Dr Pablo Maroto Hospital de Sant Pau Tratamiento en Cáncer de Próstata en progresión con niveles de castración de testosterona (CPRC) Dr Pablo Maroto Hospital de Sant Pau

Natural History of Prostate Cancer Under the care of ONCOLOGIST Castration Sensitive Asymptomatic Non Metastatic Castration Resistant Metastatic Symptomatic Local Therapy Androgen Deprivation Therapies After LHRH Agonists and Antiandrogen Chemotherapy Post Chemo Death Typical presentation of patients as they move through the different stages. The line represents level burden of disease. Time is not proportional Abbreviation: LHRH=luteinizing hormone-releasing hormone.

Phase III Docetaxel Studies in CRPC Demonstrating Survival Benefit Mitoxantrone 12 mg/m2 Prednisone 10 mg q day Q 21 days up to 10 cycles RANDOMI S E Docetaxel 30 mg/m2/wk Prednisone 10 mg q day 5 on; 1 off x 6 cycles N = 1,006 Docetaxel 75 mg/m2 Prednisone 10 mg q day Q 21 days up to 10 cycles SWOG 9916 RANDOMI S E Mitoxantrone 12 mg/m2 Prednisone 5 mg bid Q 21 days N = 770 Docetaxel 60 mg/m2 D2 Estramustine 280 mg D1–5a Dexamethasone 20 mg, tid D1–2 aWarfarin and aspirin. SWOG = Southwest Oncology Group. Tannock et al, 2004; Petrylak et al, 2004.

Opciones de tratamiento en CPRC en segunda línea Prevención de EREs Segundas líneas hormonales Abiraterona Enzalutamida Quimioterapia: Cabazitaxel Con enfermedad predominantemente ósea Radioisótopos: Radium 223

PTHrP, BMP, TGF-β, IGF, FGF, VEGF, ET1, WNT RANKL: Mediador en el “Círculo Vicioso” de destrucción ósea de la metástasis RANKL RANK Tumor Cell PTHrP, BMP, TGF-β, IGF, FGF, VEGF, ET1, WNT PDGF, BMPs TGF-β, IGFs FGFs Activated Osteoclast Osteoblasts Adapted from Roodman D. N Engl J Med. 2004;350:1655.

Denosumab interrumpiría el “Círculo Vicioso” RANKL RANK Denosumab Tumor Cell Formation Inhibited PTHrP, BMP, TGF-β, IGF, FGF, VEGF, ET1, WNT PDGF, BMPs TGF-β, IGFs FGFs Apoptotic Osteoclast Osteoblasts Adapted from Roodman D. N Engl J Med. 2004;350:1655.

Study Design: International, Randomized, Double-Blind, Active-Controlled Study Key Inclusion Hormone-refractory (castration resistant) prostate cancer and bone metastases Key Exclusion Current or prior IV bisphosphonate treatment Denosumab 120 mg SC and Placebo IV* every 4 weeks (N = 950) Zoledronic acid 4 mg IV* and Placebo SC every 4 weeks (N = 951) This was a head-to-head comparison vs. active comparator, resulting in much higher sample size per arm (almost 1000) as compared to the historic zoledronic acid registration trial, which was placebo-controlled (about 220 per arm). The key inclusion criterion was that there was evidence of bone metastasis based on x- ray, CT, or MRI. The key exclusion criterion was no prior IV bisphosphonate. Prior oral bisphosphosphonate use for osteoporosis was allowed. Zoledronic acid (ZA) was administered per Zometa® prescribing information. IV product dose that was either zoledronic acid or placebo was calculated according to baseline creatinine clearance. Subsequent doses were withheld if there was elevation of the serum creatinine and the IV product was only reinstituted once the serum creatinine had returned to within 10% of baseline levels. This dose and schedule is per the Zometa® label. Subjects with creatinine clearance <30 mL/min were excluded per the Zometa® label. There was no modification of the subcutaneous product, which included denosumab or placebo either at baseline or on study. Subjects were stratified by previous SRE (YES/NO), current chemotherapy (within 6 weeks prior to randomization) (YES/NO), Baseline PSA (<10 vs. ≥10 ng/mL). All subjects were strongly recommended to take daily supplemental calcium (≥500 mg) and vitamin D (≥400 IU). Calcium and Vitamin D supplemented in both treatment groups Accrual period from May 2006 to December 2008 Analysis cut-off date October 2009 *Per protocol and Zometa® label, IV product dose adjusted for baseline creatinine clearance and subsequent dose intervals determined by serum creatinine. No SC dose adjustments made due to increased serum creatinine.

