Manejo Sistémico del Cáncer de Próstata Resistente a Hormonoterapia

Manejo Sistémico del Cáncer de Próstata Resistente a Hormonoterapia Dr Marcelo Lavarda Servicio de Oncología y Hematología Clínica Sanatorio Allende Córdoba

Terminología Sugerida Andrógeno (hormona) Independiente: AIPC Inexacto: Cáncer de Próstata todavía responde a andrógenos (hormonas) Refractariedad Hormonal: HRPC Inexacto: Cáncer de Próstata todavía responde a bajos niveles andrógenos (hormonas) Resistente a Castración: CRPC Término Favorecido pero puede ser peyorativo, negativo Resistencia Endocrina u Hormonal: ERPC Propuesto como políticamente Correcto

Historia Natural del Cáncer de Próstata Local therapy Under UROLOGIST care Androgen deprivation Nonmetastatic Therapies after LHRH agonists and antiandrogens Asymptomatic First-line therapy Burden of disease Under ONCOLOGIST care Under Symptomatic the care of ONCOLOGIST Metastatic Salvage therapy Death Castrate sensitive Castrate resistant Higano C, Figg WD, Drug management of prostate cancer; 21.

Historia Natural del Cáncer de Próstata A 2 años, el riesgo de mortalidad para pacientes 55-74 años con Gleasson 2-4 es menor a 1 % Prostate Cancer Mortality Other Cause Mortality OS Albertsen P, JAMA. 25;293:295-211. Survival Non prostate cancer mortality Prostate cancer mortality Alive, % 1 8 6 4 2 1 8 6 4 2 1 8 6 4 2 1 8 6 4 2 Age at Diagnosis (Yrs) 55-59 6-64 65-69 7-74 Gleason Score 5 5 1 15 2 Gleason Score 6 Gleason Score 7 Gleason Score 8-1 5 1 15 2 5 1 15 2 Yrs Following Diagnosis 5 1 15 2 4 6 8 1 2 4 6 8 1 2 4 6 8 1 2 4 6 8 1 2 Deceased, %

Opciones Terapéuticas para Cáncer de Próstata Sipuleucel-T* [8] Cabazitaxel* [7] Denosumab LHRH agonists* [1,2] Zoledronic Acid [4] [9] Abiraterone* [1] Mitoxantrone [3] Docetaxel* [5,6] 1984-1989 1996 22 24... 21 211 MDV31 [11] Reversible AR blockers [1,2] * Approved agent for PCa However, this rapid change has left many unanswered questions, including the optimal selection and sequence of therapy Radium-223 [12] 1. 1. The Leuprolide Study Group. NEJM. 1984;311:1281-1286. 2. Crawford ED, NEJM 1989;321:419-424. 3. Tannock IF, J Clin Oncol. 1996;14:1756-1764. 4. Saad F, J Natl Cancer Inst. 22;94:1458-1468. 5. Petrylak DP, NEJM 24;351:1513-152. 6. Tannock IF, NEJM. 24;351:152-1512. 7. de Bono JS, Lancet. 21;376:1147-1154. 8. Kantoff PW, NEJM 21;363:411-422. 9. Fizazi K, Lancet. 211;377:813-822. 1. de Bono JS, NEJM 211;364:1995-25. 11. Scher HI, ASCO GU 212. 12. Parker C, et al. ASCO GU 212.

Docetaxel Uso de Docetaxel reemplaza a Mitoxantrone como tratamiento estándart TAX-327: Docetaxel mejoría en sobrevida, dolor, PSA y calidad de vida vs Mitoxantrone ] SWOG 99-16: Docetaxel/estramustine mejoría en sobrevida 2 meses vs Mitoxantrone 1 1 OS (%) 8 6 4 2 Weekly docetaxel Docetaxel q3w Mitoxantrone 6 9 12 15 18 21 24 27 3 Mos 33 OS (%) 8 6 4 2 Mitoxantrone + prednisone (235 deaths; median: 15.6 mos) P =.2 Docetaxel + estramustine (217 deaths; median: 17.5 mos) 12 24 36 Mos 48 1. Tannock IF, N Engl J Med. 24;351:152-1512. 2. Petrylak DP, N Engl J Med. 24;351:1513-152.

Cabazitaxel Segunda Línea Stratified by ECOG PS (, 1 vs 2) and measurable vs nonmeasurable disease Patients with mcrpc progressing on docetaxel Cabazitaxel 25 mg/m 2 IV q3w + Prednisone 1 mg/day PO for 1 courses (n = 378) (N = 755) Primary endpoint: OS Mitoxantrone 12 mg/m 2 IV q3w + Prednisone 1 mg/day PO for 1 courses (n = 377) Secondary endpoints: PFS, response rate, safety de Bono JS, Lancet. 21;376:1147-1154.

