Effectiveness of olaparib plus trastuzumab in HER2[+], BRCA–mutated (BRCAm) or homologous recombination deficient (HRD) advanced breast cancer (ABC) patients (pts). The OPHELIA study

Abstract

Abstract Background In the OlympiAD trial the use of poly(adenosine diphosphate–ribose) polymerase inhibitor (PARPi) olaparib resulted in better progression–free survival (PFS) than standard chemotherapy, which led to approval in germinal BRCAm (gBRCAm)/HER2[-] ABC pts. There is a potential therapeutic role for PARPis in pts with defective DNA repair. Preclinical data support a strong synergism with trastuzumab in HER2[+] cells that are sensitive to PARPis. This study will evaluate the efficacy and safety of olaparib plus trastuzumab in HER2[+] gBRCAm or wild–type gBRCA/HRD ABC pts. Trial design This is a multicenter, single–arm, two–cohort, Simon’s two–stage, phase II trial. The cohort A will recruit N\xa0=\xa020 gBRCAm ABC pts. The cohort B will recruit N\xa0=\xa013 wild–type gBRCA/HRD ABC pts based on HRDetect assay. Pts will receive olaparib (300mg p.o. b.i.d. during 21–day cycles) in combination with trastuzumab (IV/SC at standard dose) until progression or unacceptable toxicity. Main selection criteria: (1) Pre– and post–menopausal women with HER2[+] ABC; (2) ≤3 prior regimens of chemotherapy and/or trastuzumab–lapatinib in advanced setting, and at least 1 regimen of chemotherapy including trastuzumab; (3) Pts treated with carboplatin or platinum compounds in the last 12 months are not eligible; (4) Evaluable or measurable disease. Co–Primary objectives: Overall response rate (ORR) and PFS of olaparib plus trastuzumab in the cohort A. In the cohort A (N\xa0=\xa020), we plan a Simon’s two–stage design (7 pts in the 1st stage and 13 pts in the 2nd stage in case of any responder in 1st stage). Final ORR will be promising with ≥4 responders among 18 evaluable pts (H0: ORR≤5%; HA: ORR≥30%). PFS estimation will be based a one–arm log–rank test (H0: PFS≤3–months; HA: PFS≥6–months). These give us an 80% power at 0.025 one–sided alpha level. In the cohort B (N\xa0=\xa013) ORR will be promising with ≥3 responders among 13 pts (p\xa0 Clinical trial identification NCT03931551. First Posted: April 30, 2019. Legal entity responsible for the study Medica Scientia Innovation Research (MedSIR); Experior. Funding AstraZeneca Famaceutica Spain S.A. Disclosure J.A. Garcia-Saenz: Advisory / Consultancy, Speaker Bureau / Expert testimony: Novartis, Celgene, Eli Lilly, EISAI, Roche; Research grant / Funding (institution): AstraZeneca; Travel / Accommodation / Expenses: Novartis, Roche, Pfizer. J. Balmana: Advisory / Consultancy: AstraZeneca, Pfizer. E. Lopez-Miranda: Full / Part-time employment: Medica Scientia Innovation Research (MedSIR). J. Cortes: Advisory / Consultancy: Roche, Celgene, Cellestia, AstraZeneca, Biothera Pharmaceutical, Merus, Seattle Genetics, Daiichi Sankyo, Erytech, Athenex; Honoraria (institution): Roche, Novartis, Celgene, Eisai, Pfizer, Samsung; Research grant / Funding (institution): Roche, Ariad pharmaceuticals, AstraZeneca, Baxalta GMBH/Servier Affaires, Bayer healthcare, Eisai, F.Hoffman-La Roche, Guardanth health, Merck SharpD Advisory / Consultancy, Shareholder / Stockholder / Stock options, Officer / Board of Directors: Medica Scientia Innovation Research (MedSIR). A. Llombart Cussac: Honoraria (institution), Advisory / Consultancy: Roche, GlaxoSmithKline, Novartis, Celgene, Eisai, AstraZeneca; Research grant / Funding (institution): GlaxoSmithKline, Sanofi, Puma Biotechnology; Advisory / Consultancy, Shareholder / Stockholder / Stock options, Officer / Board of Directors: Medica Scientia Innovation Research (MedSIR). All other authors have declared no conflicts of interest.