Olaparib breast cancer activity not confined to patients with germline BRCA1/2 mutations
medwireNews: Findings from the proof-of-principle Olaparib Expanded study indicate that patients with stage IV breast cancer and germline PALB2 or somatic BRCA1/2 mutations may benefit from olaparib treatment.
Nadine Tung (Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA) explained that PARP inhibitors are approved for use in patients with germline BRCA1/2 mutations, but the identification of other patients with homologous recombination deficiencies who may benefit from such therapies “remains a critical goal.”
As reported at the virtual 2020 ASCO Annual Meeting, all participants of the phase 2 trial had stage IV breast cancer, had received no more than two chemotherapy regimens for metastatic disease, and either carried germline mutations in DNA damage response pathway genes other than BRCA1/2 (cohort 1) or somatic mutations in BRCA1/2 or other genes (cohort 2).
Treatment with olaparib 300 mg twice daily in 21-day cycles led to an objective response rate (ORR) of 33% among the 27 patients in cohort 1 and 31% among the 26 patients in cohort 2; for all patients the responses were partial. The clinical benefit rate (CBR) at 18 weeks was 44% in each cohort.
“The primary endpoint was met in both cohorts, but responses to olaparib were gene specific,” said Tung.
Indeed, all nine responses in cohort 1 occurred in patients harboring germline PALB2 mutations, giving an ORR for this subgroup (n=11) of 82%. The remaining two patients had stable disease, which meant the CBR at 18 weeks was 100%.
Similarly, all eight patients in cohort 2 who responded to olaparib had a somatic BRCA1/2 mutation and therefore the ORR for this subgroup (n=16) was 50% and the 18-week CBR was 67%.
Olaparib treatment did not elicit responses in the 10 patients with either germline or somatic ATM mutations, nor in the eight with germline CHEK2 mutations.
There were also no confirmed responses in patients with mutations in other genes such as BARD1, RAD50, CDK12, or FANCA, but there were too few of these patients “to definitively assess response to olaparib,” commented the presenter.
Nevertheless, “responses were seen in all breast cancer subtypes and after CDK4/6 inhibitor use,” emphasized Tung. Specifically, responders included 12 of the 20 patients with HER2-negative disease, four of the six with triple-negative disease, the one patient with HER2-positive disease, and 11 of the 19 participants with prior CDK4/6 inhibitor use.
Overall, 15% of patients required a dose reduction, most commonly due to anemia and nausea, and 4% discontinued treatment due to toxicity. Of note, anemia was the most common adverse event, occurring at any grade in 20% of patients and at grades 3–4 in 10% of patients.
In light of the findings from this study, Tung concluded: “We are beginning new cohorts of metastatic breast cancer patients with germline PALB2 or somatic BRCA mutations to confirm the response rates observed.”
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