Major Finding: Olaparib exhibited efficacy in a selected population of patients with mCRPC with DDR-gene mutations.
Concept: Of mutations in DNA-damage response genes, BRCA mutations conferred highest olaparib sensitivity.
Impact: The results support use of genomic testing for treatment stratification in mCRPC.
Mutations affecting DNA-damage response (DDR) genes are common in prostate cancer, and a recent trial in an unselected population uncovered a correlation between DDR-gene aberrations and response to the PARP inhibitor olaparib in metastatic castration-resistant prostate cancer (mCRPC). Mateo, Porta, and colleagues conducted a multicenter, open-label, randomized, prospective phase II clinical trial in patients with DDR-gene abberations to determine the association between DDR-gene status and olaparib response. Of patients evaluable for the primary endpoint of confirmed composite response, the trial included 92 patients with aberrations in DDR genes (including BRCA1/2, ATM, CDK12, PALB2, and 10 others) randomly assigned to receive olaparib at 300 mg (46 patients) or 400 mg (46 patients) twice per day. The composite overall response rate (including radiologic objective responses, decreases in prostate-specific antigen levels of 50% or greater, or conversion of circulating tumor-cell count) was 46.7% (43 of 92 patients) across both groups, 39.1% (18 of 46 patients) in the 300-mg dose cohort, and 54.3% (25 of 46 patients) in the 400-mg dose cohort. Interestingly, the composite overall response rate was markedly elevated (83.3%; 25 of 30 patients) in patients harboring mutations in BRCA1 or BRCA2 compared with other DDR genes. Enhanced activity was also seen in tumors harboring mutations in ATM, PALB2, FANCA, and CHEK2, implying that PARP inhibitors, alone or in combination, may also be of utility in other molecularly defined subtyles of mCRPC. The side-effect profile was as expected for olaparib, with the most common serious treatment-related adverse effect in both cohorts being anemia. One patient in the 300-mg dose cohort died of myocardial infarction that was deemed possibly related to study treatment. Altogether, this study confirms the clinical activity of olaparib in mCRPC, and several other trials of PARP inhibitors in mCRPC are now under way. Further, this trial supports the use of molecular stratification to rationally assign targeted therapies to patients with mCRPC.
Notes
Note: Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/CDNews.
- ©2019 American Association for Cancer Research.
Volume 10, Issue 2