Time to First and Subsequent On-Study SRE* (Multiple Event Analysis) 2.0 Rate Ratio = 0.82 (95% CI: 0.71, 0.94) Risk Reduction 18% 1.8 P = 0.008 1.6 1.4 1.2 Cumulative Mean Number of SREs per Patient 1.0 0.8 0.6 Events 0.4 Denosumab 494 0.2 Zoledronic acid 584 0.0 3 6 9 12 15 18 21 24 27 30 33 36 Month *Events occurring at least 21 days apart

TROPIC: Cabazitaxel vs Mitoxantrone ¿Es importante una rama control con mitoxantrone? mCRPC patients who progressed during and after treatment with a docetaxel-based regimen (N=755) Stratification factors ECOG PS (0, 1 vs. 2) • Measurable vs. non-measurable disease cabazitaxel 25 mg/m² q 3 wk + prednisone* for 10 cycles (n=378) mitoxantrone 12 mg/m² q 3 wk + prednisone* for 10 cycles (n=377) *Oral prednisone/prednisolone: 10 mg daily. Primary endpoint: OS Secondary endpoints: Progression-free survival (PFS), response rate, and safety Inclusion: Patients with measurable disease must have progressed by RECIST; otherwise must have had new lesions or PSA progression

Primary Endpoint: Overall Survival (ITT Analysis) 15.1 12.7 Median OS (months) 0.59–0.83 95% CI <.0001 P-value 0.70 Hazard Ratio CBZP MP Proportion of OS (%) 80 60 40 20 100 0 months 6 months 12 months 18 months 24 months 30 months Number at risk 28 11 4 1 231 188 90 67 300 377 MP 321 378 CBZP

 f a v o r s C B Z P | f a v o r s M P  Factor Hazard ratio (95% CI)  f a v o r s C B Z P | f a v o r s M P  All patients 0.70 (0.59–0.83) ECOG status: 0,1 0.68 (0.57–0.82) ECOG status: 2 0.81 (0.48–1.38) Measurable disease: No 0.72 (0.55–0.93) Measurable disease: Yes 0.68 (0.54–0.85) No. of prior chemo: 1 0.67 (0.55–0.83) No. of prior chemo: ≥2 0.75 (0.55–1.02) Age: <65 0.81 (0.61–1.08) Age: ≥65 0.62 (0.50–0.78) Rising PSA: No 0.88 (0.61–1.26) Rising PSA: Yes 0.65 (0.53–0.80) Total docetaxel dose: <225 mg/m² 0.96 (0.49–1.86) Total docetaxel dose: ≥225 to 450 mg/m² 0.60 (0.43–0.84) Total docetaxel dose: ≥450 to 675 mg/m² 0.83 (0.60–1.16) Total docetaxel dose: ≥675 to 900 mg/m² 0.73 (0.48–1.10) Total docetaxel dose: ≥900 mg/m² 0.51 (0.33–0.79) Progression: During last docetaxel treatment 0.65 (0.47–0.90) Progression: <3 months since last docetaxel dose 0.70 (0.55–0.91) Progression: ≥3 months since last docetaxel dose 0.75 (0.51–1.11) 1 2 0.5 1.5 1 2 0.5 1.5

Most Frequent Grade ≥3 Treatment-Emergent AEs* Safety Population 1.9 34.2 0.3 22.9 Nausea 22.6 10.2 Vomiting 16.7 0.5 3.8 Hematuria 57.4 95.7 39.4 88.4 Any adverse event 11.6 3.5 Abdominal pain 16.2 3 12.1 Back pain 4.6 20.5 2.4 12.4 Asthenia Grade ≥3 (%) All grades (%) 36.7 46.6 7.5 CBZP (n=371) 4.9 6.2 1.3 27.5 Fatigue 10.5 Diarrhea Febrile neutropenia MP (n=371) ¿Cómo condiciona el tratamiento la toxicidad?

VOLUMEN 26, Nº28 2008 Prostate Cancer: Moving Forward by Reinventing the Wheel ... But This Time It Is Round

Resistance to castration: is there still a way to play with hormonal drugs 3 4 1 2 Scher H et al, J Clin Oncol 2005

LHRH analogues Antiandrogens LHRH Prostate Cancer Testosterone Testis Adrenal Gland ACTH LH Brain LHRH Androgens LHRH Analogue Pituitary Brain Pituitary LH ACTH Adrenal Gland Testis Testosterone Androgens Antiandrogen Prostate Cancer

Abiraterone: Inhibición síntesis teste, adrenal, ¿intratumoral? MW = 391.55 N 3β-Acetoxy-17-(3-pyridyl)androsta-5,16-diene RO = AcO Prostate Cancer Testosterone Testis Adrenal Gland ACTH LH Brain LHRH Androgens Pituitary Inhibitor Inhibitor? ? De novo synthesis

CYP17 blockade inhibits androgen synthesis

The Effects of MDV3100 on the Androgen Receptor Are Distinct from Bicalutamide AR Binding Affinity DHT ~ 5nM Bicalutamide ~160 nM MDV3100 ~35 nM 2. Nuclear Import DHT: ++++ Bicalutamide: ++++ MDV3100: ++ 3. DNA Binding Bicalutamide: ++ MDV3100: - 4. Coactivator recruitment DHT: ++++ 1 HSP 90 LBD Ligand HD DBD NTD 2 4 POL II 3 DNA

