Abstract
The PARP inhibitor niraparib has activity in hereditary BRCA-mutant and sporadic cancers.
Major finding: The PARP inhibitor niraparib has activity in hereditary BRCA-mutant and sporadic cancers.
Clinical relevance: Niraparib reduces circulating tumor cells in patients with castration-resistant prostate cancer.
Impact: Sporadic cancers without germline BRCA1 or BRCA2 mutations may also be sensitive to PARP inhibition.
Cancer cells with defective homologous recombination caused by loss-of-function mutations in BRCA1 or BRCA2 become dependent on base excision repair and are sensitive to inhibitors of poly (ADP-ribose) polymerase (PARP). Studies of PARP inhibitors have largely focused on patients with breast or ovarian cancer that have germline BRCA1 or BRCA2 mutations, but sporadic cancers may also acquire mutations in genes that impair homologous recombination. Sandhu and colleagues report the results of a multicenter, two-part phase I dose-escalation study of niraparib, an orally bioavailable, potent, selective inhibitor of PARP1 and PARP2, in patients with advanced solid tumors. Enrollment in the dose-escalation and dose-confirmation part of the trial was enriched for patients with germline BRCA1 or BRCA2 mutations. Enrollment in the dose-expansion part of the study was limited to patients with sporadic castration-resistant prostate cancer or platinum-resistant high-grade serous ovarian cancer given that these tumors often have defective homologous recombination. Additionally, an exploratory analysis of predictive biomarkers was performed in prostate cancer circulating tumor cells and archival tumor tissue. Niraparib was well tolerated, had favorable pharmacokinetic properties, and led to greater than 50% PARP inhibition at most doses. Of 20 patients with BRCA-mutant ovarian cancer, eight (40%) had a confirmed partial response, and two of four (50%) patients with BRCA-mutant breast cancer had partial responses. Six of 19 (32%) patients with sporadic platinum-resistant high-grade serous ovarian cancer experienced disease control, as did nine of 21 (43%) patients with sporadic castration-resistant prostate cancer. Of note, circulating tumor cell levels dropped significantly in several prostate cancer patients with disease stabilization, but there was no association between response and genetic features such as PTEN deletion or ERG rearrangement. These results support further study of niraparib in inherited BRCA-mutant cancers as well as in sporadic cancers with potential homologous recombination defects.
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