Ca ncer de pro stata hormono-sensible metasta sico y alta carga tumoral Dra. Aránzazu González del Alba Servicio de Oncologia Médica Hospital Universitario Son Espases Palma de Mallorca Formigal, 29 de junio de 2018
Introduction Aprox 5-20% of new PCa diagnosis present with metastatic disease: 4-10% in Europe, US Prevalence of metastasis at diagnosis varies geographically, depending on screening programs, access to health system, etc 80% patient present without metastatic disease. In Spain up to 50% CRPC- M1 will present after being initially diagnosed with localized disease Siegel, Ca Cancer J Clin,2017; Castro et al. ESMO
Introduction Androgen deprivation has been the standard of care of advanced prostate cancer during the past 7 decades Orchiectomy 1 Huggins 1941 Oestrogens LHRHa/GnRHa 2 Standard of care until recently Alternatives: High vs low doses antiandrogens Maximun Androgen Blockage 3 Intermitent blockage 4 ADT may induce responses >90% of patients, but after a median of 24-36 months progression to CRPC occurs 1. Huggins C, Can Res, 1941;2. Messing EM, N Eng J Med, 1999; 3. Prostate cancer trialists collaborative group, Lancet,2000; 4. Hussain, N Eng J Med, 2013;
Introduction Since 2015, Docetaxel plus LHRHa has become the standard of care for a majority of Castration-Sensitive M1 patients AR-independent clones However, most men progress to castration-resistant status through reactivation of androgen-signalling 1. Gravis G, et al. Eur Urol. 2016:70:256-262. 2. Sweeney C, et al. N Engl J Med. 2015;373:737-746; 3. James N, et al. Lancet. 2016;387:1163-1177.
What are we learning from long term follow-up of CHAARTED: Overall Population Median Follow-up 28.9 months Median Follow-up: 53.7 months 13 months / HR 0.61 10 months / HR 0.73 Vall d'hebron Institute of Oncology (VHIO) Sweeney et al NEJM 2015, Sweeney et al ESMO 2016 Sweeney et al NEJM 2015, Sweeney et al ESMO 2016
What are we learning from long term follow-up of CHAARTED: High volume Median Follow-up 28.9 months Median Follow-up: 53.7 months 17 months / HR 0.6 17 months / HR 0.6 Vall d'hebron Institute of Oncology (VHIO) Sweeney et al NEJM 2015, Sweeney et al ESMO 2016 Sweeney et al NEJM 2015, Sweeney et al ESMO 2016
CHAARTED: Total patient population HVD LVD Kiriakopoulos JCO 2018
CHAARTED: De novo metastatic patients Kiriakopoulos JCO 2018
CHAARTED QOL
FACT-P Total CHAARTED Quality of Life (FACT-P) High volume Low volume 120 ADT + DOC 120 118 ADT alone 116 116 114 112 ADT alone 112 ADT + DOC 0 3 6 9 12 0 3 6 9 12 Significant improvement in FACT-P at 1 year with ADT + DOC No significant difference at 1 year between both arms FACT-P: Functional Assessment of Cancer Therapy Prostate (higher values=improvement) Sweeney CJ et al. Ann Oncol 2016;27(suppl 6):abstract 720
THE STAMPEDE TRI AL: A MULTI -ARM, MULTI -STAGE DESI GN ASCO 2015 ASCO 2017 No DOC 2:1 randomization against SOC= ADT +/-RT
Slide 10 Presented By Neeraj Agarwal at 2018 ASCO Annual Meeting
Overall survival STAMPEDE OS ( primary endpoint) ( n= 1,776) 61% M1; 15% N1M0; 24% N0M0; median follow-up: 43 mo 1.0 0.8 SOC + DOC Median 81 mo 0.6 SOC Median 71 mo 0.4 0.2 HR= 0.78 (95% CI: 0.66-0.93) P= 0.006 SOC by Kaplan Meier SOC + DOC by Kaplan Meier SOC by flexible parametric model SOC + DOC by flexible parametric model 0.0 0 12 24 36 48 60 72 84 Time from randomization ( months) James, ND et al. Lancet. 2016;387:1163-77.
