Progression-free survival is a suboptimal predictor for overall survival among metastatic solid tumour clinical trials


      • Phase III metastatic trial utilization of progression-free (PFS) or overall survival (OS).
      • PFS primary end-point (PEP) trials more likely to succeed (67%) versus OS PEP (33%).
      • PEP success associated with molecular profile restriction and single agent therapy.
      • PFS PEP trials had a subsequent OS benefit 38% of the time.



      The use of overall survival (OS) as the gold standard primary end-point (PEP) in metastatic oncologic randomised controlled trials (RCTs) has declined in favour of progression-free survival (PFS) without a complete understanding of the degree to which PFS reliably predicts for OS.


      Using, we identified 1239 phase III oncologic RCTs, 260 of which were metastatic solid tumour trials with a superiority-design investigating a therapeutic intervention by using either a PFS or OS PEP. Each individual trial was reviewed to quantify RCT design factors and disease-related outcomes.


      A total of 172,133 patients were enrolled from the year 1999 to 2015 in RCTs that used PFS (56.2%, 146/260) or OS (43.8%, 114/260) as the PEP. PFS trials were more likely to restrict patient eligibility by using molecular criteria (15.1% versus 4.4%, p = 0.005) use targeted therapy (80.1% versus 67.5%, p = 0.048), accrue fewer patients (median 495 versus 619, p = 0.03), and successfully meet the trial PEP (66.9% versus 33.3%, p < 0.0001). On multiple binary logistic regression analysis, factors that predicted for PFS or OS PEP trial success included choice of PFS PEP (p < 0.0001), molecular profile restriction (p = 0.02) and single agent therapy (p = 0.02). Notably, there was only a 38% (31/82) conversion rate of positive PFS-to-OS benefit; lack of industry sponsorship predicted for PFS-to-OS signal conversion (80.0% without industry sponsorship versus 35.1% with industry sponsorship, p = 0.045).


      A PFS PEP has suboptimal positive predictive value for OS among phase III metastatic solid tumour RCTs. Regulatory agency decisions should be judicious in using PFS results as the primary basis for approval.


