WHEN IS CHEMOTHERAPY INDICATED FOR HORMONE-NAÏVE PROSTATE CANCER FERRY SAFRIADI Department of Urology AMC Hasan Sadikin Hospital/Padjadjaran University 39TH ASMIUA, Surabaya 7-10 Nov 2016

Epidemiology Prostate cancer is the second leading cause of cancer deaths among North American men, with an estimated 29,720 deaths in 2013 in the United States and 3,900 deaths in Canada. American Cancer Society: Cancer Facts and Figures 2011 Advisory Committee on Cancer Statistics: Canadian Cancer Statistics 2013. In Asian countries: incidence of Pca is increasing rapidly due to a more westernized lifestyle. In Japan; mortality rate projected to increase by 2.8 times in 2020. Namiki M, et al. Jpn J Clin Oncol 2010

Incidence: Indonesia 2008 2012 6,6% 13663

Mortality: Indonesia 2008 2012 6,3% 9191

CRPC Patients Characteristic In 3 Indonesian University Hospital   N 158/1097 (14.4%) Median age 69 years old Median PSA 193.5 ng/ml Mode Gleason Score 8 Chemotherapy and Estramustine were given to patients with CRPC (5.7%) of 14.4%. Safriadi F, et al. in press

For men with androgen-sensitive metastatic disease, continuous ADT is the current standard of care. Loblaw DA, et al:.J Clin Oncol 2007 ADT is capable of achieving castrate levels of testosterone (≤50 ng/dL), and most patients with metastatic hormone naive prostate cancer initially respond to this treatment. Feldman BJ, et al. Nat Rev Cancer 2001 The majority of patients will develop resistance to these traditional hormonal approaches and the median time to progression is about 18-24 months. Denis LJ, et al..Eur Urol 1998.

TAX 327 2000-2, mHRCP: 1006 men Doce 3 weekly vs. 1 weekly vs. mitoxantrone 3 weekly. HR for death: Doce 3 weekly: 0.76 Doce weekly: 0.91 Median Survival: Mitoxantrone: 16.6 mo Doce 3 weekly: 18.9 mo Doce weekly: 17.4 mo Tannock IF, et al. NEJM 2004

PREVAIL STUDY Chemonaive setting. 872 in the enzalutamide group and 845 in the placebo group. rPFS 12 months: 65% vs.14%. Risk reduction of death: 29%. Delayed the initiation of chemotherapy. Beer TM, et al. NEJM 2014

CO-AA-302 mCRPC: chemonaive 1008 men: - abi 1000mg daily vs. plac Median rPFS: abi 16.5 mo vs.plac 8.3 mo HR 0.53 p < 0.001 Ryan CJ, et al. NEJM 2013

The M0 Challenge HR localized PCa Docetaxel ± 7-15 years (3-5) SRE ESMO2014 Tombal final The M0 Challenge Docetaxel ± 7-15 years (3-5) HR localized PCa SRE PAIN Local therapies PSA Prog. RX progr. ADT MO CRPC space Time to chemotherapy (months) Active arm Control Δ HR (95%CI) p COU-AA-302 (Prednisone) 26.5 16.8 9.5 0.61 0.51-0.72 ≤ 0.001 PREVAIL (placebo) 28.0 10.8 17.2 0.35 0.30-0.40 < 0.001 Eur Urol. 2014 Nov;66(5):815-25. Beer TM, N Engl J Med. 2014 Jul 31;371(5):424-33.

ESMO2014 Tombal final The M0 Challenge Docetaxel ± 7-15 years HR localized PCa SRE PAIN Local therapies PSA Prog. RX progr. ADT MO CRPC space PREVAIL and COU-AA-302 have induced a shift toward treatment of ± 1 year. Once approved widely, abiraterone and/or enzalutamide will be given at early entry in mCRPC Joniau S for EmPACT, Eur Urol. 2014, Widmark A, SPCG-7, Lancet. 2009. Warde P, SPCG-7, Lancet. 2011.

EAU Guidelines of Prostate Cancer 2015

Panduan Penatalaksanaan CRPC di Indonesia Indeks Pasien Gejala Metastatik Kemoterapi Status Performa Penatalaksanaan 1 - Baik Rekomendasi: dilakukan observasi serta tetap diteruskan pemberian terapi ADT 2 -/minimal + Standard: (A) Abiraterone + prednisone, (B) docetaxel 3 Standard : Docetaxel. Rekomendasi: Abiraterone + prednisone 4 Buruk Pilihan: dengan Abiraterone + prednisone, atau Ketoconazole + steroid, atau terapi radionuklida 5 Standard: Abiraterone acetate + prednisone, atau Cabazitaxel 6 Pendapat ahli: terapi paliatif abiraterone + prednisone, atau ketoconazole + steroid, atau terapi radionuklida

The impact of PREVAIL and COU-AA-302 in the modern CRPC landscape Enzalutamide Symptoms Abiraterone Chemo-based treatment Enzalutamide Cabazitaxel Abiraterone Radiographic progression Bone targeted therapies, including RA223 M0 CRPC survival Ryan et al. Lancet Oncol 2015. Beer C et al. N Engl J Med 2014; Tannock IF et al. N Eng J Med 2004;

ESMO2014 Tombal final The M0 Challenge Docetaxel ± 7-15 years (3-5) HR localized PCa SRE PAIN Local therapies PSA Prog. RX progr. ADT MO CRPC space As a consequence trials in that setting will be a very early experimental drug versus an early abiraterone or enzalutamide HN PC: hormone naïve PCa; CRPC: Castration-Resistant Prostate Cancer; M0, non-metastatic; RX progression: radiological progression; SRE skeletal related events Joniau S for EmPACT, Eur Urol. 2014, Widmark A, SPCG-7, Lancet. 2009. Warde P, SPCG-7, Lancet. 2011.

