The effect of age on efficacy, safety and patient-centered outcomes with rucaparib: A post hoc exploratory analysis of ARIEL3, a phase 3, randomized, maintenance study in patients with recurrent ovarian carcinoma

Abstract

Background: In the phase 3 trial ARIEL3, maintenance treatment with the poly(ADP-ribose) polymerase (PARP) inhibitor rucaparib provided clinical benefit versus placebo for patients with recurrent, platinum-sensitive ovarian cancer. Here, we evaluate the impact of age on the clinical utility of rucaparib in ARIEL3.

Methods: Patients with platinum-sensitive, recurrent ovarian carcinoma with ≥2 prior platinum-based chemotherapies who responded to their last platinum-based therapy were enrolled in ARIEL3 and randomized 2:1 to rucaparib 600 mg twice daily or placebo. Exploratory, post hoc analyses of progression-free survival (PFS), patient-centered outcomes (quality-adjusted PFS [QA-PFS] and quality-adjusted time without symptoms or toxicity [Q-TWiST]), and safety were conducted in three age subgroups (<65 years, 65-74 years, and ≥75 years).

Results: Investigator-assessed PFS was significantly longer with rucaparib than placebo in patients aged <65 years (rucaparib n = 237 vs placebo n = 117; median, 11.1 vs 5.4 months; hazard ratio [HR]: 0.33 [95% confidence interval (95% CI) 0.25-0.43]; P < 0.0001) and 65-74 years (n = 113 vs n = 64; median, 8.3 vs 5.3 months; HR 0.43 [95% CI 0.29-0.63]; P < 0.0001) and numerically longer in patients aged ≥75 years (n = 25 vs n = 8; median, 9.2 vs 5.5 months; HR 0.47 [95% CI 0.16-1.35]; P = 0.1593). QA-PFS and Q-TWiST were significantly longer with rucaparib than placebo across all age subgroups. Safety of rucaparib was generally similar across the age subgroups.

Conclusions: Efficacy, patient-centered outcomes, and safety of rucaparib were similar between age subgroups, indicating that all eligible women with recurrent ovarian cancer should be offered this therapeutic option, irrespective of age. https://ichgcp.net/clinical-trials-registry/NCT01968213.

Keywords: Elderly patients; Maintenance; Ovarian cancer; PARP inhibitor; Rucaparib.

