Associate Professor amp Head David Braley amp Nancy Gordon Chair Division of Urology McMaster University SPARTAN a Phase 3 DoubleBlind Randomized Study of Apalutamide vs Placebo in Patients With Nonmetastatic CastrationResistant Prostate Cancer ID: 1041886
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1. nmCRPC ASCO GU 2018Bobby Shayegan, MD FRCSCAssociate Professor & HeadDavid Braley & Nancy Gordon ChairDivision of UrologyMcMaster University
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3. SPARTAN, a Phase 3 Double-Blind, Randomized Study of Apalutamide vs Placebo in Patients With Nonmetastatic Castration-Resistant Prostate CancerEric J. Small,1 Fred Saad,2 Simon Chowdhury,3 Boris A. Hadaschik,4 Julie N. Graff,5 David Olmos,6 Paul N. Mainwaring,7 Hiroji Uemura,8 Angela Lopez-Gitlitz,9 Géralyn C. Trudel,9 Byron M. Espina,9 Youyi Shu,9 Youn C. Park,9 Wayne R. Rackoff,9 Margaret K. Yu,9 Matthew R. Smith,10 on behalf of the SPARTAN Investigators1Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA; 2Centre Hospitalier de l'Université de Montréal, Université de Montréal, Montréal, Québec, Canada; 3Guy’s, King’s and St. Thomas’ Hospitals, Great Maze Pond, London, UK; 4University of Duisburg-Essen, Essen, Germany; 5VA Portland Health Care System, Portland, and Knight Cancer Institute, Oregon Health & Science University, Portland, OR; 6Spanish National Cancer Research Centre (CNIO), Madrid, and Hospitales Universitarios Virgen de la Victoria y Regional de Málaga, Málaga, Spain;7Centre for Personalised Nanomedicine, University of Queensland, Brisbane, Australia; 8Yokohama City University Medical Center, Yokohama, Japan; 9Janssen Research & Development, Los Angeles, CA; 10Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, MAPresented by: Eric Small, MD, FASCO
4. EligibilitynmCRPCPelvic nodes < 2 cm below iliac bifurcation (N1) allowed PSADT ≤ 10 monthsOn-Study RequirementContinuous ADTStratificationsPSADT > 6 mo or ≤ 6 moBone-sparing agents, y/nN0 or N1Second Rx at MD’s discretion including open-label ABI/PREDApalutamide (APA) 240 mg QD + ADT(n = 806)Placebo (PBO) +ADT(n = 401)RandomizationMFSPROGRESSION2nd progression-free survival (PFS2)Metastasis-free survival (primary end point)2:1(N = 1207)SPARTAN ─ Overall Study Design Phase 3 Placebo-Controlled, Randomized International Study NCT019462045Presented by: Eric Small, MD, FASCONCT01946204ABI/PRED, abiraterone acetate plus prednisone; nmCPRC, nonmetastatic castration-resistant prostate cancer; MFS, metastasis-free survival.
5. Primary end pointMFS (required 372 MFS events for the final analysis with 90% power, at α = 0.05, assuming a hazard ratio [HR] of 0.7)Secondary end points (hierarchical adaptive group sequential testing): Time to metastasisProgression-free survival (PFS)Time to symptomatic progressionOverall survival (OS)Time to cytotoxic chemotherapyExploratory end pointsPFS2 Time to PSA progression, PSA decline Patient-reported outcomes (Functional Assessment of Cancer Therapy-Prostate [FACT-P], EuroQol-Five Dimensions-3L [EQ-5D-3L])5Presented by: Eric Small, MD, FASCOMethods
6. PFS26Second-progression–free survival was defined as the time from randomization to investigator-assessed disease progression (PSA progression, detection of metastatic disease on imaging, symptomatic progression, or any combination thereof) during the first subsequent treatment for metastatic castration-resistant disease or death from any cause.
