Poly (ADP-ribose) polymerase (PARP) inhibitors have emerged as a promising therapeutic strategy, particularly in epithelial ovarian cancers and breast cancers harboring BRCA1/2 mutations. These inhibitors have demonstrated notable activity, especially in relapsed platinum-sensitive high-grade serous ovarian cancer. Clinical and preclinical studies indicate that tumors with deleterious germline mutations in BRCA1 or BRCA2 are particularly sensitive to PARP inhibition. However, it's becoming increasingly clear that BRCA1/2 mutations are neither necessary nor sufficient for predicting patient benefit from PARP inhibitors.
A pivotal phase II study revealed that olaparib induces responses in BRCA1/2 mutation carriers with progressive high-grade ovarian cancer, with greater efficacy in platinum-sensitive cases. A subsequent study showed that olaparib maintenance therapy, compared to placebo, significantly improved progression-free survival (PFS) in relapsed high-grade serous ovarian cancer (8.4 months vs. 4.8 months; hazard ratio, 0.35; P < .001). A preplanned subset analysis highlighted the greatest benefit in ovarian cancer with BRCA1/2 mutations, extending PFS from 4.3 to 11.2 months (hazard ratio, 0.18; P < .001). These findings led to the approval of olaparib as maintenance therapy for platinum-responsive advanced ovarian cancer and as fourth-line monotherapy, limited to cases with BRCA1/2 mutations.
Clinical Efficacy and Ongoing Trials
Women whose ovarian cancer lacked BRCA1/2 mutations also experienced benefit in the randomized olaparib maintenance trial (hazard ratio, 0.53; 95% CI, 0.33 to 0.84; P < .001), suggesting a sensitive non-BRCA1/2-mutation subgroup. Approximately 40% and 20% of women with BRCA1/2-mutant or BRCA1/2-wild type high-grade serous ovarian cancer, respectively, did not require a different therapy within 3 years after random assignment, compared with only approximately 10% and 1% of those receiving placebo. Olaparib also prolonged time to second subsequent therapy in both BRCA1/2-mutated and non-BRCA1/2-mutated ovarian cancer.
Additional PARP inhibitors, including veliparib, rucaparib, niraparib, and BMN-673, have also demonstrated efficacy in high-grade serous ovarian cancer. Phase III trials with similar designs to the olaparib maintenance trial are ongoing in ovarian cancer, aiming to improve the identification of responsive patients through biospecimen analysis.
PARP Inhibitors in Breast Cancer and Other Solid Tumors
PARP inhibitors have generally been less efficacious in breast cancer compared to high-grade serous ovarian cancer, potentially due to the biologic heterogeneity and low BRCA1/2 somatic mutation rate in triple-negative breast cancer. Responses were observed in 11 (41%) of 27 patients in an initial phase II trial of olaparib in BRCA1/2-mutated breast cancer. Phase III trials are ongoing in BRCA1/2-mutated breast cancer and triple-negative breast cancer.
Additional solid tumors may also be responsive to PARP inhibitors. Clinical trials of single-agent PARP inhibitor treatment are ongoing in other tumor types, with responses reported in melanoma, PTEN-deficient endometrial cancer, and colorectal carcinoma.
Mechanisms of Action and Resistance
Several aspects of PARP1 biology have been proposed to explain the synthetic lethality observed with PARP inhibitors in HR-deficient cells. These include inhibition of base excision repair (BER), trapping of PARP1 on damaged DNA, defective BRCA1 recruitment, and activation of nonhomologous end joining (NHEJ). Understanding these mechanisms is crucial for predicting PARP inhibitor sensitivity and resistance.
Identifying Responders and Future Directions
BRCA1/2 mutation status has been the most extensively studied predictor of PARP inhibitor sensitivity. However, responses are not limited to this group, as ovarian cancers with somatic BRCA1/2 mutations seem to benefit similarly from PARP inhibitor maintenance therapy. Germline or somatic mutations in other genes critical to homologous recombination (HR) may also predict PARP inhibitor response. Improved understanding of PARP biology and HR deficiency (HRD) is providing new clues for predicting PARP inhibitor responders versus nonresponders.
Combination therapies involving PARP inhibitors are also being explored, with mechanisms including induction of HRD and enhancement of DNA damage. Future development should focus on efficiently identifying patients who will benefit from PARP inhibitors, learning more about drug resistance in the clinical setting, and establishing reasonable expectations for their efficacy.
