In a phase II Translational Breast Cancer Research Consortium (TBCRC) study (TBCRC 048; Olaparib Expanded) reported in the Journal of Clinical Oncology, Nadine M. Tung, MD, and colleagues found that olaparib produced high response rates in patients with metastatic breast cancer and germline PALB2 and somatic BRCA1/2 mutations.
As stated by the investigators, “Olaparib, a PARP inhibitor, is approved for the treatment of HER2-negative metastatic breast cancer in germline BRCA1/2 mutation carriers. [The current] investigator-initiated, phase II study assessed olaparib response in patients with metastatic breast cancer with somatic BRCA1/2 mutations or germline or somatic mutations in homologous recombination–related genes other than BRCA1/2.”
Nadine M. Tung, MD
The study included two cohorts of patients with measurable disease enrolled between March 2018 and January 2020: one contained those with germline mutations in non-BRCA1/2 homologous recombination–related genes (cohort 1, n = 27) and one contained those with somatic mutations in these genes or BRCA1/2 (cohort 2, n = 27). Patients with prior PARP inhibitor therapy, platinum-refractory disease, or progression on more than two chemotherapy regimens in the metastatic setting were excluded from the study.
Overall, 76% of patients had estrogen receptor–positive, HER2-negative disease, and 87% of patients had PALB2 (n = 13), somatic BRCA1/2 (n = 16), ATM (n = 8; n = 2 with CHEK2), or CHEK2 (n = 8) mutations.
Patients received olaparib at 300 mg twice daily until disease progression. The primary endpoint was objective response rate, with the endpoint being met if there were four or more responses (≥ 15% rate) in each 27-patient cohort.
Median follow-up was 4.2 months. In cohort 1 (germline mutation other than BRCA1/2), objective response was observed in nine patients (all partial responses; 33%) and the clinical benefit rate at 18 weeks was 50%. In cohort 2 (somatic mutations in homologous recombination–related genes), objective response was observed in eight patients (all partial responses; 31%) and the clinical benefit rate at week 18 was 48%. In cohort 1, all responses were observed in patients with germline PALB2 mutations (response rate = 82%); in cohort 2, all confirmed responses were observed in patients with somatic BRCA1/2 mutations (response rate = 50%); three additional patients, consisting of one each with a BRCA1, CDK12, and BLM mutation, had unconfirmed partial response and were analyzed as having stable disease. No responses were observed in patients with ATM or CHEK2 mutations alone.
In cohort 1, responses lasting longer than 1 year were observed, and median progression-free survival was 13.3 months (90% confidence interval [CI] = 12 months–not estimable). In cohort 2, responses lasting up to 18 months were observed, and median progression-free survival was 6.3 months (90% CI = 4.4 months–not estimable).
The olaparib toxicity profile was consistent with that seen in previous studies. Among all patients, grade 2 nausea (none ≥ grade 3) occurred in 9% of patients, 26% had > grade 1 anemia (≥ 3 in 13%), and 4% had grade 2 alopecia. Dose reduction was required in 15% of patients. Adverse events led to discontinuation of treatment in 4%.
The investigators concluded, “PARP inhibition is an effective treatment for patients with metastatic breast cancer and germline PALB2 or somatic BRCA1/2 mutations, significantly expanding the population of patients with breast cancer likely to benefit from PARP inhibition beyond germline BRCA1/2 mutation carriers. These results emphasize the value of molecular characterization for treatment decisions in metastatic breast cancer.”
Dr. Tung, of Beth Israel Deaconess Medical Center, Harvard Medical School, is the corresponding author for the Journal of Clinical Oncology article.
Disclosure: The study was supported by AstraZeneca. For full disclosures of the study authors, visit ascopubs.org.The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.