ADT vs chemo + ADT as initial treatment for advanced prostate cancer By Hussein Khaled Prof. Medical Oncology Cairo University
Possible Levels of Prostate Cancer At Diagnosis Local-Regional Disease Spread Systemic Spread Lymph Node GLAND PROSTATE Tumor Tumor Other Organs Bone CAPSULE
PROSTATE CANCER Commonly used therapies Disease Stage Treatment Stage I/II Radical prostatectomy (if <70 years old and healthy); Radiation (if >70 years old and healthy); or Watchful waiting (if < 10 year life expectancy, significant comorbidity, or unfavorable tumor characteristics) Stage III Radiation therapy or surgery (in rare cases) plus adjuvant hormonal therapy Source: Decision Resources, Inc, Onkos Study #47, Prostate Cancer, May 2001.
PROSTATE CANCER Response to hormonal therapy Diagnosis of Stage III/IV disease HORMONAL THERAPY 85% Respond 15% Fail to Respond Enter Hormone- Refractory Status Source: Datamonitor, Oncovision DATAMONITOR.
Endocrine Axis in Prostate Cancer GnRH agonist Adrenal Blockade Orchiectomy Antiandrogens Tumor Androgens
Docetaxel Superior to Mitoxantrone in CRPC In 2004, the standard of care for CRPC changed from mitoxantrone/prednisone to docetaxel/prednisone based on results from 2 phase III studies
Probability of Surviving Docetaxel CRPC Overall Survival TAX 327 1.0 0.9 0.8 0.7 0.6 Docetaxel 3 wkly Docetaxel wkly Mitoxantrone 0.5 0.4 0.3 0.2 0.1 0.0 Median survival Hazard (mos) ratio P-value Combined: 18.2 0.83 0.03 D 3 wkly: 18.9 0.76 0.009 D wkly: 17.3 0.91 0.3 Mitoxantrone 16.4 0 6 12 18 24 30 Months Eisenberger M, et al. ASCO Annual Meeting Proceedings. June 2004. Abstract 4.
Why ADT + Chemotherapy in CRPC 1-It is not a new idea!!
First Author No. of Pts Treatment Arms Median PFS (m) Median OS (m) Murphy 1976 1980 Murphy 1980 1983 Osborne 1982 1986 Pummer 1988 1991 Janknegt 1989 1990 Boel 1988 1991 De Reijkm 1990 1992 Kurlyama 1990 1992 Nouguchi 1995 1998 Millikan 1996 2003 Smith (SWOG) 2001-2005 35 (High risk) 246 A: DES/orch; B: DES+CTX C:CTX+Estramustine 319 A: DES/orch; B: CTX+ 5FU+DES C:Estramustine 143 A: DES/orch; B: DES/orch+CTX+Dox 145 A: Flut/orch B: Flut/orch+epirubicin 419 A: Orchiectomy B: orch+estramustine 148 A: Orchiectomy B: orch+mitomycin C 189 A: Orchiectomy B: orch+mitomycin C 136 A: DES or Orchiectomy B: DES or Orch+UFT 51 A: LHRH + FLT; B: LHRH + estramustine 286 A: LHRH or Orch B: LHRH/Orch + Ketoc + Dox + vinb + estramustine CAD + Palcitaxel, VP 16 + estramustine Not reported 16 months in all arms A: 15 B: 18 (P=0.8) A: 12 B: (P= <0.02) A: 17 B: 22 (P= 0.3) A: 29 B: 26 (P= 0.64) A: 12 B: 12 (P= 0.67) A: 30 B: 72 (P= 0.06) A: 14.6 B: 25.4 (P= 0.03) A: 24 B: 35 (P= 0.39) 23 months in all arms 33 months in all arms A: 25.6 B: 22 (P=0.55) A: 18 B: 30 (P=0.12) A: 24 B: 27 (NS) A: 31 B: 31 (NS) A: 26 B: 22 (P=0.04) A: 67 B: >96 (P=0.13) A: 30 B: 30 (NS) A: 64 B: 72 (P=0.41) 13 31
But at that time : there was no effective chemotherapy!
Why ADT + Chemotherapy in CRPC 2- How early is early?
Metastatic Disease How Early is Early? - Micro metastatic disease - Metastatic hormone senstive disease - Metastatic castration resistant disease
Metastatic Disease How Early is Early? - Micro metastatic disease - Metastatic hormone senstive disease - Metastatic castration resistant disease
If so, what is the rationale of combining ADT + CH
Pre-requisites for Success of Systemic Therapy Requires that there is: 1- An unmet need 2- Biological rationale for multi-targeted strategy 3- Effective and feasible systemic therapy 4- Appropriate patient selection 5- Randomized trials with adequate sample size
Pre-requisites for Success of Systemic Therapy Requires that there is: 1- An unmet need
Pre-requisites for Success of Systemic Therapy Requires that there is: 2- Biological rationale for multi-targeted strategy a. Mechanisms of Castration Resistance. Clonal selection. Molecular adaptation - Androgen receptor (Gene amplification, Mutations) - Alteration in survival pathways by passing AR b. In addition to blocking cell division docetaxel impairs AR signaling in PCa
Pre-requisites for Success of Systemic Therapy Requires that there is: 3- Effective and feasible systemic therapy
Probability of Surviving Docetaxel CRPC Overall Survival TAX 327 1.0 0.9 0.8 0.7 0.6 Docetaxel 3 wkly Docetaxel wkly Mitoxantrone 0.5 0.4 0.3 0.2 0.1 0.0 Median survival Hazard (mos) ratio P-value Combined: 18.2 0.83 0.03 D 3 wkly: 18.9 0.76 0.009 D wkly: 17.3 0.91 0.3 Mitoxantrone 16.4 0 6 12 18 24 30 Months Eisenberger M, et al. ASCO Annual Meeting Proceedings. June 2004. Abstract 4.
Pre-requisites for Success of Requires that there is: 4- Appropriate patient selection Systemic Therapy
Pre-requisites for Success of Systemic Therapy Requires that there is: 5- Randomized trials with adequate sample size
STRATIFICATION Extent of Mets High vs Low Age 70 vs 70 ECOG PS 0.1 vs 2 CAB > 30 days Yes vs No SRE Prevention Yes vs No Prior Adjuvant ADT 12 vs >12 months R A N D O M I Z E ARM A: ADT + Docetaxed 75 mg/m2 every 21 days for maximum 6 cycles ARM B: ADT (androgen deprivaton therapy alone) Evaluate Every 3 weeks while receiving docetaxel and at week 24 then every 12 weeks Evaluate Every 12 weeks Follow for time to progression and overall survival Chemotherapy at investigator s progression High volume: visceral metastases &/or 4 or more bone mets (at least 1 boyond pelvis and vertebral column)
SOLUTION!! James ND, et al. ASCO 2015. Abstract 5001.
STAMPEDE: Significant Improvement in OS, FFS With Docetaxel + SOC vs SOC James ND, et al. ASCO 2015. Abstract 5001.
STAMPEDE: Significant Improvement in OS, FFS With Docetaxel + SOC vs SOC Outcome SOC + Docetaxel (n = 592) SOC (n = 1184) Median OS, mos (95% CI) 77 (70-NR) 67 (60-91) Deaths, n 165 405 P Value HR, survival (95% CI) 0.76 (0.63-0.91).003 Median FFS, mos (95% CI) 37 (33-42) 21 (18-24) FFS events, n 371 750 HR, FFS (95% CI) 0.62 (0.54-0.70) < 1 x 10-9 James ND, et al. ASCO 2015. Abstract 5001.
Take Home Message!
Thanks For Your Attention 37