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

Abstract

TPS591 Background: No specific targeted therapies are available for Triple Negative Breast Cancers (TNBC), an aggressive and diverse subgroup. The basal TNBC sub-group show some phenotypic and molecular similarities with germline BRCA (gBRCA). In gBRCA patients, and potentially other homologous recombination deficiencies, these already compromised pathways may allow drugs called PARP inhibitors (olaparib) to work more effectively. Aims: To establish if the addition of olaparib to neoadjuvant platinum based chemotherapy for basal TNBC and/or gBRCA breast cancer is safe and improves efficacy (pathological complete response (pCR)). Trial design: 3-stage open label randomised phase II/III trial of neoadjuvant paclitaxel and carboplatin +/- olaparib, followed by clinicians' choice of anthracycline regimen. Stage 1 and 2: Patients are randomised (1:1:1) to either control (3 weekly carboplatin AUC5/weekly paclitaxel 80mg/m2 for 4 cycles) or one of two research arms with the same chemotherapy regimen but with two different schedules of olaparib 150mg BD for 12 days. Stage 3: Patients are randomised (1:1) to either control arm or to the research arm selected in stage 2. Methods: Stage 1 - Safety: both research arms combined. Stage 2 - Schedule selection criteria: pCR rate and completion rate of olaparib protocol treatment. It is a “pick-the-winner” design with 53 patients in each research arm. This allows a 90% power, 5% one-sided significance level to test null hypothesis of pCR ≤35% versus an alternative hypothesis of pCR ≥55% in each of the research arms. Stage 3 - Efficacy: anticipated pCR ~55-60% for all trial patients and ~60-65% for gBRCA patients. The trial is powered to detect an absolute improvement of 15% (all patients) and 20% (gBRCA patients) by adding olaparib to chemotherapy (enriched design). TNBC patient recruitment will be capped, to ensure required gBRCA patients are enrolled. Enrichment design is applied with overall significance level 0.05(α) = 0.025(αall)+ 0.025(αgBRCA) and 80% power. Target accrual: 527 [gBRCA 220] Current accrual: 17 Sites activated: 12 [expected number of sites 30-50].

The effect of neoadjuvant platinum-based chemotherapy in BRCA mutated triple negative breast cancers -systematic review and meta-analysis

“…The PARTNER study [ 39 ] presented at ASCO 2017 which intended to evaluate the efficacy of the addition of olaparib to platinum-based neoadjuvant chemotherapy in triple negative breast cancer and/or germline mutated BRCA . Patients were randomised (1,1:1) to either control carboplatin and paclitaxel or one of two research arms with the same chemotherapy regimen but with two different schedules of olaparib.…”

Triple‑negative breast cancer: A run‑through of features, classification and current therapies (Review)

“…The phase-III OlympiA trial (NCT02032823) for early TNBC is currently assessing patients with BRCA1/2 mutation treated with olaparib as monotherapy following neoadjuvant chemotherapy ( 106 ). PARTNER (NCT03150576) ( 107 ) is a phase-II/III trial that is currently ongoing checking the efficacy of olaparib and carboplatin combination in a neoadjuvant setting ( 107 ). Table II summarizes the clinical trials taken from clinicaltrials.gov.…”

PARP inhibitors in breast cancer: Bringing synthetic lethality to the bedside

“…The primary endpoint is invasive disease‐free survival with secondary endpoints of OS, distant disease‐free survival, and the development of new primary malignancies as well as safety and tolerability. Olaparib is also being studied in the neoadjuvant setting in combination with platinum‐based chemotherapy for basal TNBC and BRCA ‐mutant breast cancer …”

“…Olaparib is also being studied in the neoadjuvant setting in combination with platinum-based chemotherapy for basal TNBC and BRCA-mutant breast cancer. 58 Finally, rucaparib is being tested in a phase 2 trial as adjuvant treatment with cisplatin in patients who have TNBC and BRCA-mutant breast cancer with residual disease after receiving anthracycline and/or taxane neoadjuvant therapy. 59 Patients were randomized to cisplatin with or without rucaparib for 24 weeks.…”