7. ResultsPatient Demographics and Disease Characteristics7APA(n = 806)PBO(n = 401)Median age, yrs74.074.0Median time from initial diagnosis to randomization, yrs 7.957.85Median PSADT, mos4.404.50PSADT, % ≤ 6 mos > 6 mos71297129Bone-sparing agent use, % Yes No10901090Nodal status at study entry, % N0 N183178416Prior prostate cancer therapy, % Definitive local therapy GnRH agonist First-generation antiandrogen779773779772Presented by: Eric Small, MD, FASCOGnRH, gonadotropin-releasing hormone.
8. APAPBO806Primary End Point: Metastasis-Free Survival 72% risk reduction of distant progression or death020406080100Metastasis-Free Survival (%)APA, 40.5 mo(median)PBO, 16.2 mo(median) HR, 0.28 (95% CI, 0.23-0.35) P < 0.0001MonthsNo. at risk71365251439828218096361630401291220153915834135100048121624202832364044Presented by: Eric Small, MD, FASCO8
9. Consistent MFS Benefit Across All SubgroupsPresented by: Eric Small, MD, FASCOECOG, Eastern Cooperative Oncology Group.RegionPrior hormonal therapy, no.Baseline PSA valueBone-sparing agent0.51.02.50.15AgeRaceBaseline ECOG valuePSA doubling timeLocal-regional nodal diseaseAPA betterPBO better N10.15(0.09-0.25) Yes0.38(0.19-0.76) 10.40(0.27-0.60) 10.34(0.21-0.53) Asia Pacific0.30(0.17-0.54) N00.33(0.26-0.41) No0.29(0.23-0.36) > 6 months0.30(0.20-0.47) At or below median0.28(0.20-0.39) 00.27(0.21-0.34) Europe0.29(0.22-0.39) North America0.30(0.21-0.42) Above median0.29(0.23-0.38)0.29(0.23-0.36)≥ 20.29(0.23-0.36)≤ 6 monthsSubgroupHR95% CI White(0.21-0.34)0.26 Black(0.23-1.72)0.63 Asian(0.16-0.67)0.33 Others(0.24-0.65)0.40All patients(0.24-0.36)0.30 < 65 years(0.08-0.27)0.14 65<75 years(0.18-0.34)0.25(0.31-0.56)≥ 75 years0.429
10. Secondary End Point: Time to Metastasis73% risk reduction of distant progression10Presented by: Eric Small, MD, FASCO HR, 0.27 (95% CI, 0.22-0.34) P < 0.0001Patients WithoutMetastasis (%)80664951339828117996361630401290219153915834135100020406080100048121620242832364044APA, 40.5 mo (median)PBO, 16.6 mo(median)711MonthsNo. at riskAPAPBO
11. Secondary End Point: Progression-Free Survival 71% risk reduction of local progression, distant progression, or death11Presented by: Eric Small, MD, FASCO HR, 0.29 (95% CI, 0.24-0.36) P < 0.0001Progression-Free Survival80670564550639127717894361630401283212145875633125100048121620242832364044APA, 40.5 mo (median)PBO, 14.7 mo (median)020406080100No. at riskAPAMonthsPBO
12. Secondary End Point: Time to Symptomatic Progression 55% risk reduction of SRE, pain progression/worsening sx, clinically significant sx requiring intervention 12Presented by: Eric Small, MD, FASCO HR, 0.45 (95% CI, 0.32-0.63) P < 0.0001048121620242832364044806769732601478344226127491940401373344270206152964517700APA, not reachedPBO, not reachedPatients Without Symptomatic Progression (%)020406080100MonthsNo. at riskAPAPBO
