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Navigating the evolving therapeutic landscape in M1 Prostate Cancer

Navigating the evolving therapeutic landscape in M1 Prostate Cancer. Karim Fizazi, MD, PhD Institut Gustave Roussy Villejuif, France. Disclosure. Participation to advisory boards/honorarium for: Amgen, Astellas, Astrazeneca, Bayer, Curevac, Essa, Janssen, MSD, Orion, Sanofi.

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Navigating the evolving therapeutic landscape in M1 Prostate Cancer

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  1. Navigating the evolving therapeutic landscape in M1 Prostate Cancer Karim Fizazi, MD, PhD Institut Gustave Roussy Villejuif, France

  2. Disclosure Participation to advisory boards/honorarium for: Amgen, Astellas, Astrazeneca, Bayer, Curevac, Essa, Janssen, MSD, Orion, Sanofi

  3. Incidence of de novo metastatic prostate cancer 5-30% <5% 60% Wu JN, Cancer 2014; 120: 818-823

  4. Who Dies of Prostate Cancer? Upfront localized cancer 44% of deaths Metastases Death De novo metastases 56% of deaths Patrikidou A. Prostate Cancer Prostatic Dis. 2014;17:348-352.

  5. The « ECG » of clinical research in M1 prostate cancer Charles Huggins 1966 Nobel Prize Medical castration with LHRH agonists OS improved by Abiraterone and Docetaxel 1980 2013 2018 PC inhibited by castration 1940

  6. 2013-2015: Establishing the role of Docetaxel in metastatic castration-naive prostate cancer • GETUG 15: • Median: 15 vs 23 months • HR: 0.75 [0.59-0.94] p=0.015 • Chaarted: • Median: 19.8 vs 32.7 months • HR=0.49 (0.37-0.45) (<0.0001) Gravis G, Lancet Oncol 2013; 14: 149-58 Sweeney C, N Engl J Med. 2015;373:737-746

  7. Stampede Phase III trial: Docetaxel: Survival (M1) SOC 343 deaths SOC+Doc 134 deaths HR (95%CI) 0.73 (0.59, 0.89) P-value 0.002 SOC+Doc SOC Non-PH p-value 0.23 Median OS (95% CI) SOC 43m (24, 88m) SOC+Doc 65m (27, NR) Restricted mean OS time SOC 49.3m SOC+Doc 56.1m Diff (95%CI) 6.8m (2.8, 11.0m) James N, Lancet 2016; 387: 1163-77

  8. Trial name CHAARTED GETUG15 STAMPEDE (SOC +/- Doc) STAMPEDE (SOC+ZA +/- Doc) Overall HR=0.77 (0.68, 0.87) p<0.0001 .5 1 2 M1 docetaxel: Survival • Results based on 2993 men / 1254 deaths Favours SOC + docetaxel Favours SOC Heterogeneity:2=4.80, df=3, p=0.187, I2 = 37.5% 10% absolute improvement in survival (from 40% to 50%) at 4 years Vale C, Lancet Oncol 2016;17:243-56

  9. CHAARTED: Updated Overall survival Kyriakopoulos CE, J Clin Oncol 2018

  10. Assessing prognosis in M1 Sweeney C, N Engl J Med 2015; 373: 737-46 Fizazi K, N Eng J Med 2017; 377: 352-60

  11. Assessing prognosis in M1 Sweeney C, N Engl J Med 2015; 373: 737-46 Fizazi K, N Eng J Med 2017; 377: 352-60

  12. Chaarted: OS by extent of metastatic disease at start of ADT Update ESMO 2016 Hazard Ratio 0.63 (95% CI 0.50-0.79) P=<0.0001 Hazard Ratio 1.04 (95% CI 0.70-1.55) P=<0.86 Sweeney C, ESMO 2016

  13. LATITUDE: Design • Patients • De novo mCNPC • Meets at least 2 of 3 high-risk criteria • Gleason score ≥ 8 • Presence of ≥ 3 lesions on bone scan • Presence of measurable visceral lesion • Efficacy endpoints • Primary: • OS • rPFS • Secondary: • Time to next skeletal-related event • Time to PSA progression • Primary endpoints • OS • rPFS Abiraterone 1000 mg QD+ Prednisone 5 mg QD+ ADT ADT + abiraterone 1000 mg q.d.+ prednisone 5 mg q.d. Randomization 1:1 Placebo 1000 mg QD + Placebo 5 mg QD+ ADT ADT + placebos q.d. Fizazi K, N Engl J Med 2017; 377: 352-60 Clinicaltrials.gov: NCT01715285

  14. LATITUDE: Abiraterone in mCSPC38% risk reduction of death 53% risk reduction of progression/death Overall survival rate at 3 years:ADT + AA + P: 66% ADT + placebos: 49% Median follow-up: 30.4 months Fizazi K, N Engl J Med 2017

  15. ADT + AA + P significantly improved pain 37% risk reductionfor worst pain progression 0.6 100 Mean change from baseline differed from Cycle 2 onward 0.4 80 Worse ADT + AA + P, NR 0.2 60 Mean change from baseline in worst pain score (BPI-SF) Patients without worst pain progression (%) ADT + Placebos, NR 0.0 40 Better -0.2 20 HR 0.63 (95% CI, 0.52-0.77) P < 0.0001 -0.4 0 0 1 2 3 4 5 6 7 8 9 15 17 19 21 23 25 27 29 31 33 10 11 12 13 0 6 12 18 24 30 36 42 Months Cycle* Patients at risk ADT + AA + P 597 456 356 299 218 115 47 2 ADT + Placebos ADT + AA + P ADT + Placebos 602 387 246 162 99 44 10 1 *1 cycle = 28 days. Chi K, Lancet Oncol 2018

