In the randomised, placebo-controlled, phase 3 study ARIEL3, patients were randomised 2:1 to oral rucaparib (600 mg BID) or placebo as maintenance treatment following response to platinum-based chemotherapy. Rucaparib significantly improved progression-free survival (PFS) vs placebo in all patient populations regardless of biomarker status (Coleman et al. Lancet. 2017;390:1949-61). This post hoc exploratory analysis investigated the effect of the number of prior chemotherapy regimens on the primary and secondary endpoints of investigator-assessed and blinded independent central review (BICR)-assessed PFS in ARIEL3.
In ARIEL3, all patients received ≥2 prior platinum-based regimens in accordance with the protocol. PFS was explored in subgroups of patients who received 2 or ≥ 3 prior chemotherapy regimens. These subgroup analyses were presented for the following predefined cohorts: BRCA mutant; BRCA mutant or BRCA wild type/high loss of heterozygosity (LOH); and intent-to-treat (ITT) population (ie, all randomised patients).
The visit cutoff dates for efficacy and safety were 15 April 2017 and 15 August 2017, respectively. In each predefined cohort, rucaparib significantly improved PFS compared to placebo irrespective of the number of prior chemotherapy regimens (ie, 2 or ≥ 3) (Table). Rucaparib’s safety profile was consistent between patients who received 2 or ≥ 3 prior chemotherapy regimens as assessed by the rate of all grade (100% and 100%) and grade ≥3 (59% and 59%) treatment-emergent adverse events (TEAEs) and dose modifications (ie, treatment interruptions and/or dose reductions due to a TEAE) (70% and 74%) in each respective subgroup.Table: 947P
|Cohort||Rucaparib, n||Placebo, n||PFS (investigator review)||PFS (BICR)|
|HR* (95% CI)||Median PFS, mo; P value†||HR* (95% CI)||Median PFS, mo; P value†|
|Rucaparib vs placebo||Rucaparib vs placebo|
|Patients with 2 prior chemotherapy regimens|
|BRCA mutant||73||40||0.24 (0.14–0.40)||21.9 vs 5.4; P<0.0001||0.24 (0.13–0.45)||26.8 vs 5.5; P<0.0001|
|BRCA mutant or BRCA wild type/ high LOH||136||75||0.34 (0.23–0.49)||14.1 vs 5.5; P<0.0001||0.33 (0.21–0.52)||26.8 vs 5.5; P < 0.0001|
|ITT||231||124||0.42 (0.32–0.55)||10.4 vs 5.4; P<0.0001||0.37 (0.27–0.50)||17.1 vs 5.4; P<0.0001|
|Patients with ≥3 prior chemotherapy regimens|
|BRCA mutant||57||26||0.21 (0.11–0.40)||13.7 vs 5.4; P<0.0001||0.17 (0.08–0.35)||18.0 vs 5.4; P<0.0001|
|BRCA mutant or BRCA wild type/high LOH||100||43||0.27 (0.16–0.44)||11.1 vs 5.4; P<0.0001||0.30 (0.18–0.52)||13.6 vs 5.4; P<0.0001|
|ITT||144||65||0.28 (0.19–0.41)||11.1 vs 5.3; P<0.0001||0.36 (0.24–0.53)||13.3 vs 5.3; P<0.0001|
Cox proportional hazards model; P values for treatment-by-prior chemotherapy regimen subgroup interaction were nonsignificant for all analyses. †Stratified log-rank P value. CI, confidence interval; HR, hazard ratio.
Maintenance treatment with rucaparib improved PFS vs placebo in all 3 predefined cohorts regardless of the number of prior chemotherapy regimens received.
Clinical trial identification
Legal entity responsible for the study
Clovis Oncology, Inc.
Clovis Oncology, Inc.
Writing and editorial support, funded by Clovis Oncology, Inc. (Boulder, CO, USA) was provided by Nathan Yardley, PhD, and Shannon Davis of Ashfield Healthcare Communications (Middletown, CT, USA).
