E3805 CHAARTED Study Antonio ALCARAZ, MD PHD Professor

E3805 CHAARTED Study Antonio ALCARAZ, MD PHD Professor

E3805 CHAARTED Study Antonio ALCARAZ, MD PHD Professor of Urology University of Barcelona E3805 CHAARTED: ChemoHormonal Therapy Versus Androgen Ablation Randomized Trial for Extensive Disease in Prostate Cancer Abstract LBA2 Sweeney C, Chen Y-H, Carducci M, Liu G, Eisenberger M, Wong Y-N, Hahn N, Kohli M, Dreicer R, Vogelzang N, Picus J, Shevrin D, Hussain M, Garcia J, DiPaola R A Quick Review of the History of Hormone Sensitive Metastatic Prostate Cancer ASCO 2004, abstracts 3 and 4
mCRPC Early Chemo+ADT: A debate in one slide a need for randomized phase 3 trial Pro Androgen Deprivation Therapy Regression Re-emergence Attack de-novo testosterone independent clones early - allow ADT to keep PrCa in remission

longer Some patients at the time of progression are too frail for chemo. Con ADT will take cells out of cycle and be less responsive to cytotoxics Some patients respond for a long time and never need chemotherapy Volume of disease at time of starting ADT consistently identifies pts more likely to progress early SWOG: S8494 NEJM 1989: Leuprolide +/- Flutamide Minimal Disease: Absence of mets in ribs, long bones, skull, soft tissue other than LN Median OS Leuprolide Alone Metastasis Burden Minimal: 39.0 months Severe: 26.0 months N Engl J Med 1989; 321:41924 Volume of disease at time of starting ADT consistently identifies pts more likely to progress early Median OS Orch +/- Flutamide Metastasis Burden Minimal:

51 months Extensive: 27 months SWOG - S8894: NEJM 1998: Orchiectomy +/- Flutamide Minimal disease: Nodal metastases and/or bone mets limited to pelvic and axial skeleton Extensive disease included appendicular skeletal involvement (with or without axial skeletal involvement), visceral (lung or liver) metastasis, or both. Improve OS from 1980s to 1990s Stage Migration 3 Sequential SWOG phase 3 trials Pre-PSA era S8494: Median OS: 33 months (Accrue: 1985-86) S8894: Median OS: 35 months (Accrue: 1989-94) PSA era S9346 Median OS: 49 months (Accrue: 1995-2009) (No difference for African Americans - unlike the other 2 studies) Tangen et al J. Urology 2012

Prostate Cancer Disease Landscape Non Metastatic Prostate Cancer Localized Prostate Cancer Local Disease with Rising PSA Post Radial Therapy Non-Metastatic castration resistant (M0) Non-Metastatic Hormone Sensitive Patients Patients at at Diagnosis Diagnosis ADT Progression Newly diagnosed Metastatic Hormone

Sensitive Prostate Cancer ADT Intermittent ADT and develop mets on Rx break with normal testo Metastatic Castration Resistant Prostate Cancer E3805 CHAARTED Treatment STRATIFICATION Extent of Mets -High vs Low Age 70 vs < 70yo 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 MI Z E ARM A: ADT + Docetaxel 75mg/m2 every 21 days for maximum 6 cycles ARM B: ADT (androgen deprivation therapy alone) Evaluate every 3 weeks while receiving docetaxel and at week 24 then every 12 weeks Evaluate every 12 weeks

ADT allowed up to 120 days prior to randomization. Intermittent ADT dosing was not allowed Standard dexamethasone premedication but no daily prednisone Follow for time to progression and overall survival Chemotherapy at investigators discretion at progression Study Endpoints Primary Endpoint Overall survival Secondary Endpoints Rate of PSA < 0.2 ng/mL at 6 months and 12 months Time to biochemical, radiographic or symptomatic PD Time to radiographic or symptomatic progressive disease (PD) Define adverse event profile and tolerability Quality of life (FACT-P) until 12 months after randomization Patient characteristics

ADT + Doc (N=397) N Age (year) Median Range Race White Other Unknown ECOG PS 0 1 2 Unknown % ADT alone (N=393) N 64 36-88 % 63 39-91 344 44 9

88.7% 11.3% 330 48 15 87.3% 12.7% 276 114 6 1 69.7% 28.8% 1.5% 272 114 5 2 69.6% 29.2% 1.3% Patient characteristics ADT + Doc (N=397)

N ADT alone (N=393) % Volume of Mets Low 134 33.8% High 263 66.2% Gleason Score 4-6 21 5.9% 7 96 26.9% 8-10 240 67.2% Unknown 40 PSA (ng/mL) at time of ADT start Median 56.0 Range 0.4-8540.1

N % 142 251 36.1% 63.9% 21 82 240 50 6.1% 23.9% 70.0% 50.5 0.1-8056.0 Patient characteristics ADT + Doc (N=397) ADT alone (N=393) N %