13. Secondary End Point: Overall Survival30% risk reduction of death13Presented by: Eric Small, MD, FASCO HR, 0.70 (95% CI, 0.47-1.04) P = 0.078067887566475273922751626426404013873743192481831266429900APA, not reachedOverall Survival020406080100PBO, 39.0 mo(median)048121620242832364044MonthsNo. at riskAPAPBO104 events/427 target events = 24%
14. APAPBOReceived study treatment803398Discontinued study treatment314279Received approved therapy for mCRPC, n (%)165 (53)217 (78)First subsequent approved treatment, n Abiraterone acetate plus prednisone125161 Enzalutamide2028 Docetaxel1518 Cabazitaxel01 Sipuleucel-T49 Radium-22310Subsequent Treatment14Presented by: Eric Small, MD, FASCO
15. APAPBOReceived study treatment803398Discontinued study treatment314279Received approved therapy for mCRPC, n (%)165 (53)217 (78)First subsequent approved treatment, n Abiraterone acetate plus prednisone125161 Enzalutamide2028 Docetaxel1518 Cabazitaxel01 Sipuleucel-T49 Radium-22310Subsequent Treatment15Presented by: Eric Small, MD, FASCO189/279 (68%) of PBO patients who dc’d study treatment were treated with an ASI145/314 (46%) of APA patients who dc’d study treatment were treated with an ASI189/279 (68%)
16. 16PFS2 End Point51% risk reduction of progression (PSA, radiographic, symptomatic, or any combination)Presented by: Eric Small, MD, FASCO HR, 0.49 (95% CI, 0.36-0.66) P < 0.0001Second Progression-Free Survival (%)048121620242832364044020406080100806778746619492346237129461940401386357279206150873914200APA, not reachedPBO, 39.0 mo(median)MonthsNo. at riskAPAPBO
17. Time to PSA Progression94% risk reduction in PSA progression17Presented by: Eric Small, MD, FASCO HR, 0.06 (95% CI, 0.05-0.08) P < 0.000180669559743530621512869292040113950148400000011Patients Without PSAProgression (%)APA, not reachedPBO, 3.7 mo(median)020406080100048121620242832364044MonthsNo. at riskAPAPBO
18. PSA End Points18PSA ≥ 50% decline APA: 90% PBO: 2%Presented by: Eric Small, MD, FASCOPSA Change From Baseline-100-60206010020APA (n = 753)-100-60206010020PBO (n = 372)
19. PRO End Points: FACT-P and EQ-5D VASHRQoL was maintained with the addition of APA to ADT19Presented by: Eric Small, MD, FASCOFACT-PEQ-5D VASBaselineC2C3C4C5C6C7C9C11C13C17C21C25C290.0012.0024.0036.0048.0060.0072.0084.0096.00108.00120.00132.00144.00156.00Scale Value Range (Group Means)115.10117.83113.57116.53116.37116.39117.82117.43117.24116.65116.71117.13117.10116.59117.16117.61116.86117.63118.52118. 46118.88118.67119.13119.06119.32119.39120.65116.35BaselineC2C3C4C5C6C7C9C11C13C17C21C25C290.0010.0020.0030.0040.0050.0060.0070.0080.0090.00100.00Scale Value Range (Group Means)80.8679.5176.8778.5777.6477.4077.7277.6978.1477.5377.5876.2476.0976.8176.1776.0076.2477.1377.2177.2977.7677.4478.1477.8778.6279.6880.4177.41PRO, patient-reported outcome; VAS, visual analog scale; HRQoL, health-related quality of life. APA PBO
20. APA(n = 803)PBO(n = 398)Grade 3 or 4 AE45%34%Any serious AE25%23%Any AE leading to treatment discontinuation11%7%Percent of patients remaining on treatment at the clinical cutoff date61%30%20Presented by: Eric Small, MD, FASCOResults: All Adverse EventsAE, adverse event.