Cabazitaxel Segunda Línea Patients Remaining Alive (%) 1 Patients at Risk, n MP CBZP 8 6 4 2 377 378 299 321 195 241 Median OS for MP vs CBZP: 12.7 vs 15.1 mos HR :.72 (95% CI:.61-.84; P <.1) 6 12 18 24 3 Mos 94 137 31 6 9 19 Censored MP CBZP Combined median follow-up: 13.7 mos Data cutoff: March 1, 21 de Bono JS, Lancet. 21;376:1147-1154.

Inmunoterapia en Cáncer de Próstata Hormono Resistente Sipuleucel-T (IMPACT) 1 Probability of Survival (%) 8 6 4 2 HR :.78 (95% CI:.61-.98; P =.3) 21.7 mos Sipuleucel-T Placebo 12 24 36 48 6 72 Mos Since Randomization Kantoff PW, N Engl J Med. 21;363:411-422.

Abiraterone Mecanismo de Acción Pregnenolone Deoxycorticosterone Corticosterone Aldosterone CYP17: 17α-hydroxylase 17OH-Pregnenolone 11-deoxycortisol Cortisol x 2 CYP17: C17,2-lyase Testosterone < 1 ng/dl DHEA x 3 Androstenedione < 2 ng/dl Estradiol < 8 ng/dl Attard G, J Clin Oncol. 28;26:4563-4571.

Inhibidores del Eje Androgénico Androgen Biosynthesis Inhibitors (ABI): Ketoconazole Abiraterone TAK7 ABI ARI Second generation AR inhibitors (ARI): Enzalutamide (MDV31) ARN59 Chen Y, et al. Lancet Oncology. 29;1:981-991

COU-AA-31: Abiraterona Abiraterone aumenta SV vs Placebo con beneficio en todos los subgrupos Group n HR (95% CI) Baseline ECOG -1 168.64 (.53-.78) BPI < 4 659.64 (.5-.82) 4 536.68 (.53-.85) Previous chemotherapy 1 regimen 833.63 (.51-.78) 2 regimens 362.74 (.55-.99) Progression type PSA only 363.59 (.42-.82) Radiographic 832.69 (.56-.84) Visceral disease 363.7 (.52-.94) de Bono JS, N Eng J Med. 211;364:1995-25.

COU-AA-31: Abiraterona 1 Survival (%) 8 6 4 2 Placebo Median OS: 1.9 mos (95% CI: 1.2-12.) HR:.646 (95% CI:.54-.77; P <.1) Abiraterone acetate Median OS: 14.8 mos (95% CI: 14.1-15.4) Median OS with 2 previous chemos: 14. mos AA vs 1.3 mos placebo 3 6 9 12 15 18 21 Mos Median OS with 1 previous chemo: 15.4 mos AA vs 11.5 mos placebo de Bono J, N Engl J Med. 211;364:1995-25.

Abiraterona en Pacientes sin Quimioterapia Previa Ryan, C.NEJM 213;368:138-48.

Abiraterona en Pacientes sin Quimioterapia Previa Ryan, C.NEJM 213;368:138-48.

Abiraterona en Pacientes sin Quimioterapia Previa Ryan, C.NEJM 213;368:138-48.

Abiraterona en Pacientes sin Quimioterapia Previa Ryan, C.NEJM 213;368:138-48.

Enzalutamida AFFIRM Randomized 2:1 Patients with mcrpc progressing on docetaxel (N = 1199) Enzalutamide 16 mg PO daily (n = 8) Placebo PO daily (n = 399) Primary endpoint: OS Key secondary endpoints: PSA response, soft-tissue objective response, radiographic PFS, time to PSA progression Scher HI, ASCO GU 212..

Enzalutamida AFFIRM N Engl J Med 212;367:1187-97

Enzalutamida AFFIRM N Engl J Med 212;367:1187-97

Enzalutamida AFFIRM N Engl J Med 212;367:1187-97

Enzalutamida AFFIRM SRE Free (%) 1 Pts at Risk, n Enzalutamide Placebo 9 8 7 6 5 4 3 2 1 Placebo: 13.3 mos (95% CI: 5.5-NYR) HR:.621 (P <.1) Enzalutamide: 16.7 mos (95% CI: 14.6-19.1) 3 6 9 12 15 18 21 24 Time to Event (Mos) 8 399 676 278 548 196 379 128 29 68 87 33 19 11 2 De Bono JS, ASCO 212. Abstract 4519.

Enzalutamida AFFIRM 1 HR:.631 (95% CI:.529-.752; P <.1) 37% reduction in risk of death Enzalutamide: 18.4 mos (95% CI: 17.3-NYR) 5 Placebo: 13.6 mos (95% CI: 11.3-15.8) 6 12 OS (Mos) 18 24 Enzalutamide Placebo 8 399 71 317 4 167 72 33 7 3 Scher HI, ASCO GU 212.

