Antonio ALCARAZ, MD PHD Professor of Urology University of Barcelona 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<br />mCRPC

Androgen Deprivation Therapy Early Chemo+ADT: A debate in one slide – a need for randomized phase 3 trial Pro 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. Androgen Deprivation Therapy Regression Re-emergence 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

In vivo data Shionogi Mouse Model Box: Paclitaxel > AA at week 4 Triangle: AA > Paclitaxel at progression (wk 4) Circle: AA + Paclitaxel Concurrent Nadir reduction: 94% AA-P vs 99.5% concurrent (p=0.08) Median TTP: 38 days versus 65 days, (P < 0.005) Clin Cancer Res 2005;11:4905-4911

ADT plus docetaxel greater tumor regression ADT + Docetaxel AR independent clones AR dependent clones

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; 321:419–24

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 1980’s to 1990’s 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

On therapy: PSA decline at 7 months identifies those destined for longer response to ADT At Risk PSA ≤ 0.2 ng/ml 453 210 63 0.2 < PSA ≤ 4.0 219 77 20 PSA > 4.0 92 17 7 Hussain et al. J Clin Oncol, 2006

Volume of disease at time of starting ADT still identifies pts more likely to progress early even when limit to patients with PSA < 4ng/dL after 7 months of therapy SWOG Intermittent vs Continuous: SWOG-9346 Med OS Continuous Arm: Minimal 6.9 yrs versus Extensive 4.4 years Hussain et al NEJM 2013; 368:1314-25

Other efforts of early chemohormonal therapy in Hormone Sensitive Metastatic PrCa ADT +/- keto+doc alt with vinblastine and estramustine High-volume: bone or visceral disease, Low-volume bone (ie, one or two areas of presumably pathologic uptake on bone scan), local/nodal with prior definitive local therapy, and local/nodal without prior definitive therapy. ? For high volume C-HT numerically better (p=0.29) Millikan et al J. Clin Oncol 2008; 26: 5936-42

Prostate Cancer Disease Landscape Non – Metastatic Prostate Cancer Localized Prostate Cancer Local Disease with Rising PSA Post Radial Therapy Non-Metastatic Hormone Sensitive Non-Metastatic castration resistant (M0) ADT Intermittent ADT and develop mets on Rx break with normal testo Progression Patients at Diagnosis Metastatic Castration Resistant Prostate Cancer Metastatic Hormone Sensitive Prostate Cancer Newly diagnosed ADT

How common is hormone sensitive metastatic prostate cancer? 5% of a country PSA screened with de novo metastatic disease Lower % in high socioeconomic (interval cancers) Higher % in VA and county hosp population 230,000 in the USA = 11,000 pts Possible major contributor of 30,000 deaths Rapid recurrence after localized therapy Hard to quantify and depends on practice patterns

Paths to CRPC and Pr Ca Death 1) De novo metastatic: most present with symptoms and presumably have high volume disease and most die of prostate cancer ~11,000 patients in USA High volume: median OS 24-33 months with ADT alone Most will die of prostate cancer Very few of these patients die of other diseases Older patients (75yo) with competing risks for death who have low volume disease and live > 5 years with ADT alone

Paths to CRPC and Pr Ca Death 2) Localized disease: 95% of PrCa in PSA screened population 90% of 230,000 cases probably present with localized disease = 207,000 and get active surveillance, XRT (+/-ADT) or surgery 75% of 207,000 cured (or not need therapy / not relapse) 25% = 51,000 PSA relapse (estimate) ?5% of 230,000 get watchful waiting or primary ADT and not get AS or local Rx due to co-morbidities

Paths to CRPC and PrCa Death 2) Localized disease: Estimate 80% of the 51K who relapse commence ADT with PSA rise Die of something else (85% in NCIC PR-7 Int vs Cont PSA rise died of PrCa with 10 yr follow-up - Crook et al NEJM) Develop CRPC and die of mCRPC (~18% of 51,000 = 9,000 over 15 year time - estimate) Minority have rapid recurrence with mets on imaging despite PSA surveillance: Estimate 10% of 51,000 = 5,100 (of 207,000 = 2.5% of local dz) Few followed with PSA rise and ADT only with mets

~20K mHSPC patients (estimates) Estimated Incidence of mHSPC-eligible patients in US of 230K US prostate cancer patients ~20K mHSPC patients (estimates) 10K (denovo) + 10K (relapse after local Rx) ~20K of 30K prostate cancer deaths/year would be mHSPC ~10K of the deaths follow PSA relapse -> ADT -> CRPC PSA -> mCRPC -> death Unknown as to how many of 20K are fit for docetaxel early

Registry Data Median OS of 30 months and med age of 72 yrs in California registry of M1 HSPC “Real world” data Interesting to note chemofit study population ADT alone in CHAARTED median OS was 44 months with median age of 62 yrs How much improvement with better CRPC Rx viable for oncogeriatric patient?

