Buyse, ME

Clarke, NW

Collette, L

Dignam, JJ

Fizazi, K

Habibian, M

Halabi, S

ICECaP Working Group, .

Kantoff, PW

Nakabayashi, M

Parulekar, W

Regan, M

Sandler, HM

Sartor, O

Soule, HR

Sweeney, C

Sydes, MR

Tombal, BF

Williams, SG

Xie, W

UCL Discovery

Disease free survival (DFS) is a surrogate for Overall Survival (OS) in Localized Prostate Cancer (CaP). INTERMEDIATE CLINICAL ENDPOINTS IN CANCER OF THE PROSTATE (ICECaP) Working Group Background • The most promising approach for decreasing the death rate from prostate cancer is by preventing relapse after localized therapy when the disease is of very low burden and most vulnerable to therapy (e.g. build upon the benefits of ADT plus radiation over radiation alone)  • The conduct of adjuvant CaP clinical trials is hampered by taking longer than a decade to reach the meaningful endpoint of OS.  • An intermediate clinical endpoint (ICE) that is a robust surrogate for OS could accelerate conduct of adjuvant trials • There are potential challenges in identifying an ICE for CaP • heterogeneous disease with a variable natural history after disease relapse • heterogeneous treatments in the localized disease setting • impact of comorbidities and non-prostate cancer deaths in older population • ICECaP is an international collaboration to determine whether an ICE for OS can be identified when assessing the efficacy of localized CaP therapy. Objectives • Determine whether disease free survival (DFS) is a surrogate for OS for localized prostate cancer  • Determine whether time to disease recurrence (TDR) is a surrogate for disease specific survival (DSS) for localized prostate cancer Study Design • Meta analysis of pooled data from early stage CaP randomized trials.  • Systematic reviews of studies are performed following the PRISMA statement (http://www.prisma-statement.org).  • Trial Eligibility: Randomized, controlled trials for localized CaP Conducted in Canada, UK, Europe, Australia/New Zealand, US Studies with accrual completed /terminated  Exclude trials that have a primary endpoint such as safety, toxicity, QOL, feasibility, dosimetry, patient decision making without systematic long-term follow-up • Buyse’s two-stage validation model (Buyse et al, 2000, 2011)   Acknowledgments Funding: Prostate Cancer Foundation (PCF) Challenge Award; Grants from Industry (awarded to PCF or DFCI: Millennium-Takeda, Sotio, Janssen, Astellas/Medivation, Sanofi. Industry funders: no role in the writing. Executive Committee: Christopher Sweeney (DFCI)-Chair; Philip Kantoff (PCF); Howard Soule (PCF) Writing Committee:   Co-ordinating Center at Dana Farber Cancer Institute (DFCI): Christopher Sweeney (Chair DFCI)), Brandon Bernard (DFCI), Mari Nakabayashi (DFCI), Meredith Regan (DFCI), Wanling Xie (DFCI),  Members Independent of Coordinating Center overseeing Statistical Analysis Plan: Marc Buyse (International Drug Development Institute), Susan Halabi (Duke University), Philip Kantoff (PCF), A. Oliver Sartor (Tulane University), Howard Soule (PCF),   ICECaP Working Group Members (in alphabetical order) Ove Andren, John Armstrong, Donald Berry, Michel Bolla, Marc Buyse, Simon Chowdhury, Noel Clarke, Laurence Collette, Matthew Cooperberg, Jim Denham, Mario Eisenberger, James Dignam, Karim Fizazi, Boris Freidlin, Martin Gleave, Muriel Habibian, Susan Halabi, Julia Hayes, Nick James, Jonathan Jarow, Nancy Keating, Philip Kantoff, Gary Kelloff, Laurence Klotz, Suhui Li, Himu Lukka, Brandon Mahal, Malcolm Mason, Andrea Miyahira, Mari Nakabayashi, Wendy Parulekar, Tomas Philipson, Meredith Regan, Howard Sandler, Oliver Sartor, Peter Scardino, Howard Scher, Richard Simon, Jonathan Simons, Eric Small, Howard Soule, Christopher Sweeney, Matthew Sydes, Catherine Tangen, Ian Thompson, Bertrand Tombal, Anders Widmark, Thomas Wiegel, Scott Williams and Wanling Xie   Surrogate endpoint  True  endpoint Condition 1 Surrogate and final endpoints must be correlated Therapy Condition 2 Treatment effects on both endpoints must be correlated  *other causes: n=5082 (64%); unknown cause: n=645 (8%); **if metastasis occurs prior to local/regional recurrence or within 3 months of a local/recurrence event; ***Recurrence site cannot be determined for 4 studies (EPC24, EPC25, ECOG3886, Australian Study Yeoh et al). Kaplan Meier estimates of OS  and DFS (all patients)  Kaplan Meier estimates of DSS  and TDR (all patients) Death and DFS failure hazard  over time (all patients) DSS and TDR failure hazard over time (all patients) Conclusions and Future Work •DFS can be used as a surrogate of OS and TDR as a surrogate of DSS in both RT and RP based studies. •The trend is consistent when RT based trials are analyzed separately.  • Future work:  Determine surrogacy threshold effect   Assess surrogacy of Metastasis Free Survival   Pharmaco-economic analyses of using surrogate and preventing relapses Condition 1: Surrogate and final endpoints must be correlated   N % Type of treatment 201 1 Comparing primary therapies  RP+/-Adj RT or ADT  5518 26 RT dose  1366 6 RT+/-ADT  11619 55 No primary therapy +/- ADT/other  2436 12 Age at randomization 14 0 NA  64 or younger 6043 29 65-74  11857 56 75 or older  3226 15 D'Amico risk group 1618 8 NA  Low  2096 10 INTM  4453 21 High  12973 61 Type of First Failure Event Disease recurrence PC death Non-PC death /unknown No. (%) of Events Local/ Regional  Distant Metastasis**  Unknown sites*** Total OS 7996(37.8) 2269(28) 5727(72)* DSS 2269(10.7) 2269(100) DFS 9509(45.0) 1560 1511 1233 4304(45) 381(4) 4824(51) TDR 4685(22.2) 1560 1511 1233 4304(92) 381(8) Condition 2: Treatment effects on both endpoints must be correlated* OS at 8 yrs versus DFS at 5 yrs  DSS at 8 yrs versus TDR at 5 yrs No. of unit R-square (95% CI) No. of unit R-square (95% CI) All 56* 0.86 (0.78,0.90) 56* 0.80 (0.70,0.85) RT-based 37 0.68 (0.48,0.78) 37 0.71 (0.52,0.80) Disease Free Survival (DFS)    Disease Free Survival  (DFS)  Events local/regional progression  distant metastases death from any cause     Primary Objective (DFS as a surrogate for OS) Disease Free Survival (DFS)   Overall Survival  (OS) Events death from any cause    True  Endpoint Disease Free Survival (DFS)    Time to Disease Recurrence  (TDR) Events local/regional progression  distant metastases death from CaP*       Disease Specific Survival (DSS)  Events death from CaP*  *death is    Surrogate Endpoint Secondary Objective (TDR as a surrogate for DSS) *Non-CaP death is censored or considered as a competing risk   Type of first failure event for DFS by Study Between DFS and OS Between TDR and DSS    No. of units (patients) Kendall’s Tau (95%CI) No. of units (patients) Kendall’s Tau (95%CI) All patients 31(21,140) 0.85(0.85,0.86) 28(20,496)* 0.68(0.67,0.69)  RT based 21(13,186) 0.84(0.83,0.84) 19(12,770) 0.66(0.65,0.67)  Correlation at the patient level estimated from Plackett’s copula    *excluding 3 studies with number of PC- death <3 *The analysis unit comprised of 24 trials with 31 units and when arm specific units are used excluding 3 studies with median follow-up < 6 years, we have 56 units (31units x 2 arms - 6arms from 3 trials=56 units) R-square from weighted linear regression of Kaplan Meier estimates of endpoints R-square from weighted linear regression of treatment effects (log-HR) on endpoints Log(HR)-OS versus Log(HR)-DFS Log(HR)-DSS versus Log(HR)-TDR No. of units R-square (95% CI)** No. of units R-square (95% CI)** All 31 0.73 (0.53,0.82) 28* 0.63 (0.36,0.75) RT-based 21 0.75 (0.48,0.84) 19 0.63 (0.27,0.77) *excluding 3 studies with number of PC- death <3 • Not Suitable (36 trials) • Still in Discussion (8 trials) • Future participate*(12 trials) Letters sent 99 trials Agreed to participate (43 trials: 28,905 pts) 102 trials Identified* (completed or ongoing) 28 trials with IPD on 22,825 in repository 24 trials with 21,140 pt data suitable for DFS analysis *Pending publication/data maturity *as of June 2013 *No. of units for analyses = 31 as 5 trials were split to multiple units by type of primary therapy or if there were multiple experimental arms.   *Hazard ratios were estimated from Cox proportional hazards models 

Disease free survival (DFS) as a surrogate for Overall Survival (OS) in Localized Prostate Cancer (CaP) - Intermediate Clinical Endpoints in Cancer of the Prostate (ICECaP) Working Group

http://discovery.ucl.ac.uk/1514477/1/Sweeney%20et%20al%20Disease-free%20survival%20%28DFS%29%20is%20a%20surrogate%20for%20overall%20survival%20%28OS%29%20in%20localized%20prostate%20cancer%20%28CaP%29%20Poster.pdf

Disease free survival (DFS) as a surrogate for Overall Survival (OS) in Localized Prostate Cancer (CaP) - Intermediate Clinical Endpoints in Cancer of the Prostate (ICECaP) Working Group

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