Olaparib Monotherapy in Patients With Advanced Cancer and a Germline BRCA1/2 Mutation

By B. Kaufman, R. Shapira-Frommer, Rita K Schmutzler, M. Audeh, M. Friedlander, J. Balmaña, G. Mitchell, G. Fried, Salomon M. Stemmer, A. Hubert and 6 more. Journal of Clinical Oncology, 2014

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Purpose Olaparib is an oral poly (ADP-ribose) polymerase inhibitor with activity in germline BRCA1 and BRCA2 (BRCA1/2) –associated breast and ovarian cancers. We evaluated the efficacy and safety of olaparib in a spectrum of BRCA1/2-associated cancers. Patients and Methods This multicenter phase II study enrolled individuals with a germline BRCA1/2 mutation and recurrent cancer. Eligibility included ovarian cancer resistant to prior platinum; breast cancer with ≥ three chemotherapy regimens for metastatic disease; pancreatic cancer with prior gemcitabine treatment; or prostate cancer with progression on hormonal and one systemic therapy. Olaparib was administered at 400 mg twice per day. The primary efficacy end point was tumor response rate. Results A total of 298 patients received treatment and were evaluable. The tumor response rate was 26.2% (78 of 298; 95% CI, 21.3 to 31.6) overall and 31.1% (60 of 193; 95% CI, 24.6 to 38.1), 12.9% (eight of 62; 95% CI, 5.7 to 23.9), 21.7% (five of 23; 95% CI, 7.5 to 43.7), and 50.0% (four of eight; 95% CI, 15.7 to 84.3) in ovarian, breast, pancreatic, and prostate cancers, respectively. Stable disease ≥ 8 weeks was observed in 42% of patients (95% CI, 36.0 to 47.4), including 40% (95% CI, 33.4 to 47.7), 47% (95% CI, 34.0 to 59.9), 35% (95% CI, 16.4 to 57.3), and 25% (95% CI, 3.2 to 65.1) of those with ovarian, breast, pancreatic, or prostate cancer, respectively. The most common adverse events (AEs) were fatigue, nausea, and vomiting. Grade ≥ 3 AEs were reported for 54% of patients; anemia was the most common (17%). Conclusion Responses to olaparib were observed across different tumor types associated with germline BRCA1/2 mutations. Olaparib warrants further investigation in confirmatory studies.

Subfields: Genetics, Oncology, Reproductive Medicine

View Paper: https://www.semanticscholar.org/paper/66dd7b289f52d2c642cb4ed2d4cdbaba477058a8

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Citations in the corpus

PARP inhibitor upregulates PD-L1 expression and enhances cancer-associated immunosuppression (2017, background): “Because PARPi is commonly used to treat BRCAdeficient cancers (21), we also investigated the effects of olaparib on BRCA-mutant SUM149 cells.”
Precision Oncology: The Road Ahead (2017, background): “To address these issues, more general approaches have been suggested, such as interfering with tumor evolutionary programs, for instance, by increasing genomic instability to lethal levels (e.g. PARP inhibitors in tumors with homologous recombination deficit) [25].”
Maintenance Olaparib for Germline BRCA-Mutated Metastatic Pancreatic Cancer (2019, neutral): “Other platinum‐based treatments 10 (11) 8 (13)”
Survival with Olaparib in Metastatic Castration-Resistant Prostate Cancer. (2020, neutral): “Anemia§ 127 (50) 58 (23) 20 (15) 7 (5) 43 (52) 24 (29)”
PARP Inhibitors: The First Synthetic Lethal Targeted Therapy (2017, background): “Phase 2 trials involving patients with gBRCAm breast, ovarian, pancreatic or prostate cancers confirmed that olaparib offered significant clinical benefit (46-48) (Fig.”
A decade of clinical development of PARP inhibitors in perspective (2019, background): “A basket trial of olaparib in patients with gBRCA1/2 mutations identified responding patients beyond the ovarian or breast cancer population, suggesting that other HR-defective tumours could be suitable for PARPi treatment [41].”