21. 21Presented by: Eric Small, MD, FASCO APA(n = 803)PBO(n = 398) AllGr 3/4AllGr 3/4 Fatigue30.4%0.9%21.1%0.3% Rash23.8%5.2%5.5%0.3% Weight loss16.1%1.1%6.3%0.3% Arthralgia15.9%07.5%0 Fall15.6%1.7%9.0%0.8% Fracture11.7%2.7%6.5%0.8% Hypothyroidism8.1%02.0%0 Seizure0.2%000Results: Treatment Associated Adverse Events
22. Apalutamide decreased the risk of metastasis or death by 72%, and prolonged the median MFS by more than 2 years in men with high-risk nmCRPCThe MFS benefit was consistently seen across all subgroupsThese results are supported by consistent improvement across all evaluable end pointsTime to metastasisProgression-free survivalTime to symptomatic progressionTime to PSA progressionPSA decline22Presented by: Eric Small, MD, FASCOConclusions
23. Apalutamide was associated with a 30% reduction in risk of death at this early interim analysis for survival (p = NS)23Presented by: Eric Small, MD, FASCOThe majority of placebo patients received an approved second therapyApalutamide resulted in a 51% risk reduction in PFS2 even in the face of a high rate of secondary ASI use in the placebo armThe addition of apalutamide to ADT was well tolerated, with maintained HRQoLOverall, these data suggest that apalutamide should be considered as a new standard of care for men with high-risk nmCRPCConclusionsNS, non-significant.
24. PROSPER: A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study of Enzalutamide in Men With Nonmetastatic Castration-Resistant Prostate CancerPresented By Maha Hussain at 2018 Genitourinary Cancers Symposium: Translating Evidence to Multidisciplinary Care
25. PROSPER Study DesignPresented By Maha Hussain at 2018 Genitourinary Cancers Symposium: Translating Evidence to Multidisciplinary Care
26. Baseline Patient Characteristics (N = 1401)Presented By Maha Hussain at 2018 Genitourinary Cancers Symposium: Translating Evidence to Multidisciplinary Care
27. Adverse Events of Special Interest*Presented By Maha Hussain at 2018 Genitourinary Cancers Symposium: Translating Evidence to Multidisciplinary Care
28. Progression Event by TypePresented By Maha Hussain at 2018 Genitourinary Cancers Symposium: Translating Evidence to Multidisciplinary Care
29. Primary Endpoint: MFSPresented By Maha Hussain at 2018 Genitourinary Cancers Symposium: Translating Evidence to Multidisciplinary Care
30. Subgroup Analysis of MFSPresented By Maha Hussain at 2018 Genitourinary Cancers Symposium: Translating Evidence to Multidisciplinary Care
31. Time to PSA ProgressionPresented By Maha Hussain at 2018 Genitourinary Cancers Symposium: Translating Evidence to Multidisciplinary Care
32. Time to First Use of New Antineoplastic TherapyPresented By Maha Hussain at 2018 Genitourinary Cancers Symposium: Translating Evidence to Multidisciplinary Care
33. Overall Survival: First Interim AnalysisPresented By Maha Hussain at 2018 Genitourinary Cancers Symposium: Translating Evidence to Multidisciplinary Care
34. ConclusionsPresented By Maha Hussain at 2018 Genitourinary Cancers Symposium: Translating Evidence to Multidisciplinary Care
35. Discussion
36. 2 highly positive trialsClearly meet their endpoints of MFSPotentially new therapeutic options in an area with an UNMET needBut treatment of asymptomatic patients must carry a certain burden of proof wherein the benefit must outweigh the risk
37. Surrogacy of MFS for OSICECaP DataCOU-AA-302PREVAIL
38. Slide 18Presented By Philip Kantoff at 2018 Genitourinary Cancers Symposium: Translating Evidence to Multidisciplinary Care
39. COU-302-rPFS predicts OSPresented By Philip Kantoff at 2018 Genitourinary Cancers Symposium: Translating Evidence to Multidisciplinary Care
40. PREVAIL-rPFS predicts OSPresented By Philip Kantoff at 2018 Genitourinary Cancers Symposium: Translating Evidence to Multidisciplinary Care
41. Questions?