mcrpc 2014 TRA EVOLUZIONE E RIVOLUZIONE: COME ORIENTARSI NEL LABIRINTO DELLE TERAPIE

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1 mcrpc 2014 TRA EVOLUZIONE E RIVOLUZIONE: COME ORIENTARSI NEL LABIRINTO DELLE TERAPIE IL CARCINOMA PROSTATICO, UNA MALATTIA ETEROGENEA? RAZIONALE E RISULTATI DEL TRATTAMENTO CHEMIOTERAPICO ASSOCIATO ALL ANDROGENO-DEPRIVAZIONE Marcello Tucci SCDU Oncologia Medica Azienda Ospedaliero Universitaria San Luigi di Orbassano Università degli studi di Torino

2 Tombal. B. Eur J Cancer 2011;47:S ADT: Androgen Deprivation Therapy; AR: androgen receptor; mets: metastases

3 The CHAARTED hypothesis ADT ADT + Docetaxel AR independent clones AR dependent AR clones independent clones Sweeney C et al. J Clin Oncol 2014;32(June 20 suppl):abstract LBA2 ADT: Androgen Deprivation Therapy; AR: androgen receptor

4 <br /><br />E3805<br />CHAARTED: ChemoHormonal Therapy versus Androgen Ablation Randomized Trial for Extensive Disease in Prostate Cancer Presented By Christopher Sweeney at 2014 ASCO Annual Meeting

5 E3805 CHAARTED study Newly diagnosed M1 PCa Key stratification Extent of mets (High vs low) Age ( 70 vs < 70 y) R A N D O M I Z E ARM A (n=397) ADT + Docetaxel for 6 cycles ARM B (n=393) ADT Follow for time to progression and overall survival Chemotherapy at investigator s discretion at progression Open label, multicenter, phase III trial conducted in US Standard dexamethasone premedication but no daily prednisone Sweeney C et al. J Clin Oncol 2014;32(June 20 suppl):abstract LBA2. ADT: androgen deprivation therapy; Mets: Metastases; PS: Performance Status; SRE: Skeletal Related Events; CAB: Complete Androgen Blockade; docétaxel (75mg/m2 every 21 days)

High volume disease is prognostic in metastatic hormone sensitive prostate cancer 1. Eisenberg M et al. N Engl J Med 1988;339:1036 42; 2.

6 High volume disease is prognostic in metastatic hormone sensitive prostate cancer 1. Eisenberg M et al. N Engl J Med 1988;339: ; 2. Crawford E et al. N Engl J Med 1989;321:419 24; 3. Hussain M et al. N Engl J Med 2013;368: ; 4. Millikan E et al. J Clin Oncol 2008;26:

7 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 progressive disease (PD) Time to radiographic or symptomatic PD Define adverse event profile and tolerability Quality of life (FACT P) until 12 months after randomization Sweeney C et al. J Clin Oncol 2014;32(June 20 suppl):abstract LBA2 PSA: Prostate Specific Antigen; PD: Progressive Disease

8 CHAARTED Key eligibility criteria High volume metastatic disease: visceral metastases and/or 4 or more bone metastases (with at least 1 beyond pelvis and vertebral column) At study initiation, only patients with high volume disease were to be accrued Study amendment to allow patients with low volume to be enrolled, with stratification on disease volume Is high volume disease definition based on robust data? Sweeney C et al. J Clin Oncol 2014;32(June 20 suppl):abstract LBA2. ADT: androgen deprivation therapy;

9 Patient characteristics (1) ADT + Docetaxel (n=397) ADT alone (n=393) n % n % Age (year) Median Volume of mets Low % % High % % Gleason Score % % % % % % PSA (ng/ml) at time of ADT start Median Range Sweeney C et al. J Clin Oncol 2014;32(June 20 suppl):abstract LBA2 Mets: Metastases; ADT: androgen deprivation therapy; Docetaxel 75mg/m²

10 Patient characteristics (2) ADT + Docetaxel (n=397) ADT alone (n=393) n % n % Prior Treatment No localized Rx % % Primary radiation % % Prostatectomy % % Adjuvant ADT Yes % % 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% Sweeney C et al. J Clin Oncol 2014;32(June 20 suppl):abstract LBA2 ADT: androgen deprivation therapy; Docetaxel 75mg/m²

11 Primary endpoint: overall survival Overall survival Hazard Ratio 0.61 (95% CI ) P= ADT alone Median 44.0 mths ADT + DOC Median 57.6 mths Sweeney C et al. J Clin Oncol 2014;32(June 20 suppl):abstract LBA2 ADT: androgen deprivation therapy; DOC: docétaxel; OS: overall survival; mths: months