N % 289 72.8% 286 73.0% 27 6.8% 33 8.4% 81 20.4% 73 18.6% Prior Treatment No localized Rx Primary

radiation Prostatectomy Missing Adjuvant ADT 0 1 21 5.3% 15 Median time from start ADT to randomization Months (range) No ADT prior to randomization 1.1 (0-3.9) 46 12% 3.8% 1.2 (0-3.9) 45 11% Primary endpoint: Overall survival 1.0

0.9 0.8 0.7 0.6 Probability 0.5 HR=0.61 (0.47-0.80) p=0.0003 Median OS: ADT + D: 57.6 months ADT alone: 44.0 months 0.4 0.3 0.2 0.1 0.0 0 12 24 36 48 60

72 OS (Months) Arm A TOTAL 397 DEAD 101 ALIVE 296 MEDIAN 57.6 84 Causes of Death ADT + Doc (N=397) Due to prostate cancer Due to protocol Rx Other cause Unknown Missing Total

ADT alone (N=393) N 84 % 83.2 N 112 % 83.6 1 8 8 0 101 1.0 7.9 7.9 0 11 11 2 136

0.0 8.2 8.2 OS by extent of metastatic disease at start of ADT High volume 1.0 1.0 0.9 0.9 0.8 0.8 0.7 0.7 0.6 0.6 0.5 0.5 p=0.0006 HR=0.60 (0.45-0.81)

Median OS: ADT + D: 49.2 months ADT alone: 32.2 months 0.4 0.3 0.2 Probability Probability Low volume 0.3 0.2 0.1 0.1 0.0 0.0 0 12 24 p=0.1398

HR=0.63 (0.34-1.17) Median OS: ADT + D: Not reached ADT alone: Not reached 0.4 36 48 60 72 84 0 12 24 TOTAL 48 60 72

OS (Months) OS (Months) Arm 36 DEAD ALIVE MEDIAN Arm A In patients disease, there is a 17 month A with high volume 263 82metastatic 181 49.2 B B 251 110 141 32.2 improvement in median overall survival from 32.2 months to 49.2 months

We projected 33 months in ADT alone arm with collaboration of SWOG9346 team TOTAL 134 142 DEAD 19 26 ALIVE 115 116 MEDIAN . . 84 ADT + Docetaxel benefited all subgroups Secondary Endpoints ADT + ADT Doc alone (N=397) (N=393) PSA <0.2 ng/mL at 6

months PSA <0.2 ng/mL at 12 months Median time to CRPC - biochemical, symptoms, or radiographic (months) Median time to clinical progression - symptoms or radiographic (months) *CI: confidence intervals P-value Hazard Ratio (95%CI*) 27.5% 14.0% <0.0001 22.7% 11.7% <0.0001 20.7

14.7 <0.0001 0.56 (0.44, 0.70) 32.7 19.8 <0.0001 0.49 (0.37, 0.65) Therapy beyond progression Biochem, Sympt, Radiog PD Symptom or Radiograph PD Docetaxel Other Chemotherapy Cabazitaxel Mitoxantrone &/or Platinum Hormonal Therapy Abiraterone/Enzalutamide Antiandrogen/ketocon Immunotherapy Sipuleucel T Radiotherapy

ADT + Docet (N=397) N 145 93 ADT alone (N=393) N 174 133 49 129 43 29 22 23 92 87 79 99

20 54 18 67 Chemotherapy Doses Given ADT + Docetaxel (N=397) Arm A Number of cycles 1 2 3 4 5 6 Total N % 11 7 6 8 12 308

352* 3.1 2.0 1.7 2.3 3.4 87.5 74% with no dose modifications *Missing data on 45 pts due to form change (24 pts), never started Rx (6 pts), data missing (15 pts) Non-Hematologic Toxicity (%) ADT + Docetaxel (N=397) Grade 3 4 5 Allergic reaction 2 <1

- Fatigue 4 - - Colitis/Diarrhea 1 - - Stomatitis Neuropathymotor Neuropathysensory Thromboembolism 1 - - 1

- - 1 - - <1 1 - - - 1 patient Sudden death Hematologic Toxicity (%) Grade Anemia Thrombocytopenia Neutropenia Febrile neutropenia

Infection with neutropenia Worst grade heme and nonheme toxicity per patient ADT + Docetaxel (N=397) 3 4 5 1 <1 <1 3 9 4 2 1 1 16% 12% 1 patient Clinical interpretation 6 cycles of docetaxel in addition to ADT represents an appropriate option for men with metastatic prostate cancer commencing ADT who are suitable for docetaxel therapy The benefit in patients with a high volume of metastases is clear and justifies the treatment burden

longer follow-up is required for patients with low volume metastatic disease Are these results believable? GETUG-15 Comparison to GETUG15 What is extensive disease? Selected early disease trials +/- docetaxel Conclusions

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