCRPC.

MAGNITUDE is a phase 3, randomized, double-blinded study that evaluated niraparib and abiraterone acetate plus prednisone vs placebo and abiraterone acetate.⁷ The primary end point, radiographic progression-free survival, was significantly longer in the niraparib and abiraterone acetate plus prednisone group compared with placebo (HR 0.53, 95% CI 0.36-0.79). Based on these results, the FDA approved the combination of niraparib and abiraterone in August 2023 for mCRPC patients with BRCA mutations.

Finally, TALAPRO-2 randomized patients to talazoparib plus enzalutamide vs placebo plus enzalutamide in patients with mCRPC.⁸ The primary end point was radiographic progression-free survival, and this was significantly longer in the intervention group who received talazoparib plus enzalutamide compared to the control (HR 0.73, 95% CI 0.56-0.96). This combination has also been FDA approved for patients with mCRPC harboring HRR mutations.

Common adverse events from PARP inhibitors include anemia, thrombocytopenia, fatigue, nausea, and gastrointestinal symptoms, with anemia being one of the most commonly reported. Patients should be monitored for symptoms and undergo appropriate laboratory testing, with dose interruptions or reductions as deemed necessary.

PARP inhibitors alone or in combination with AR blockers offer an additional promising treatment strategy for patients with castrate-resistant prostate cancer harboring somatic or germline DNA damage mutations. With more widespread use of genetic testing, urologists can now tailor care as we move towards precision medicine in advanced prostate cancer.