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 Prior Adjuvant ADT ≤12 vs > 12 months ARM A: ADT + Docetaxel 75mg/m2 every 21 days for maximum 6 cycles Evaluate every 3 weeks while receiving docetaxel and at week 24 then every 12 weeks RANDOMIZe Follow for time to progression and overall survival Chemotherapy at investigator’s discretion at progression ARM B: ADT (androgen deprivation therapy alone) 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

Study Endpoints Primary Endpoint Secondary Endpoints Overall survival 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) ADT alone (N=393) N % Age (year) Median 64 63 Range 36-88 39-91 Race White 344 88.7% 330 87.3% Other 44 11.3% 48 12.7% Unknown 9   15 ECOG PS 276 69.7% 272 69.6% 1 114 28.8% 29.2% 2 6 1.5% 5 1.3%

Patient characteristics ADT + Doc (N=397) ADT alone (N=393) N % Volume of Mets Low 134 33.8% 142 36.1% High 263 66.2% 251 63.9% Gleason Score 4-6 21 5.9% 6.1% 7 96 26.9% 82 23.9% 8-10 240 67.2% 70.0% Unknown 40   50 PSA (ng/mL) at time of ADT start Median 56.0  50.5  Range 0.4-8540.1 0.1-8056.0

Patient characteristics ADT + Doc (N=397) ADT alone (N=393) N % Prior Treatment No localized Rx 289 72.8% 286 73.0% Primary radiation 27 6.8% 33 8.4% Prostatectomy 81 20.4% 73 18.6% Missing   1 Adjuvant ADT 21 5.3% 15 3.8% Median time from start ADT to randomization Months (range) 1.1 (0-3.9) 1.2 (0-3.9) No ADT prior to randomization 46 12% 45 11%

Primary endpoint: Overall survival HR=0.61 (0.47-0.80) p=0.0003 Median OS: ADT + D: 57.6 months ADT alone: 44.0 months

Causes of Death ADT + Doc (N=397) ADT alone (N=393) N % Due to prostate cancer 84 83.2 112 83.6 Due to protocol Rx 1 1.0 0.0 Other cause 8 7.9 11 8.2 Unknown Missing 2 Total 101 136

OS by extent of metastatic disease at start of ADT High volume Low volume p=0.0006 HR=0.60 (0.45-0.81) Median OS: ADT + D: 49.2 months ADT alone: 32.2 months p=0.1398 HR=0.63 (0.34-1.17) Median OS: ADT + D: Not reached ADT alone: Not reached In patients with high volume metastatic disease, there is a 17 month 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

ADT + Docetaxel benefited all subgroups

Secondary Endpoints ADT + Doc (N=397) ADT alone (N=393) P-value Hazard Ratio (95%CI*) PSA <0.2 ng/mL at 6 months 27.5% 14.0% <0.0001 PSA <0.2 ng/mL at 12 months 22.7% 11.7% Median time to CRPC - biochemical, symptoms, or radiographic (months) 20.7 14.7 0.56 (0.44, 0.70) Median time to clinical progression - symptoms or radiographic (months) 32.7 19.8 0.49 (0.37, 0.65) *CI: confidence intervals

Therapy beyond progression ADT + Docet (N=397) N ADT alone (N=393) Biochem, Sympt, Radiog PD 145 174 Symptom or Radiograph PD 93 133 Docetaxel 49 129 Other Chemotherapy Cabazitaxel 43 29 Mitoxantrone &/or Platinum 22 23 Hormonal Therapy Abiraterone/Enzalutamide 92 79 Antiandrogen/ketocon 87 99 Immunotherapy Sipuleucel T 20 18 Radiotherapy 54 67

Chemotherapy Doses Given ADT + Docetaxel (N=397)   Arm A Number of cycles N % 1 11 3.1 2 7 2.0 3 6 1.7 4 8 2.3 5 12 3.4 308 87.5 Total 352* 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 Colitis/Diarrhea 1 Stomatitis Neuropathy-motor Neuropathy-sensory Thrombo-embolism Sudden death 1 patient

Hematologic Toxicity (%) ADT + Docetaxel (N=397) Grade 3 4 5 Anemia 1 <1 - Thrombocytopenia Neutropenia 9 Febrile neutropenia 2 Infection with neutropenia Worst grade heme and non-heme toxicity per patient 16% 12% 1 patient

Conclusion The combination of standard ADT and 6 cycles of docetaxel significantly improved overall survival compared to standard ADT alone in men with hormone sensitive prostate cancer

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

What is the underlying biology of early docetaxel benefit? Sweeney speculation: Chemo did not make ADT more effective ADT made chemo very effective Recent insights into ADT + XRT Better than XRT or ADT alone (clinical trials)1,2 Preclinical mechanistic work AR signaling upregulates DNA repair enzymes ADT down regulates DNA repair enzymes: XRT sensitize3,4 Question: Does ADT down regulates chemoresistance genes? 1Warde et al. Lancet 2011, 2Bolla et al. Lancet 2002 3 Polkinghorn et al. Cancer Discovery 2013; 4Goodwin et al. Cancer Discovery 2013

Are these results believable?

GETUG-15

Comparison to GETUG15

Is the control group contemporary and representative?

How to adapt to practice?

What is extensive disease?

Selected early disease trials +/- docetaxel

Conclusions

Conclusions