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

Abstract

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.

Effect of Itraconazole and Rifampin on the Pharmacokinetics of Olaparib in Patients With Advanced Solid Tumors: Results of Two Phase I Open-label Studies

“…8 In a study of patients with a germline BRCA1/2m and solid tumors refractory to standard therapy, treatment with a capsule formulation of olaparib 400 mg bid prolonged tumor responses across a spectrum of malignancies, including ovarian, breast, pancreatic, and prostate cancers. 9 To receive the recommended 400 mg bid dose of olaparib, patients are required to take 16 x 50 mg large capsules per day and consequently patient compliance may be compromised. A tablet formulation has therefore been developed to deliver a therapeutic dose in fewer and smaller units.…”

Standards and Guidelines for the Interpretation and Reporting of Sequence Variants in Cancer

“…A multicenter clinical trial showed responses of multiple advanced tumors, including ovarian, breast, pancreatic, and prostate cancers, to poly(adenosine diphosphate-ribose) polymerase inhibitors, which led to the FDA approval of olaparib for treatment of women with BRCA-related advanced ovarian cancer (FDA Olaparib, http://www.fda.gov/drugs/ informationondrugs/approveddrugs/ucm427598.htm, last accessed July 6, 2016). 92 Germline pathogenic variants leading to the diagnosis of a hereditary cancer syndrome that has an established guideline for clinical surveillance should also be reported with recommendation of cancer genetic counseling. For example, certain pathogenic germline TP53 variants lead to Li-Fraumeni syndrome, a hereditary cancer syndrome with increased risk for a wide spectrum of TP53-associated malignancies, including, but not limited to, breast cancer, sarcomas, brain tumors, and leukemias.…”

FDA Approval Summary: Olaparib Monotherapy in Patients with Deleterious Germline BRCA-Mutated Advanced Ovarian Cancer Treated with Three or More Lines of Chemotherapy

“…FDA approval of olaparib was primarily based on an openlabel, nonrandomized clinical trial in 298 patients with deleterious or suspected deleterious gBRCAm-associated cancer, including 193 patients with ovarian cancer (16). Patients were treated with olaparib capsules at a dose of 400 mg orally twice daily until disease progression or intolerance to therapy.…”