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.
This is a multicenter, single–arm, two–cohort, Simon’s two–stage, phase II trial. The cohort A will recruit N = 20 gBRCAm ABC pts. The cohort B will recruit N = 13 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 = 20), 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 = 13) ORR will be promising with ≥3 responders among 13 pts (p < 0.025; H0: ORR≤5%). Secondary objectives: Safety–related outcomes, clinical benefit rate, overall survival, and quality of life. Exploratory objectives: Prevalence of gBRCAm and HRD in HER2[+] ABC, and identification of new potential predictive markers.
NCT03931551. First Posted: April 30, 2019.
Medica Scientia Innovation Research (MedSIR); Experior.
AstraZeneca Famacéutica Spain S.A.
J.A. García-Sáenz: 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. López-Miranda: Full / Part-time employment: Medica Scientia Innovation Research (MedSIR). J. Cortés: 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 Sharp&Dohme, Pfizer, Piqur Therapeutics, Puma C, Queen Mary University of London; 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.