Conflict of interest statement

Declaration of competing interest Nicoletta Colombo: Served in a consulting or advisory role for Clovis Oncology, AstraZeneca, BIOCAD, Pfizer, PharmaMar, Roche, and Tesaro. Amit M. Oza: Served on advisory boards for Clovis Oncology, Amgen, AstraZeneca, GlaxoSmithKline, and Immunovaccine. Domenica Lorusso: Served in a consulting or advisory role for Clovis Oncology, AstraZeneca, ImmunoGen, Merck, PharmaMar, Roche, Takeda, and Tesaro and received support for travel or accommodation from PharmaMar and Roche. Carol Aghajanian: Served on a steering committee for Clovis Oncology, AbbVie, Genentech, and Mateon Therapeutics; served on advisory boards for Clovis Oncology, Cerulean Pharma, Eisai/Merck, ImmunoGen, and Tesaro; received research grants from Clovis Oncology, AbbVie, AstraZeneca, and Genentech; and received honoraria from Clovis Oncology, Cerulean Pharma, Eisai/Merck, ImmunoGen, Mateon Therapeutics, and Tesaro. Ana Oaknin: Served on advisory boards for Clovis Oncology, AstraZeneca, ImmunoGen, Genmab/Seattle Genetics, PharmaMar, Roche, and Tesaro; received support for travel or accommodation from Clovis Oncology, AstraZeneca, PharmaMar, and Roche; and received research grants from Clovis Oncology, AbbVie Deutschland, Ability Pharmaceuticals, Advaxis, Aeterna Zentaris, Amgen SA, Aprea Therapeutics AB, Bristol-Myers Squibb, Eisai, F. Hoffmann-La Roche, ImmunoGen, Merck Sharp & Dohme de España SA, Millennium Pharmaceuticals, PharmaMar, Regeneron Pharmaceuticals, and Tesaro. Andrew Dean: Served in a consulting or advisory role for Precision Oncology Australia, Shire Pharmaceuticals, and Specialised Therapeutics Australia. Johanne I. Weberpals: Received research support from AbbVie and AstraZeneca and served on advisory boards for AstraZeneca. Andrew R. Clamp: Served on advisory boards for AstraZeneca; received research funding from Clovis Oncology and AstraZeneca; and received support for travel and accommodation for congress attendance from Clovis Oncology, AstraZeneca, and Roche. Giovanni Scambia: Served in a consulting or advisory role for Clovis Oncology, AstraZeneca, PharmaMar, Roche, and Tesaro. Alexandra Leary: Served on advisory boards for Clovis Oncology, AstraZeneca, BIOCAD, GamaMabs, Genmab/Seattle Genetics, Merck Sharp & Dohme, Pfizer, PharmaMar, and Tesaro; received support for travel and accommodation from Clovis Oncology, AstraZeneca, Roche, and Tesaro; and reports institutional research grant support from Clovis Oncology, AstraZeneca, GamaMabs, Inivata, Merck Sharp & Dohme, Merus, Sanofi, and Tesaro. Robert W. Holloway: Served on speakers bureaus for Clovis Oncology, AstraZeneca, and Tesaro. Margarita Amenedo Gancedo: Served on advisory boards for Clovis Oncology and on speakers bureaus for AstraZeneca, PharmaMar, and Roche. Peter C. Fong: Served on advisory boards for Clovis Oncology and AstraZeneca and received honoraria from AstraZeneca. Jeffrey C. Goh: Served in a consulting or advisory role for AstraZeneca, Bristol-Myers Squibb and Tesaro; served on speakers bureaus for Ipsen and Merck Sharp & Dohme; and received support for travel or accommodation from Astellas, AstraZeneca, and Bristol-Myers Squibb. David M. O'Malley: Served on advisory boards for Clovis Oncology, AbbVie, AstraZeneca, Eisai, Genentech/Roche, Genelux, Iovance Biotherapeutics, Janssen, Novocure, Regeneron, and Tesaro; has served on steering committees for Clovis Oncology, Agenus, Amgen, and Novocure; has served as a consultant for AbbVie, Ambry, AstraZeneca, Genentech/Roche, Gynecologic Oncology Group Foundation, and Tesaro; has given a presentation on ovarian cancer at the National Comprehensive Cancer Network; and his institution has received research support from Clovis Oncology, AbbVie, Agenus, Amgen, Ajinomoto, Array BioPharma, AstraZeneca, Bristol-Myers Squibb, Cerulean Pharma, Eisai, EMD Serono, ERGOMED Clinical Research, Genentech, Gynecologic Oncology Group, INC Research, inVentiv Health Clinical, Iovance Biotherapeutics, Janssen Research and Development, Ludwig Institute for Cancer Research, New Mexico Cancer Care Alliance, Novocure, PRA International, Regeneron Pharmaceuticals, Serono, Stemcentrx, Tesaro, TRACON Pharmaceuticals, VentiRx, and Yale University. Deborah K. Armstrong: Served as a scientific advisor for Morphotek and received research funding from Clovis Oncology, Advaxis, AstraZeneca, Pfizer, Syndax, and Tesaro. Susana Banerjee: Served on advisory boards and received honoraria from Clovis Oncology, AstraZeneca, PharmaMar, Seattle Genetics, and Tesaro; received honoraria from Merck Serono and Roche; and received support for travel or accommodation from NuCana and Tesaro. Jesus García-Donas: Received research funding from AstraZeneca, Pierre Fabre, and Pfizer; received personal fees from Clovis Oncology, Astellas, Pierre Fabre, and Pfizer; and received nonfinancial support from Astellas, Pierre Fabre, and Pfizer. Elizabeth M. Swisher: Has nothing to disclose. Juliette Meunier: Employee of Modus Outcomes, which was contracted by Clovis Oncology to conduct these analyses. Terri Cameron, Lara Maloney, Sandra Goble, and Josh Bedel: Employees of Clovis Oncology and may own stock or have stock options in that company. Jonathan A. Ledermann: Received lecture fees from Clovis Oncology, AstraZeneca, Merck/Merck Sharp & Dohme, Pfizer, and Tesaro; served on advisory boards for Clovis Oncology, Artios Pharma, AstraZeneca, Cristal Therapeutics, Merck/Merck Sharp & Dohme, Pfizer, Regeneron, Roche, Seattle Genetics, and Tesaro; and received research grants from AstraZeneca and Merck/Merck Sharp & Dohme. Robert L. Coleman: Reports grants from Clovis Oncology, AstraZeneca, Gateway Foundation, Janssen, Judy Reis/Albert Pisani, MD, Ovarian Cancer Research Fund, Merck, National Institutes of Health, Roche/Genentech, and V-Foundation; has served as an advisor to Clovis Oncology, Agenus, AstraZeneca, GamaMabs, Genmab, Janssen, OncoQuest, Pfizer (Medivation), Regeneron, Roche/Genentech, and Tesaro; and has an endowment as the Ann Rife Cox Chair in Gynecology.

Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.

Figures

Fig. 1.

Probability of PFS as assessed by investigator (A, B, C) and BICR (D, E, F) according to age subgroup (A, D:

Fig. 2.

Comparison of investigator-assessed PFS and QA-PFS according to age subgroup (A:

Fig. 3.

TWiST analyses with TOX defined as all grade ≥3 TEAEs (A: a (G) and as grade ≥2 TEAEs of nausea, vomiting, fatigue, and astheniab (H). aμTOX values: 0.90 (<65 years), 0.87 (65–74 years), 0.94 (≥75 years). bμTOX values: 0.86 (<65 years), 0.84 (65–74 years), 0.83 (≥75 years). μTOX, mean utility weight for TOX health state; CI, confidence interval; Q-TWiST, quality-adjusted time without symptoms or toxicity; TEAE, treatment-emergent adverse event; TOX, time with toxicity of treatment.

Fig. 3.

TWiST analyses with TOX defined as all grade ≥3 TEAEs (A: a (G) and as grade ≥2 TEAEs of nausea, vomiting, fatigue, and astheniab (H). aμTOX values: 0.90 (<65 years), 0.87 (65–74 years), 0.94 (≥75 years). bμTOX values: 0.86 (<65 years), 0.84 (65–74 years), 0.83 (≥75 years). μTOX, mean utility weight for TOX health state; CI, confidence interval; Q-TWiST, quality-adjusted time without symptoms or toxicity; TEAE, treatment-emergent adverse event; TOX, time with toxicity of treatment.

Fig. 4.

Forest plot of relative risk of most frequent any grade TEAEs (≥35% of patients. in any age subgroup) and grade ≥3 TEAEs. aCombined AST elevation and ALT elevation. bCombined anemia and decreased hemoglobin. cCombined asthenia and fatigue. dCombined thrombocytopenia and decreased platelet count. ALT, alanine aminotransferase; AST, aspartate aminotransferase; CI, confidence interval; TEAEs, treatment-emergent adverse events.