Proportion of patients with bone metastases Denosumab and bone-metastasis-free survival in men with CRPC 1.0 0.8 Key eligibility criteria CRPC with: PSA  8 ng/ml or PSA DT  10 months No bone metastases No prior IV bisphosphonate use HR = 0.85 (95% CI, 0.730.98) P = 0.028 0.6 Proportion of patients with bone metastases 0.4 Median: Events: 0.2 Placebo (n = 716) 25.2 months 370 Denosumab (n = 716) 29.5 months 335 0.0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 Study month Smith, et al. Lancet. 2012

BTT risk reduction 25% Saad F, et al. Eur Urol 2015

GETUG-AFU15 Controversial results: # of docetaxel cycles Sample size Length of follow up Proportion of high-vol disease HR 0.88 (0.68-1.14), p= 0.3 Gravis G et al. Lancet Oncol 2013

CHAARTED STUDY High volume Low volume ESMO2014 Sweeney final CHAARTED STUDY High volume Low volume Hazard Ratio 0.60 (95% CI 0.45-0.81) P=0.0006 ADT + DOC Not reached ADT alone Not reached ADT + DOC 49.2 mths ADT alone 32.2 mths Hazard Ratio 0.63 (95% CI 0.34-1.17) P=1398 high volume: >4 bone lesions and >1 lesion in any bony structure beyond the spine/pelvis or visceral disease 17-month benefit in median OS (from 32.2 to 49.2 months) for high volume Sweeney C et al. J Clin Oncol 201475mg/m2 plus prednisone

STAMPEDE : Survival – M1 Patients SOC+Doc SOC SOC 343 deaths SOC + Doc 134 deaths HR (95%CI) 0.73 (0.59, 0.89) P-value 0.002 Median OS (95% CI) SOC 43m (24, 88m) SOC+Doc 65m (27, NR) James ND et al. Lancet. 2015.

Docetaxel : Failure-free survival SOC 750 FFS events SOC+Doc 371 FFS events HR (95%CI) 0.62 (0.54, 0.70) P-value <0.0000000001* SOC+Doc Median FFS (95% CI) SOC 21m (18, 24m) SOC+Doc 37m (33, 42m) SOC James ND et al. Lancet. 2015.

The impact of PREVAIL and COU-AA-302 in the modern CRPC landscape Enzalutamide1 Chemo-based treatment3 ? Abiraterone2 Radiographic progression M0 CRPC survival Ryan et al. Lancet Oncol 2015. Beer C et al. N Engl J Med 2014; Tannock IF et al. N Eng J Med 2004;

FIRSTANA: randomized, open-label phase 3 trial of CABA 25 mg/m2 and 20 mg/m2 vs DOC in chemo-naive mCRPC pts CABA 25 mg/m² every 3 wks + prednisone 10 mg/d N=388 159 centers worldwide R A N D O M I Z E mCRPC patients who have not previously received chemotherapy N=1,168 CABA 20 mg/m² every 3 wks + prednisone 10 mg/d N=389 DOC 75 mg/m² every 3 wks + prednisone 10 mg/d N=391 Primary endpoint: OS Secondary endpoints: Safety, PFS, tumor response (if measurable disease), PSA response, pain response, time to SREs, QoL, pharmacokinetics, pharmacogenomics Exploratory: cDNA Prophylactic G-CSF NOT allowed at cycle 1 Statistics: OS superiority of CABA over DOC (HR 0.75) Sartor AO et al. J Clin Oncol 2016;34(suppl):abstract 5006 - ClinicalTrials.gov NCT01308567

FIRSTANA OS (primary endpoint) PFS (composite)* Median PFS, months (95% CI) DOC + P 5.3 (4.86-5.78) CABA 20 + P 4.4 (3.91-5.09) CABA 25 + P 5.1 (4.60-5.72) CABA 20 vs DOC HR=1.009 (0.85-1.197) P=0.9967 CABA 25 vs DOC HR=0.97 (0.819-1.16) P=0.7574 CABA 20 vs DOC HR=1.063 (0.913-1.236) P=0.4218 CABA 25 vs DOC HR=0.989 (0.849-1.152) P=0.8035 Median OS, months (95% CI) DOC + P 24.3 (22.18-27.60) CABA 20 + P 24.5 (21.75-27.20) CABA 25 + P 25.2 (22.90-26.97) Sartor AO et al. J Clin Oncol 2016;34(suppl):abstract 5006 -

Effect of the addition of docetaxel on survival in men with M1 disease Addition of docetaxel to standard of care translates into an absolute improvement in 4-year OS of 9% (95% CI 5-14). an absolute 4-year failure rates of 16% (95% CI 12-19) Vale CL et al. Lancet Oncol. 2016

The advanced PCa landscape Abiraterone Enzalutamide Docetaxel Cabazitaxel PSA progr. RX progr. SRE PAIN ADT M1 HNPC Bone targeted therapies ± 2-4 years ± 7-15 years High-risk localized PCa SRE PAIN Local therapies RX progr. ADT MO CRPC space PSA progr. ADT: androgen deprivation therapy; HNPC: hormone-naïve prostate cancer; PCa: prostate cancer; PSA: prostate-specific antigen; RX progr.: radiological progression; SRE: skeletal-related events Mottet N et al. EAU guidelines on prostate cancer, update 2015; http://uroweb.org/guideline/prostate-cancer/ (accessed March 2016) Vale CL et al. Lancet Oncol 2016;17:243-46

Newly diagnosed Fit enough https://uroweb.org/guideline/prostate-cancer/

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