D. Lorusso: Consulting or advisory role: AstraZeneca, Clovis Oncology, Roche, Tesaro, PharmaMar; Support for travel or accommodation: Roche, PharmaMar. R.L. Coleman: Grants: AstraZeneca, Roche/Genentech, Janssen, OncoMed, Millennium, Merck, Clovis Oncology, Esperance, AbbVie; Advisor: AstraZeneca, Roche/Genentech, Janssen, OncoMed, Millennium, Merck, Clovis Oncology, Esperance, Tesaro, GamaMabs, Pfizer, Genmab, Gradalis, Bayer, AbbVie. A.M. Oza: Steering committees: AstraZeneca, Clovis Oncology, Tesaro. C. Aghajanian: Steering committee: Mateon Therapeutics, Clovis Oncology; Advisory boards: Clovis Oncology, Cerulean Pharma, Bayer, VentiRx, Tesaro; Honorarium: Mateon Therapeutics, Clovis Oncology, Cerulean Pharma, Bayer, VentiRx, Tesaro. A. Oaknin: Advisory boards: Roche, AstraZeneca, PharmaMar, Clovis Oncology, Tesaro; Travel or accommodation: Roche, AstraZeneca, PharmaMar. A. Dean: Consulting or advisory role: Specialised Therapeutics Australia, Shire Pharmaceuticals, Precision Oncology Australia. N. Colombo: Consulting or advisory role: Roche, AstraZeneca, Tesaro, PharmaMar, Clovis Oncology, Pfizer, Advaxis. J.I. Weberpals: Research support: AbbVie and AstraZeneca; Advisory boards: AstraZeneca. A.R. Clamp: Advisory boards: AstraZeneca, Roche; Research funding: AstraZeneca; Travel and accommodation for congress attendance: AstraZeneca. G. Scambia: Consulting or advisory role: Roche, AstraZeneca, PharmaMar, Clovis Oncology, Tesaro. A. Leary: Advisory board: Clovis Oncology, Pfizer, PharmaMar; Institutional research grant support: GamaMabs, Merus; Boarding and travel expenses for congress activities: AstraZeneca. R.W. Holloway: Speakers bureau: AstraZeneca, Clovis Oncology, Tesaro; Advisory board: Clovis Oncology. P.C. Fong: Advisory boards: Clovis Oncology, AstraZeneca; Honoraria: AstraZeneca. J.C. Goh: Honoraria: Bristol-Myers Squibb, AstraZeneca; Consulting or advisory role: Bristol-Myers, Squibb, AstraZeneca, Janssen; Speakers bureau: AstraZeneca, Novartis; Support for travel or accommodation: Roche, Bristol-Myers Squibb, Astellas. D.M. O’Malley: Advisory board: Clovis Oncology, AstraZeneca, Janssen, Gynecologic Oncology Group, Myriad, Tesaro; Steering committees: Clovis Oncology, Amgen, Immunogen; Consultant to AbbVie, AstraZeneca, Tesaro, Health Analytics, Ambry; Institution received research support from Agenus, Ajinomoto, Array BioPharma, AstraZeneca, Bristol-Myers Squibb, Clovis Oncology, Ergomed Clinical research, Exelixis, Genentech, GlaxoSmithKline, Gynecologic Oncology Group, ImmunoGen, INC Research, inVentiv Health Clinical, Janssen Research and Development, Ludwig Institute for Cancer Research, Novartis Pharmaceuticals, PRA International, Regeneron Pharmaceuticals, Serono, Stemcentrx, Tesaro, Tracon Pharmaceuticals. S. Banerjee: Institutional research support: AstraZeneca, Janssen-Cilag; Consulting or advisory role: AstraZeneca, Roche, GamaMabs Pharma, PharmaMar, AstraZeneca/MedImmune, Tesaro, Clovis Oncology; Support for travel or accommodation: AstraZeneca, Clovis Oncology, Tesaro. S. Goble, T. Cameron: Employee of Clovis Oncology and may own stock or have stock options in that company. J.A. Ledermann: Advisory role: Clovis Oncology, AstraZeneca, Pfizer; Speakers bureau for and research grants from: AstraZeneca, Merck/MSD. All other authors have declared no conflicts of interest.