COU-AA-301: Fase III post-quimioterapia ¿Influye en la decisión de tratar la necesidad de prednisona? Fase III, multicéntrico, aleatorizado, doble ciego, para estudiar los beneficios clínicos de abiraterona junto a prednisona, en pacientes con cáncer de próstata metastásico que han progresado tras uno o dos regímenes de quimioterapia. Objetivo principal OS Objetivos secundarios TTPP rPFS Respuesta PSA Pacientes Abiraterona 1000 mg/día Prednisona 10 mg/día N=797 N=1195 1 o 2 regímenes de QT previa, uno de ellos docetaxel ALEATORIZACIÓN 2:1 Estratificación de acuerdo al (ECOG) performance status (0-1 vs. 2), peor dolor en las pasadas 24 h (BPI)-Short Form (0-3 [absent] vs. 4-10 [present]), número de regímenes de quimioterapia previos (1 vs. 2), y tipo de progresión(PSA only vs. radiographic progression with or without PSA progression). El tratamiento se prolongó hasta progresión de los siguientes tipos 1) PSA, 2) radiológica 3) sintomática o clínica, o toxicidad inaceptable Efficacy analysis set: ITT (intent-to-treat). Placebo Prednisona 10 mg/día N=398 Gráfico extraído de: de Bono, J.S. et al. Abiraterone and increased survival in metastasic prostate cancer. NEJM: 2011;364(21):1995-2005.

¿Metástasis viscerales también?

¿Tiene importancia la respuesta por PSA?

Diseño del estudio ALSYMPCA TRATAMIENTO 6 injections at 4-week intervals PACIENTES ESTRATIFICACIÓN R A N D OM I S E D 2:1 Confirmed symptomatic CRPC ≥ 2 bone metastases No known visceral metastases Post-docetaxel or unfit for docetaxel Radium-223 (50 kBq/kg) + Best standard of care Total ALP: < 220 U/L vs ≥ 220 U/L Bisphosphonate use: Yes vs No Prior docetaxel: Yes vs No Placebo (saline) + Best standard of care N = 922 Planned follow-up is 3 years Clinicaltrials.gov identifier: NCT00699751.

ALSYMPCA: Supervivencia Global 100 HR 0.695; 95% CI, 0.552-0.875 P = 0.00185 90 80 70 60 Radium-223, n = 541 Median OS: 14.0 months % 50 40 30 Placebo, n = 268 Median OS: 11.2 months 20 10 Month 3 6 9 12 15 18 21 24 27 Radium- 223 541 450 330 213 120 72 30 Placebo 268 218 147 89 49 28 7

ALSYMPCA: Tiempo al primer SRE 100 HR 0.610; 95% CI, 0.461-0.807 P = 0.00046 90 80 70 Radium-223, n = 541 Median: 13.6 months 60 50 % Without SRE 40 Placebo, n = 268 Median: 8.4 months 30 20 10 Month 3 6 9 12 15 18 21 Radium-223 541 379 214 111 51 22 Placebo 268 159 74 30 7 2

ALSYMPCA: Efectos adversos de interés All Grades Grades 3 or 4 Radium-223 n (%) Placebo Haematologic Anaemia 136 (27) 69 (27) 54 (11) 29 (12) Neutropenia 20 (4) 2 (1) 9 (2) Thrombocytopenia 42 (8) 14 (6) 22 (4) 4 (2) Non-Haematologic Bone pain 217 (43) 147 (58) 89 (18) 59 (23) Diarrhoea 112 (22) 34 (13) 6 (1) 3 (1) Nausea 174 (34) 80 (32) 8 (2) Vomiting 88 (17) 32 (13) 10 (2) 6 (2) Constipation 46 (18)

Resumen: Resultados Ensayos fase III en CPRC Agent (trial, year) Disease State Comparator Hazard Ratio P value Radium-223 (ALSYMPCA 2011) Symptomatic Bone metastases Placebo 0.695 0.00185 Docetaxel1 (TAX327 2004) Chemo-naive Mitoxantrone Prednisone 0.76 0.009 Cabazitaxel2 (TROPIC 2010) Post-docetaxel 0.70 <0.0001 Enzalutamide3 (AFFIRM 2012) Post- Docetaxel 0.63 0.0001 Abiraterone4 (COU-AA-301 2010) Placebo Prednisone 0.65 <0.001

No hay criterios definitorios para recomendar un tratamiento para un paciente dado ¿Seguro?

PMR: 60 a. ECOG 0. Gleason 9. Respuesta hormona previa <12 m PMR: 60 a. ECOG 0. Gleason 9. Respuesta hormona previa <12 m. Metástasis hepáticas. PSA de 19. Respuesta docetaxel intervalo 2 meses sin toxicidades relevantes JMR: 70 a. ECOG 0. Gleason 7. Respuesta hormona previa 19 m. Metástasis Óseas. PSA de 198. Respuesta docetaxel intervalo 4 meses

Definir un algoritmo similar para hormonoterapia de rescate

GRACIAS