12 Overall survival by extent of metastatic disease at start of ADT High volume Low volume ADT alone Median 32.2 mths Hazard Ratio 0.60 (95% CI ) P= ADT + DOC Median 49.2 mths ADT alone Not reached ADT + DOC Not reached Hazard Ratio 0.63 (95% CI ) P= month benefit in median OS (from 32.2 to 49.2 months) for high volume disease Sweeney C et al. J Clin Oncol 2014;32(June 20 suppl):abstract LBA2 ADT: androgen deprivation therapy; DOC: docétaxel 75mg/m²

13 Secondary endpoints ADT + DOC (N=397) ADT alone (N=393) P value HR (95%CI*) PSA <0.2 ng/ml at 6 months 27.5% 14.0% < PSA <0.2 ng/ml at 12 months 22.7% 11.7% < Median time to CRPC (months) biochemical, symptoms, or radiographic Median time to clinical progression (months) symptoms or radiographic < < (0.44, 0.70) 0.49 (0.37, 0.65) Sweeney C et al. J Clin Oncol 2014;32(June 20 suppl):abstract LBA2 ADT: androgen deprivation therapy; DOC: Docetaxel 75mg/m 2

14 Non hematologic adverse events (%) ADT + Docetaxel (N=397) Grade Allergic reaction 2 <1 Fatigue 4 Colitis/Diarrhea 1 Stomatitis 1 Neuropathy motor 1 Neuropathy sensory 1 Thrombo embolism <1 1 Sudden death 1 patient Safety collected only in the chemotherapy arm Sweeney C et al. J Clin Oncol 2014;32(June 20 suppl):abstract LBA2 ADT: androgen deprivation therapy; Docetaxel 75mg/m 2

15 Hematologic adverse events (%) ADT + Docetaxel (n=397) Grade Anemia 1 <1 Thrombocytopenia <1 Neutropenia 3 9 Febrile neutropenia 4 2 Infection with neutropenia 1 1 Worst grade hem. and non hem. toxicity per patient 16% 12% 1 patient Safety collected only in the chemotherapy arm Sweeney C et al. J Clin Oncol 2014;32(June 20 suppl):abstract LBA2 ADT: androgen deprivation therapy; Docetaxel 75mg/m 2 ; hem=hematological

GETUG 15 results: PFS and OS Clinical PFS OS 100 100 90 90 Clinical progression free survival (%) 80 70 60 50 40 30 20 10 ADT: 15.4 mths ADT + D: 23.

16 GETUG 15 results: PFS and OS Clinical PFS OS Clinical progression free survival (%) ADT: 15.4 mths ADT + D: 23.5 mths Overall survival (%) ADT: 54.2 mths ADT + D: 58.9 mths Time since randomisation (months) Time since randomisation (months) Number at risk Number at risk ADT plus Docetaxel ADT plus Docetaxel ADT alone ADT alone ):abstract LBA2 Gravis G et al. Lancet Oncol 2013;2: ADT plus Docetaxel ADT alone

17 N pts: 385 GETUG 15 study

18 ):abstract LBA2 Gravis G et al. Lancet Oncol 2013;2:149 58; Sweeney C et al. J Clin Oncol 2014;32(June 20 suppl ):abstract LBA2

19 GETUG 15: Study underpowered? Glass classification defined 21.5% of patients as high risk How many of these patients could be considered high risk according to CHAARTED high risk definition? OS in ADT arm in GETUG 15 much longer than in CHAARTED (58.9 vs 32.2 months) Better prognosis GETUG 15 vs CHAARTED: why this difference in outcomes? Docetaxel prescribed mainly at PSA progression vs clinical/radiological progression in CHAARTED May have contributed to a better overall survival NO DIRECT COMPARISON POSSIBLE Gravis G et al. Lancet Oncol 2013;2:149-58; Sweeney C et al. ESMO 2014 Meeting Abstract 7560

20 The near future Long term overall survival in GETUG 15 STAMPEDE trial

21 Conclusions Adding 6 cycles of docetaxel to ADT significantly improves OS in patients with metastatic hormone sensitive prostate cancer Combination of docetaxel + ADT upfront should be proposed to fit patients with hormone sensitive and high volume metastatic disease Longer follow up is required for men with low volume metastatic disease data from both CHAARTED and GETUG 15 trials

SESSIONE PLATINUM SERIES (Best Papers Poster o Abstract on Prostate Cancer) In Oncologia

SESSIONE PLATINUM SERIES (Best Papers Poster o Abstract on Prostate Cancer) In Oncologia Divisione di Oncologia Medica Unità Tumori Genitourinari SESSIONE PLATINUM SERIES (Best Papers Poster o Abstract