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        • Garrett S.B.
        • Koenig C.J.
        • Trupin L.
        • et al.
        What advanced cancer patients with limited treatment options know about clinical research: a qualitative study.
        Support Care Canc. 2017; 25: 3235-3242
        • Kay A.
        • Higgins J.
        • Day A.G.
        • Meyer R.M.
        • Booth C.M.
        Randomized controlled trials in the era of molecular oncology: methodology, biomarkers, and end points.
        Ann Oncol. 2012; 23: 1646-1651
        • Kemp R.
        • Prasad V.
        Surrogate endpoints in oncology: when are they acceptable for regulatory and clinical decisions, and are they currently overused?.
        BMC Med. 2017; 15: 134
        • Kim C.
        • Prasad V.
        Cancer drugs approved on the basis of a surrogate end point and subsequent overall survival: an analysis of 5 years of US Food and drug administration approvals.
        JAMA Intern Med. 2015; 175: 1992-1994
        • Robinson A.G.
        • Booth C.M.
        • Eisenhauer E.A.
        Progression-free survival as an end-point in solid tumours–perspectives from clinical trials and clinical practice.
        Eur J Canc. 2014; 50: 2303-2308
        • Davis S.
        • Tappenden P.
        • Cantrell A.
        A review of studies examining the relationship between progression-free survival and overall survival in advanced or metastatic cancer.
        2012 (London)
        • Booth C.M.
        • Eisenhauer E.A.
        Progression-free survival: meaningful or simply measurable?.
        J Clin Oncol. 2012; 30: 1030-1033
        • Buyse M.
        • Burzykowski T.
        • Carroll K.
        • et al.
        Progression-free survival is a surrogate for survival in advanced colorectal cancer.
        J Clin Oncol. 2007; 25: 5218-5224
        • Foster N.R.
        • Renfro L.A.
        • Schild S.E.
        • et al.
        Multitrial evaluation of progression-free survival as a surrogate end point for overall survival in first-line extensive-stage small-cell lung cancer.
        J Thorac Oncol. 2015; 10: 1099-1106
        • Oza A.M.
        • Castonguay V.
        • Tsoref D.
        • et al.
        Progression-free survival in advanced ovarian cancer: a Canadian review and expert panel perspective.
        Curr Oncol. 2011; 18: S20-S27
        • Soria J.C.
        • Massard C.
        • Le Chevalier T.
        Should progression-free survival be the primary measure of efficacy for advanced NSCLC therapy?.
        Ann Oncol. 2010; 21: 2324-2332
        • Burzykowski T.
        • Buyse M.
        • Piccart-Gebhart M.J.
        • et al.
        Evaluation of tumor response, disease control, progression-free survival, and time to progression as potential surrogate end points in metastatic breast cancer.
        J Clin Oncol. 2008; 26: 1987-1992
        • Armstrong A.J.
        • Febbo P.G.
        Using surrogate biomarkers to predict clinical benefit in men with castration-resistant prostate cancer: an update and review of the literature.
        Oncologist. 2009; 14: 816-827
        • Haslam A.
        • Hey S.P.
        • Gill J.
        • Prasad V.
        A systematic review of trial-level meta-analyses measuring the strength of association between surrogate end-points and overall survival in oncology.
        Eur J Canc. 2019; 106: 196-211
        • Raphael M.J.
        • Robinson A.
        • Booth C.M.
        • et al.
        The value of progression-free survival as a treatment end point Among patients with advanced cancer: a systematic review and qualitative assessment of the literature.
        JAMA Oncol. 2019; 5: 1779-1789
        • Saad E.D.
        • Buyse M.
        Statistical controversies in clinical research: end points other than overall survival are vital for regulatory approval of anticancer agents.
        Ann Oncol. 2016; 27: 373-378
        • Bennette C.S.
        • Ramsey S.D.
        • McDermott C.L.
        • Carlson J.J.
        • Basu A.
        • Veenstra D.L.
        Predicting low accrual in the National Cancer Institute's Cooperative Group clinical trials.
        J Natl Cancer Inst. 2016; 108
        • Naci H.
        • Smalley K.R.
        • Kesselheim A.S.
        Characteristics of preapproval and postapproval studies for drugs granted accelerated approval by the US food and drug administration.
        J Am Med Assoc. 2017; 318: 626-636
        • Prasad V.
        Double-crossed: why crossover in clinical trials may be distorting medical science.
        J Natl Compr Canc Netw. 2013; 11: 625-627
        • Prasad V.
        • Grady C.
        The misguided ethics of crossover trials.
        Contemp Clin Trials. 2014; 37: 167-169
        • Hashim M.
        • Pfeiffer B.M.
        • Bartsch R.
        • Postma M.
        • Heeg B.
        Do surrogate endpoints better correlate with overall survival in studies that did not allow for crossover or reported balanced postprogression treatments? An application in advanced non-small cell lung cancer.
        Value Health. 2018; 21: 9-17
        • IQWiG
        Validity of surrogate endpoints in oncology executive summary of rapid report A10-05, Version 1.1.
        Institute for Quality and Efficiency in Health Care: Executive Summaries, Cologne, Germany2005
        • Dodd L.E.
        • Korn E.L.
        • Freidlin B.
        • et al.
        Blinded independent central review of progression-free survival in phase III clinical trials: important design element or unnecessary expense?.
        J Clin Oncol. 2008; 26: 3791-3796
        • Jones C.F.
        • Soto Barrientos J.F.
        • Monnickendam G.
        Investigating discrepancies in assessments of PFS by study investigators and independent review.
        Ann Oncol. 2017; 28
        • Zhang J.
        • Zhang Y.
        • Tang S.
        • et al.
        Systematic bias between blinded independent central review and local assessment: literature review and analyses of 76 phase III randomised controlled trials in 45 688 patients with advanced solid tumour.
        BMJ Open. 2018; 8e017240
        • Stone A.
        • Gebski V.
        • Davidson R.
        • Bloomfield R.
        • Bartlett J.W.
        • Sabin A.
        Exaggeration of PFS by blinded, independent, central review (BICR).
        Ann Oncol. 2019; 30: 332-338
        • Davis C.
        • Naci H.
        • Gurpinar E.
        • Poplavska E.
        • Pinto A.
        • Aggarwal A.
        Availability of evidence of benefits on overall survival and quality of life of cancer drugs approved by European Medicines Agency: retrospective cohort study of drug approvals 2009-13.
        BMJ. 2017; 359: j4530
        • Prasad V.
        • Cifu A.
        • Ioannidis J.P.
        Reversals of established medical practices: evidence to abandon ship.
        J Am Med Assoc. 2012; 307: 37-38
        • Prasad V.
        • Vandross A.
        • Toomey C.
        • et al.
        A decade of reversal: an analysis of 146 contradicted medical practices.
        Mayo Clin Proc. 2013; 88: 790-798
        • Dillekas H.
        • Rogers M.S.
        • Straume O.
        Are 90% of deaths from cancer caused by metastases?.
        Cancer Med. 2019; 8: 5574-5576
        • Broglio K.R.
        • Berry D.A.
        Detecting an overall survival benefit that is derived from progression-free survival.
        J Natl Cancer Inst. 2009; 101: 1642-1649