Exploring the Impact of Treatment Switching on Overall Survival from the PROfound Study in Homologous Recombination Repair (HRR)-Mutated Metastatic Castration-Resistant Prostate Cancer (mCRPC)

Rachel Evans*, Neil Hawkins, Pascale Dequen-O’Byrne, Charles McCrea, Dominic Muston, Christopher Gresty, Sameer R. Ghate, Lin Fan, Robert Hettle, Keith R. Abrams, Johann de Bono, Maha Hussain, Neeraj Agarwal

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

Abstract

Background: In oncology trials, treatment switching from the comparator to the experimental regimen is often allowed but may lead to underestimating overall survival (OS) of an experimental therapy. Objective: This study evaluates the impact of treatment switching from control to olaparib on OS using the final survival data from the PROfound study and compares validated adjustment methods to estimate the magnitude of OS benefit with olaparib. Patients and methods: The primary population from PROfound (Cohort A) was included, alongside two populations approved for treatment with olaparib by the European Medicines Agency and US Food and Drug Administration: BRCAm and Cohort A+B (excluding the PPP2R2A gene). Five methods were explored to adjust for switching: excluding or censoring patients in the control arm who receive subsequent olaparib, Rank Preserving Structural Failure Time Model (RPSFTM), Inverse Probability of Censoring Weights, and Two-Stage Estimation. Results: The RPSFTM was considered the most appropriate approach for PROfound as the results were robust to sensitivity analysis testing of the common treatment effect assumption. For Cohort A, the final OS hazard ratio reduced from 0.69 (95% CI 0.5–0.97) to between 0.42 (0.18–0.90) and 0.52 (0.31–1.00) for olaparib versus control, depending on the RPSFTM selected. Median OS reduced from 14.7 months to between 11.73 and 12.63 months for control. Conclusions: The magnitude of the statistically significant (P < 0.05) survival benefit of olaparib versus control observed in Cohort A of PROfound is likely to be underestimated if adjustment for treatment switching from control to olaparib is not conducted. The RPSFTM was considered the most plausible method, although further development and validation of robust methods to estimate the magnitude of impact of treatment switching is needed.

Original languageEnglish (US)
Pages (from-to)613-623
Number of pages11
JournalTargeted Oncology
Volume16
Issue number5
DOIs
StatePublished - Sep 2021

Funding

This study was funded by AstraZeneca and is part of an alliance between AstraZeneca and Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Rachel Evans—Advisory/consultancy: AstraZeneca. Employment: Visible Analytics. Neil Hawkins—Advisory/consultancy: AstraZeneca. Employment: Health Economics and Health Technology Assessment, University of Glasgow, Glasgow, UK. Employee of Visible Analytics. Pascale Dequen-O’Byrne—Advisory/consultancy: AstraZeneca. Employment: Visible Analytics. Charles McCrea—Employment and stock ownership: AstraZeneca. Dominic Muston—Employment: Merck. Christopher Gresty—Employment and stock ownership: AstraZeneca. Sameer Ghate—Employment: Merck. Lin Fan—Employment: Merck. Robert Hettle—Employment and stock ownership: AstraZeneca. Keith Abrams—Advisory/consultancy: AstraZeneca. Affiliated (as an employee until 31 December 2020) to: Department of Health Sciences, University of Leicester, Leicester, UK. Partially supported as a UK National Institute for Health Research (NIHR) Senior Investigator Emeritus (NF-SI-0512-10159). The views expressed are those of the author and not necessarily those of NHS, NHS or Department of Health & Social Care. Employee of Visible Analytics. Johann de Bono—Advisory boards and received fees from many companies, including: Astra Zeneca, Astellas, Bayer, Bioxcel Therapeutics, Boehringer Ingelheim, Cellcentric, Daiichi, Eisai, Genentech/Roche, Genmab, GSK, Janssen, Merck Serono, Merck Sharp & Dohme, Menarini/Silicon Biosystems, Orion, Pfizer, Qiagen, Sanofi Aventis, Sierra Oncology, Taiho, Vertex Pharmaceuticals. Employment: The ICR, which have received funding or other support for his research work from AZ, Astellas, Bayer, Cellcentric, Daiichi, Genentech, Genmab, GSK, Janssen, Merck Serono, MSD, Menarini/Silicon Biosystems, Orion, Sanofi Aventis, Sierra Oncology, Taiho, Pfizer, Vertex, and which has a commercial interest in abiraterone, PARP inhibition in DNA repair defective cancers and PI3K/AKT pathway inhibitors (no personal income). Patent: Named as an inventor, with no financial interest, for patent 8,822,438. He has been the CI/PI of many industry sponsored clinical trials. JDB is a National Institute for Health Research (NIHR) Senior Investigator. The views expressed in this article are those of the author(s) and not necessarily those of the NHS, the NIHR, or the Department of Health. Maha Hussain—Grant support (paid to Northwestern University): AstraZeneca, Prostate Cancer Clinical Trials Consortium. Advisory board fees, travel support and grant support (paid to Northwestern University): Bayer. Advisory board fees, travel support and grant support (paid to University of Michigan): Pfizer. Advisory board fees, lecture fees, travel support and grant support (paid to Northwestern University): Genentech. Travel support and honoraria (lecture): Astellas. Honoraria (lecture): Physicians’ Education Resource, Sanofi/Genzyme, Phillips Gilmore Oncology, MLI Peer Review. Honoraria (educational material): Projects in Knowledge. Honoraria (educational review): Research to Practice. Neeraj Agarwal—Advisory board fees: Astellas Pharma, AstraZeneca, Bayer, Bristol-Myers Squibb, Clovis Oncology, Eisai, Eli Lilly, EMD Serono, Exelixis, Foundation Medicine, Genentech, Janssen Biotech, Merck, Nektar Therapeutics, Novartis, Pfizer, Pharmacyclics (an AbbVie company), Seattle Genetics. ®

ASJC Scopus subject areas

  • Oncology
  • Cancer Research
  • Pharmacology (medical)

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