Slide 12 Presented By Neeraj Agarwal at 2018 ASCO Annual Meeting
ADT + docetaxel in mhspc GETUG-15 1,2 CHAARTED 3,4 STAMPEDE 5 Accrual 2004 2008 2006 2012 2005 2013 Total sample size, n 385 790 1,776 Patients with mhspc, % 100 100 61 Patients with high-volume mhspc, % 48 65 (513) a NE Patients with de novo M1, % 72 72.8 58 Median follow-up, months 83.9 53.7 43 Median age, years 63 64 65 Treatment duration Docetaxel cycles 9 6 6 Prednisone No No Yes Not head-to-head comparison studies. a Data are presented as % (n). * p value non-significant. mhspc, metastatic hormone-sensitive 1. Gravis G, et al. Lancet prostate Oncol. 2013;14:149-58. cancer; 2. Gravis G, NE, et al. Eur not Urol. evaluable. 2016;70:256-62. 3. Sweeney CJ, et al. N Engl J Med. 2015;373:737-46. 4. Sweeney C, et al. Ann Oncol. 2016;27:abstr 720PD. 5. James ND, et al. Lancet. 2016;387:1163-77. Vall d'hebron Institute of Oncology (VHIO) Dr J Carles
ADT + docetaxel in mhspc (cont.) GETUG-15 1,2 CHAARTED 3,4 STAMPEDE 5 Patients, n 385 183 790 513 1,776 1,086 OS Experimental arm (median), months Benefit, months All HVD All HVD All M1 62.1 39.8 57.6 51.2 81 60 13.5 (48.6 to 62.1) 4.7 (35.1 to 39.8) 10.4 (47.2 to 57.6) 16.8 (34.42 to 51.2) 10 (71 to 81) 15 (45 to 60) HR for OS 0.88* 0.78* 0.73 0.63 0.78 0.76 Progression cpfs Time to clinical progression FFS Experimental arm (median), months Benefit, months 23.5 NE 33.0 27.3 37 NA 8.1 (15.4 to 23.5) NE 13.2 (19.8 to 33.0) 14.3 (13.0 to 27.3) 17 (20 to 37) HR for progression 0.75 NE 0.62 0.53 0.61 0.61 NA Not head-to-head comparison studies. a Data are presented as % (n). * p value non-significant 1. Gravis G, et al. Lancet Oncol. 2013;14:149-58. 2. Gravis G, et al. Eur Urol. 2016;70:256-62. 3. Sweeney CJ, et al. N Engl J Med. 2015;373:737-46. 4. Sweeney C, et al. Ann Oncol. 2016;27:abstr 720PD. 5. James ND, et al. Lancet. 2016;387:1163-77. cpfs, clinical progression free survival, FFS, failure-free survival; HR, hazard ratio; HVD, high-volume disease; NA, not available, NE, not evaluated. Vall d'hebron Institute of Oncology (VHIO) Dr J Carles
LATITUDE: Phase III Trial of Abiraterone in patients with newly diagnosed metastatic prostate cancer (n=1,199) Patients Newly diagnosed adult men with high-risk mhnpc Stratification Factors Presence of visceral disease (yes/no) ECOG PS (0, 1 vs 2) R A N D O M I Z E D ADT + Abiraterone acetate 1000 mg QD + Prednisolone 5 mg QD (n = 597) ADT + placebos (n = 602) High-risk defined as meeting at least 2 of 3 high-risk criteria: G easo scoreof 8 Prese ceof 3 esio s o bo esca Presence of measurable visceral lesion Efficacy Endpoints Co-primary: OS rpfs Secondary: Time to pain progression PSA progression next symptomatic skeletal event chemotherapy subsequent PC therapy Fizazi K et al. J Clin Oncol. 2017;35 (suppl; abstr LBA3); Fizazi K et al. N Engl J Med. 2017;377(4):352 60.
Overall survival (% ) Radiographic progression- free survival (% ) LATI TUDE: Co-primary End Points 38% Risk Reduction for Death 53% Risk Reduction for rpfs 100 90 80 70 60 50 40 30 20 10 HR, 0.62 (95% CI, 0.51-0.76) P < 0.001 ADT + Placebos, 34.7 mo ADT + AA + P, NR 0 0 6 12 18 24 30 36 42 Months Patients at risk ADT + AA + P 597 565 529 479 388 233 93 9 ADT + Placebos 602 564 504 432 332 172 57 2 100 90 80 70 60 50 40 30 20 10 Patients at risk ADT + AA + P ADT + Placebos 0 ADT + Placebos, 14.8 mo HR, 0.47 (95% CI, 0.39-0.55) P < 0.001 0 4 8 12 16 20 24 28 32 36 40 Months ADT + AA + P, 33.0 mo 597 533 464 400 353 316 251 177 102 51 21 602 488 367 289 214 168 127 81 41 17 7 Median follow up 30.4 m 12 Fizazi K, et al. N Engl J Med. 2017;377:352-360. CI, confidence interval; HR, hazard ratio; NR, not reached.