  16. ADT + AA + P Persistently Improved General Health Status (VAS) and EQ-5D-5L Health Utility Scores 6.0 Mean Change From Baseline Differed from Cycle 5 Onward Mean Change From Baseline Differed from Cycle 5 Onward 4.0 0.2 Better Better 0.0 2.0 Mean change from baseline in EQ-5D-5L utility score Mean change from baseline in EQ-5D-5L health status score (VAS) -0.3 0.0 Worse Worse -0.5 -0.2 10 11 12 13 0 1 2 3 4 5 6 7 8 9 15 17 19 21 23 25 27 29 31 33 Cycle* ADT + Placebos ADT + Placebos 10 11 12 13 0 2 3 4 5 6 7 8 9 15 17 19 21 23 25 27 29 31 33 1 Cycle* ADT + AA + P ADT + AA + P *1 cycle = 28 days. Chi K, Lancet Oncol 2018

  17. LATITUDE: AEs Fizazi K, N Engl J Med 2017; 377: 352-360

  18. LATITUDEPrimary endpoint: overall survival 100 80 ADT + AA + P 60 Overall survival (%) 40 ADT + placebos 20 0 0 6 12 18 24 30 36 42 48 54 60 66 Months from randomization No. at risk AA+P 597 565 529 479 425 389 351 311 240 124 40 0 Placebo 602 564 505 432 368 315 256 220 165 69 23 0 AA+P and ADT continued to significantly reduce the risk of death

  19. Life-extending therapy for prostate cancer

  20. Abiraterone in High-risk M1 pts: STAMPEDE confirms LATITUDE OS PFS HR 0.54 (0.41-0.70) p<0.001 PSA Progression (FFS) SSE Hoyle A, ESMO 2018

  21. Abiraterone in Low-risk M1 pts:New datafrom STAMPEDE OS PFS HR: 0.63 (0.42-0.95) P=0.027 PSA Progression (FFS) SSE Hoyle A, ESMO 2018

  22. Abiraterone vs Docetaxel(OS, indirect comparison) Feyerabend S, Eur J Cancer 2018; 103: 78-87 Rydzewska L, Eur J Cancer 2017; 84: 88-101

  23. PRO: Indirect comparison of LATITUDE and CHAARTED Patient function (FACT-P) Pain (BPI) Feyerabend S, et al. Eur J Cancer 2018; 103: 78-87

  24. Abiraterone vs Docetaxel (STAMPEDE post-hoc analysis)Failure-free survival [driven by PSA failure] SOC+AAP SOC+DocP Key: HR<1 favours SOC+AAP HR>1 favours SOC+DocP Interactn = test for interaction (heterogeneity of treatment effect) Sydes M, Ann Oncol 2018; 29: 1235-48

  25. PEACE-1: European Phase III Trial in de novo Metastatic Prostate Cancer (revised design) SOC SOC + Abiraterone 1000 mg Prednisone 5 mg BID RANDOMIZED • Patients with newly diagnosed (castration-naïve) metastatic CaP • 1156 pts planned Co-primary endpoints: OS and PFS (HR: 0.75) SOC + Local radiotherapy SOC + Local radiotherapy + Abiraterone-Pred Standard of Care (SOC)= Androgen deprivation therapy (ADT) +/- docetaxel (Stratification) Study sponsor: Unicancer ClinicalTrials.gov. Identifier: NCT01957436.

  26. PEACE-1 accrual 1173 patients

  27. Phase 3 Ongoing Combination Therapy Trials

  28. Enzalutamide in M1: ARCHES primary endpoint: rPFS CI, confidence interval; HR, hazard ratio; NR, not reached. Armstrong AJ, et al. Oral presentation at ASCO GU 2019; abstract 687.

  29. ARCHES secondary endpoint: OS Armstrong AJ, et al. Oral presentation at ASCO GU 2019; abstract 687.

  30. Local treatment in M1 (HORRAD)? Boeve L, Eur Urol 2018

  31. Overall survival: prostate radiotherapy in M1 (STAMPEDE) Low burden High burden SOC+RT SOC SOC SOC+RT HR: 0.68 (95% CI 0.52-0.90); p=0.007 3 year OS (%): SOC = 73% SOC+RT = 81% HR: 1.07 (95% CI 0.90-1.28); p=0.420 3 year OS (%): SOC = 54% SOC+RT = 53% Parker C, Lancet 2018

  32. Standard of care for M1 prostate cancer (assuming patients are fit)

  33. What about costs?Expected access to generic Abiraterone in 2019 (results from an informal survey)

  34. Next PEACE-6 trial in M1 CSPC Oligo-M1 RANDOMIZED SOC • Patients with newly diagnosed (ADT naïve) metastatic CaP • To be discussed: pts with M1 relapse after local treatment (ADT naïve) DNA repair signature MSI high Cdk12-/- SOC Elderly (>75y+coM or >80) SOC All others (Bone) SOC Study sponsor: Unicancer

  35. Conclusion • Current systemic treatment for M1 patients: • ADT + Abiraterone • ADT + Docetaxel • ADT alone for frail/very elderly patients? • RXT to prostate for oligo-M1 • Triplet? (ADT+Abiraterone+Docetaxel): PEACE-1 • Next-generation trial stratified on clinical/molecular parameters: PEACE-6

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