PARTNER: A randomized, phase II/III trial to evaluate the safety and efficacy of the addition of olaparib to platinum-based neoadjuvant chemotherapy in patients with triple-negative and/or germline BRCA-mutated breast cancer.

Abstract

TPS619 Background: Triple negative breast cancers (TNBCs) are a biologically diverse and aggressive subgroup lacking targeted therapy. TNBC and germline BRCA (gBRCA) breast cancer share certain phenotypic and molecular similarities, with gBRCA mutations seen in 10% to 20% of TNBC patients. Homologous recombination-deficient tumors, especially those caused by germline or somatic BRCA mutations, are thought to be particularly sensitive to PARP inhibitors. Methods: This is a 3-stage open-label randomized phase II/III trial of neoadjuvant paclitaxel and carboplatin +/- olaparib, followed by clinicians' choice of anthracycline regimen. The aim is to establish whether the addition of olaparib to neoadjuvant platinum-based chemotherapy in the treatment of basal TNBC and/or gBRCA breast cancer is safe and increases efficacy. In stages 1 and 2, all patients receive 4 cycles of 3-weekly carboplatin AUC5/weekly paclitaxel 80mg/m2. They are randomly assigned 1:1:1 to a control arm, or to one of two research arms. These research arms include different treatment schedules of olaparib 150 mg BD for 12 days. In stage 3, patients are randomly assigned 1:1 to either the control or research arm chosen following stage 2. The primary endpoints are: Stage 1: Safety; Stage 2: Schedule selection based on pCR rate and olaparib completion rate using a “pick-the-winner” design. Stage 3: pCR rate. Key eligibility criteria are age 16-70; histologically confirmed invasive breast cancer; ER-negative, HER2-negative with TNBC basal phenotype or gBRCA positive, HER2-negative irrespective of hormone status; stage T1-4 N0-2; performance status 0-1; treatment within 6 weeks of diagnostic biopsy; biomarker scores: TILs, CK 5/6, EGFR +/- AR. The recruitment of TNBC non-gBRCA and gBRCA patients is independent. Enrichment design is applied with an overall significance level 0.05(α) and 80% power. A minimum of 780 patients will be included to detect an absolute improvement of 15% (all patients) and 20% (gBRCA patients) by combining olaparib with platinum-based chemotherapy. This trial includes an optional pathway called PARTNERING for patients with residual disease after six chemotherapy cycles. This aims to establish if adding new agents (ATR inhibitor and PD-L1 inhibitor) improves treatment response. Each cohort will consist of 15 patients. Since May 2016, 756 patients from 30 sites have been enrolled. An IDSMC review following stages 1 and 2 identified no safety concerns and Research Arm 2 was selected (olaparib administration on days 3-14). Stage 3 phase I (recruitment of non-gBRCA and gBRCA patients) completed December 2021. Stage 3 phase II (recruitment of gBRCA patients) remains open to patients in the U.K. and internationally. 5 patients have enrolled in PARTNERING. Follow-up duration is 10 years. Clinical trial information: NCT03150576.

Neoadjuvant Talazoparib in Patients With Germline BRCA1/2 Mutation-Positive, Early-Stage Triple-Negative Breast Cancer: Results of a Phase II Study

“…Notably, the PARTNER study (NCT03150576) is a randomized phase II/III study evaluating the addition of olaparib to platinum-based neoadjuvant chemotherapy in patients with TNBC and/or germline BRCA -mutated breast cancer ( N = 756) and pCR as the primary endpoint. 36 In addition, following FDA approval of pembrolizumab plus platinum-containing neoadjuvant chemotherapy as a standard of care for patients with TNBC, 37 further investigation of PARP inhibitors with immunotherapy is in progress for patients with TNBC (talazoparib plus avelumab, NCT03330405; olaparib plus durvalumab, NCT03544125 and NCT03740893; niraparib plus ­dostarlimab, NCT04837209).…”

Key Proteins of Replication Stress Response and Cell Cycle Control as Cancer Therapy Targets

“…Some trials indicated that PARPi treatment may be improved by addition of ATRi [168,169]. That being the case, many up-to-date studies suggest that PARPi as single agents or in combination with particular compounds can be sufficiently effective against a wider variety of tumors than was thought before.…”