LATITUDE: Características basales y subgrupos
Slide 13 Presented By Neeraj Agarwal at 2018 ASCO Annual Meeting
STAMPEDE- OS Abiraterone ( n= 1,917) Events 262 Control 184 Abiraterone SOC+AAP mixed population of M1 and MO patients This represents a 37% improvement in survival SOC HR 0.63 95% CI 0.52 to 0.76 P-value 0.00000115 James ND et al, N Engl J Med. 2017 Jul 27;377(4):338-351
Slide 15 Presented By Neeraj Agarwal at 2018 ASCO Annual Meeting
Patients without degradation in FACT-P total score (%) FACT-P total score ADT + AA + P Significantly Improved HRQoL per FACT-P 15% Risk Reduction for HRQoL Degradation 0.6 Mean Change From Baseline Differed from Cycle 5 Onward 100 0.4 80 60 ADT + AA + P, 12.9 mo 0.2 Better 40 ADT + Placebos, 8.3 mo 0.0 20 0 Patients at risk ADT + AA + P ADT + Placebos *1 cycle = 28 days. HR 0.85 (95% CI, 0.74-0.99) P = 0.0322 0 6 12 18 24 30 36 42 Months 597 602 338 309 250 192 202 119 135 77 65 33 20 7 0 0-0.2-0.4 0 1 2 3 4 5 6 7 8 9 1011 1213 15 17 19 21 23 25 27 29 31 33 Cycle* ADT + AA + P ADT + Placebos Worse 23
Failure-free survival Favours SOC+AAP Favours SOC+DocP Summary Head-to-head data in 566 pts (Nov-2011 to Mar-2013) Progression-free survival Strong evidence favouring AAP Metastatic progression-free survival Weak evidence favouring AAP Symptomatic skeletal events No good evidence of a difference Cause-specific survival Overall survival Proportionately different time spent in each disease state Hazard ratio Toxicity profiles quite different and well known
Adverse events worst toxicity ever Safety population SOC+DocP SOC+AAP Patients included in adverse event analysis 172 (91%) 373 (>99%) Grade 1+ AE 172 (100%) 370 (99%) Grade 3+ AE 86 (50%) 180 (48%) Grade 3+ AEs by category (incl. expected AEs) Endocrine disorder (incl. hot flashes, impotence) 15 (9%) 49 (13%) Febrile neutropenia 29 (17%) 3 (1%) Neutropenia 22 (13%) 4 (1%) Musculoskeletal disorder: 9 (5%) 33 (9%) Cardiovascular disorder (incl. hypertension, MI, cardiac dysrhythmia): 6 (3%) 32 (9%) Gastrointestinal disorder: 9 (5%) 28 (8%) Hepatic disorder (incl. increased AST, increased ALT): 1 (1%) 32 (9%) General disorder (incl. fatigue, oedema): 18 (10%) 21 (6%) Respiratory disorder (incl. breathlessness): 12 (7%) 11 (3%) Renal disorder 5 (3%) 20 (5%) Lab abnormalities (incl. hypokalaemia): 9 (5%) 11 (3%)
Implicaciones de las terapias posteriores a Docetaxel Datos retrospectivos de seguimiento GETUG-15
First-line Docetaxel in mcrpc setting in <br />GETUG AFU-15 Trial Presented By Neeraj Agarwal at 2018 ASCO Annual Meeting
SIOG classification for advanced prostate cancer Vall d'hebron Institute of Oncology (VHIO) Droz et al. BJU Int 2010, 106, 462-69
FÁRMACO Docet axel (vial 140 mg) 1 vial Abirat erona (comp. 500 mg) 60 comp Precio unit ario 307, 79 (PVL) 3. 400 (PVL) 3. 145 (* ) Posología 75 mg/m 2 iv c/3 sem 1000 mg/día vo Dosis (Sc =1, 75 m 2 ) Cost e x ciclo Cost e x mes Cost e x mes + pred. Cost e t rat amient o complet o (* * * ) 132 mg 1000 mg = 2 comp/día 290,2 (**) 2.935,3 1 Ciclo = 28 días 3.145 30 días (1 mes) 3. 145, 85 30 días (1 mes) 1. 741, 2 103. 813, 21 (*): PVL -7,5% RDL 8/2010 (**) Con aprovechamiento de viales para el caso de Docetaxel (***) Calculado para 6 ciclos de docetaxel = 4,5 meses) y 33 meses de tratamiento con Abiraterona (Ensayos CHAARTED y LATITUDE https:/botplusweb.com/ Cortesia de Jordi Gines
Conclusiones Docetaxel y Abiraterona son tratamiento estandar en CPHSm En enfermedad de alto volumen ambas opciones han demostrado mismo impacto en SG con diferencias en duración tto, tolerancia y coste Que hacer en enfermedad de bajo volumen? No disponemos de datos prospectivos para la mejor secuencia posterior
GRACIAS