Abstract 622P
Background
In oncology trials, patients switching from the comparator to the experimental treatment may lead to underestimation of the ‘true’ OS benefit for the experimental treatment. By adjusting for switching, further insight can be gained into OS benefit. In the phase 3 PROfound study (NCT02987543) of olaparib versus physician’s choice of new hormonal agent (pcNHA) in patients with metastatic castration-resistant prostate cancer and a homologous recombination repair gene alteration, patients in the pcNHA arm were eligible to receive olaparib after progression assessed by blinded independent central review. We explored the impact of switching on the interim OS results for Cohort A in PROfound using five statistical approaches, including simple and more complex methods.
Methods
Following guidance from health technology assessment agencies and the European Medicines Agency, the switching-adjustment methods comprised two simple methods of 1) excluding patients in the pcNHA arm who received subsequent olaparib, 2) censoring patients in the pcNHA arm on receiving subsequent olaparib, and three more complex methods of 3) rank preserving structural failure time model (RPSFTM), 4) inverse probability of censoring weights (IPCW), and 5) two-stage estimation (TSE).
Results
At the interim analysis, the OS hazard ratio (HR) in Cohort A was 0.64 (95% confidence interval [CI] 0.42–0.97), with 61% of patients randomized to pcNHA having switched to olaparib. With simple methods, the switching-adjusted HRs (95% CI) ranged from 0.36 (0.20–0.64) to 0.63 (0.35–1.13). The more complex methods of RPSFTM and IPCW yielded HRs of 0.41 (0.22–0.77) to 0.52 (0.28–0.95); the TSE method could not be reliably performed as a suitable secondary baseline was not identified.
Conclusions
This analysis shows that the effect of olaparib versus pcNHA is likely to be underestimated if switching is not adjusted for, with all methods demonstrating a meaningful benefit in interim OS for olaparib. RPSFTM and IPCW provided more clinically credible results than alternative methods. Limitations include the number of ‘unswitched’ patients in the pcNHA arm and the assumptions required of each method. Further switching analyses on the final OS data are planned.
Clinical trial identification
NCT02987543 (release date 19 October 2016).
Editorial acknowledgement
Legal entity responsible for the study
AstraZeneca and Merck Sharp & Dohme Corp, a subsidiary of Merck & Co, Inc, Kenilworth,NJ, USA.
Funding
AstraZeneca and Merck Sharp & Dohme Corp, a subsidiary of Merck & Co, Inc, Kenilworth, NJ, USA.
Disclosure
N. Agarwal: Advisory/Consultancy: Argos; Advisory/Consultancy: Clovis; Advisory/Consultancy: Foundation One; Advisory/Consultancy: Astellas; Advisory/Consultancy: Eli Lilly; Advisory/Consultancy: Nektar; Advisory/Consultancy: Seattle Genetics; Advisory/Consultancy, Research grant/Funding (institution): Merck; Advisory/Consultancy, Research grant/Funding (institution): Pfizer; Advisory/Consultancy, Research grant/Funding (institution): Exelixis; Advisory/Consultancy, Research grant/Funding (institution): EMD Serono; Advisory/Consultancy, Research grant/Funding (institution): Eisai; Advisory/Consultancy, Research grant/Funding (institution): Bayer; Advisory/Consultancy, Research grant/Funding (institution): Novartis; Advisory/Consultancy, Research grant/Funding (institution): Genentech; Advisory/Consultancy, Research grant/Funding (institution): AstraZeneca; Advisory/Consultancy, Research grant/Funding (institution): Medivation; Research grant/Funding (institution): Active Biotech; Research grant/Funding (institution): Bavarian Nordic; Research grant/Funding (institution): Calithera; Research grant/Funding (institution): GlaxoSmithKline; Research grant/Funding (institution): Celldex; Research grant/Funding (institution): Immunomedics; Research grant/Funding (institution): Janssen; Research grant/Funding (institution): New Link Genetics; Research grant/Funding (institution): Prometheus; Research grant/Funding (institution): Rexahn; Research grant/Funding (institution): Sanofi; Research grant/Funding (institution): Takeda; Research grant/Funding (institution): Tracon. R. Evans: Advisory/Consultancy: AstraZeneca; Advisory/Consultancy: Visible Analytics. K. Abrams: Advisory/Consultancy: AstraZeneca; Research grant/Funding (self): UK National Institute for Health Research; Full/Part-time employment: University of Leicester; Advisory/Consultancy: Visible Analytics. P. Dequen-O'Byrne: Advisory/Consultancy: AstraZeneca; Advisory/Consultancy: Visible Analytics. C. McCrea: Shareholder/Stockholder/Stock options, Full/Part-time employment: AstraZeneca. D. Muston: Full/Part-time employment: Merck. C. Gresty: Shareholder/Stockholder/Stock options, Full/Part-time employment: AstraZeneca. S. Ghate: Full/Part-time employment: Merck. L. Fan: Full/Part-time employment: Merck. R. Hettle: Shareholder/Stockholder/Stock options, Full/Part-time employment: AstraZeneca. N. Hawkins: Advisory/Consultancy: AstraZeneca; Full/Part-time employment: University of Glasgow; Advisory/Consultancy: Visible Analytics.