https://orcid.org/0000-0002-1032-1479
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Abstract
Patients with platinum-resistant or -refractory high-grade serous ovarian cancer (HGSOC) have a poor prognosis, and their management represents a substantial unmet medical need. Preclinical data and results from a phase Ib trial demonstrated the efficacy and tolerability of the combination of the α-specific phosphatidylinositol-3-kinase (PI3K) inhibitor alpelisib plus the poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitor olaparib in platinum-resistant, non-BRCA-mutated ovarian cancer. Here, we describe the study design and rationale for the phase III, multicenter, open-label, randomized, active-controlled EPIK-O/ENGOT-OV61 trial investigating alpelisib in combination with olaparib compared with standard-of-care chemotherapy in patients with platinum-resistant or -refractory HGSOC with no germline BRCA mutation. Progression-free survival (blinded independent review committee) is the primary end point. Overall survival is a key secondary end point.
Clinical Trial Registration:: NCT04729387 (ClinicalTrials.gov)
Author contributions
All authors made substantial contributions to the conception or design of the work, drafting the work or revising it critically for important intellectual content, provided final approval of the version to be published and agreed to be accountable for all aspects of the work.
Acknowledgments
The authors would like to thank all of the patients and their families and the investigators participating in this study.
Financial & competing interests disclosure
The study is sponsored by Novartis Pharmaceuticals Corporation. Olaparib is supplied by or on behalf of AstraZeneca UK Ltd. The authors would also like to acknowledge the support of the preclinical work and the previous phase Ib investigator-initiated trial by the Breast Cancer Research Foundation, the Stand Up To PI3K Cancer Dream Team Translational Research grant (SU2C-AACR-DT0209) and the Stand Up To Cancer/Ovarian Cancer Research Fund Alliance/National Ovarian Cancer Coalition Ovarian Cancer Dream Team Translational Research grant (grant no: SU2C-AACR-DT16–15). Stand Up To Cancer is a division of the Entertainment Industry Foundation. Research grants are administered by the American Association for Cancer Research, the Scientific Partner of SU2C. Medical editorial assistance was provided by T Wabbersen, PhD, W Ho, PhD, and S Tandon, PhD, of MediTech Media and funded by Novartis Pharmaceuticals Corporation. Drs PA Konstantinopoulos and UA Matulonis are supported by the NCI-funded Dana-Farber/Harvard Cancer Center SPORE grant (P50CA240243). PA Konstantinopoulos reports membership on the advisory board of AstraZeneca. A Gonzalez-Martin reports consulting fees from Alkermes, Amgen, AstraZeneca, Clovis, GSK, Genmab, Mersana, Roche, MSD, ImmunoGen, Oncoinvent, PharmaMar, SOTIO Biotech and Takeda; lecture fees from AstraZeneca, Clovis, GSK, Roche and MSD; travel/meeting fees from AstraZeneca, GSK, Roche and MSD; and a position as president of the European Network for Gynaecological Oncological Trial (ENGOT) groups and Grupo Español de Investigación en Cáncer de Ovario (GEICO). FM Cruz reports speaker fees from Janssen; travel/meeting fees from Janssen and Novartis; and membership on the advisory boards of Janssen and Novartis. M Friedlander reports grants paid to institution from Novartis, AstraZeneca and Beigene; consulting fees from AstraZeneca, MSD, GSK, Lilly, Takeda, Eisei and Novartis; lecture fees from AstraZeneca, MSD and GSK; and travel/meeting fees from AstraZeneca. Rosalind Glasspool reports consulting fees paid to the institution from Novartis; grants from Boehringer Ingelheim, Lilly/Ignyta and Clovis Oncology; membership on the advisory boards of AstraZeneca, Clovis Oncology, MSD, SOTIO Biotech, ImmunoGen and GSK/Tesaro; lecture fees from AstraZeneca, Clovis Oncology and GSK/Tesaro; travel/meeting fees from AstraZeneca and GSK; membership in the International Gynecologic Cancer Society council, National Cancer Research Institute ovarian workstream group and Scottish Gynaecological Cancer Trials Group; a position as chair of the Gynecological Cancer InterGroup (GCIG) Meta-Analysis Working Group; and receipt of niraparib from GSK as part of a patient drug donation scheme. D Lorusso reports grants from GSK, PharmaMar, MSD and Clovis Oncology; consulting fees from PharmaMar; lecture fees from GSK, AstraZeneca, Clovis Oncology and MSD; expert testimony fees from Clovis Oncology; travel/meeting fees from GSK, Roche, AstraZeneca and PharmaMar; membership on the advisory boards of Roche, PharmaMar, AstraZeneca, GSK, MSD, Merck Serono, ImmunoGen, Genmab, Clovis Oncology and Amgen; membership on the board of directors for GCIG and MITO; and a position as chair of the CGA of ENGOT. C Marth reports lecture fees from Roche, Novartis, MSD, PharmaMar, AstraZeneca, GSK and Seagen; travel/meeting fees from Roche, Novartis, MSD, PharmaMar, AstraZeneca, GSK and Seagen; and membership on the advisory board of GSK. BJ Monk and J-W Kim have nothing to disclose. Olga Ajipa reports employment by Novartis. V Pretre and Y Han report employment by and ownership of stock or stock options with Novartis. UA Matulonis reports consulting fees from NextCure, AstraZeneca, 2X Oncology, GSK and Merck; participation on advisory boards for Novartis, Blueprint Medicines, Trillium Therapeutics and Agenus; scientific advisory board membership with the Clearity Foundation, Rivkin Center and Ovarian Cancer Research Alliance; and data safety monitoring board membership with Symphogen, Advaxis and Alkermes. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
Medical editorial assistance was provided by T Wabbersen (PhD), W Ho (PhD), and S Tandon (PhD), of MediTech Media and funded by Novartis Pharmaceuticals Corporation.
Ethical conduct of research
The authors state that they have obtained appropriate institutional review board approval and have followed the principles outlined in the Declaration of Helsinki for all human experimental investigations. In addition, informed consent has been obtained from the participants involved.
Open access
This work is licensed under the Attribution-NonCommercial-NoDerivatives 4.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/4.0/
Notes
† Platinum-resistant disease is defined as progression 1–6 months after completion of platinum-based therapy. Platinum-refractory disease is defined as progression during treatment or within 4 weeks of the last dose.
‡ Patients with primary platinum-refractory disease (never responded to platinum and progressed during initial platinum-based chemotherapy) are not eligible.
§ Patients with any grade of alopecia are allowed to enter the study.
¶ Only applicable to patients with non-measurable disease by RECIST 1.1.
# Testing for somatic BRCA mutation is not a requirement for eligibility.
†† Adequately treated basal- or squamous-cell carcinoma, non-melanomatous skin cancer or curatively resected cervical cancer are allowed.
CNS: Central nervous system; CTCAE: Common Terminology Criteria for Adverse Events; ECOG: Eastern Cooperative Oncology Group; GCIG: Gynecological Cancer InterGroup criteria; GI: Gastrointestinal; NCI: National Cancer Institute; RECIST: Response Evaluation Criteria in Solid Tumors.