Enzalutamida AFFIRM N Engl J Med 212;367:1187-97

Radium-223 ALSYMPCA Stratified by total ALP, previous docetaxel, and bisphosphonate use; randomized 2:1 Up to 6 treatments at 4-wk intervals Patients with symptomatic CRPC and 2 bone metastases with no known visceral metastases, either post-docetaxel or unfit for docetaxel (N = 921) Radium-223 5 kbq/kg + BSC Placebo (saline) + BSC Primary endpoint: OS Secondary endpoints: time to first SRE, time to total ALP progression, total ALP response, ALP normalization, time to PSA progression, safety, QoL Parker C, ASCO GU 212. Abstract 8.

Radium-223 ALSYMPCA OS (%) 1 9 8 7 6 5 4 3 2 1 Pts at Risk, n HR:.695 (95% CI:.552-.875; P =.185) Placebo (n = 268) Median OS: 11.2 mos Radium-223 (n = 541) Median OS: 14. mos 3 6 9 12 15 18 21 24 27 Mos Parker C, 212 ASCO GU Abstract 8.

Radium-223 ALSYMPCA Adverse Event, n (%) Hematologic Anemia Neutropenia Thrombocytopenia Radium-223 (n = 59) 136 (27) 2 (4) 42 (8) All Grades Grade 3/4 Placebo (n = 253) 69 (27) 2 (1) 14 (6) Radium-223 (n = 59) 54 (11) 9 (2) 22 (4) Placebo (n = 253) 29 (12) 2 (1) 4 (2) Nonhematologic Bone pain Diarrhea Nausea Vomiting Constipation 217 (43) 112 (22) 174 (34) 88 (17) 89 (18) 147 (58) 34 (13) 8 (32) 32 (13) 46 (18) 89 (18) 6 (1) 8 (2) 1 (2) 6 (1) 59 (23) 3 (1) 4 (2) 6 (2) 2 (1) Parker C, 212 ASCO GU Abstract 8.

Interacción entre MET y VEGFR en Tumores Óseos MET es activado en metástasis óseas Células Tumorales expresan MET Activación del MET por HGF en forma autocrina y paracrina Proliferation differentiation survival Osteoblast Migration proliferation survival Stroma VEGF HGF VEGF HGF HGF VEGF HGF MET Angiogenesis VEGF NP-1 Migration proliferation survival Tumor Cell Osteoblastos y Osteoclastos expresan MET y VEGFRs Osteoclast Zhang S, et al. Mol Cancer. 21;9:9.

Rol de MET Androgen Deprivation Activates MET Signaling Stromal HGF X AR MET Androgen deprivation AR MET HGF (autocrine + paracrine) Activated MET Is Highly Expressed in Bone Metastases Zhang S, et al. Mol Cancer. 21;9:9.

Cabozantinib vs Placebo Baseline Wk 12 Bone Scan Evaluable (N = 18) n (%) Complete resolution 21 (19) Partial resolution 61 (56) Stable 23 (21) Progressive disease 3 (3) Docetaxel pretreated Hussain M, ASCO 211. Abstract 4516. % Best Change From Baseline 1 8 6 2-2 -4-6 -8-1 Pts With Baseline t-alp Levels 2 x ULN and 12 Wks of Follow-up (N = 28) 1 Bisphosphonate treated 8 Bisphosphonate naive 6 4 2-2 -4-6 -8-1 Samples From Wk 6 and 12 (N = 118)

Cabozantinib Dolor Óseo y Uso de Narcóticos Randomized Discontinuation Trial; Post Hoc Investigator Survey Bone metastases and bone pain at baseline (n = 83): pain improvement at Wk 6 or 12 Narcotics for bone pain at baseline (n = 67): pain improvement at Wk 6 or 12 Evaluable for narcotics change (n = 55): decrease or discontinuation of narcotics 7/27 (26%) patients discontinued narcotics entirely n (%) 56 (67) 47 (7) 31 (56) % Change in Average Worst Pain From Baseline 2-2 -4-6 -8-1 Nonrandomized Expansion Trial Prospective: Pts With Average Worst Pain 4 at Baseline ** * Previous docetaxel Previous docetaxel + abiraterone and/or cabazitaxel *Previous radionuclide therapy Improved Median best pain reduction from baseline: 46% Hussain M, ASCO 211. Abstract 4516.

Cabozantinib Estudios Fase III Randomizados Patients with bone-metastatic CRPC, moderate to severe bone pain, and previous treatment with docetaxel, abiraterone, or enzalutamide (Planned N = 246) Cabozantinib 6 mg QD + Mitoxantrone Placebo Mitoxantrone/Prednisone + Cabozantinib Placebo Pain Endpoint Trial [1] Primary endpoint: durable pain response at Wk 12 Secondary endpoints: bone scan response by IRF, OS Patients with bone-metastatic CRPC, and previous treatment with docetaxel, abiraterone, or enzalutamide (Planned N = 246) 1. ClinicalTrials.gov. NCT1522443. 2. ClinicalTrials.gov. NCT165227. Cabozantinib 6 mg QD + Placebo Prednisone 5 mg BID + Placebo OS Endpoint Trial [2] Primary endpoint: OS Secondary endpoints: bone scan response by IRF

Dasatinib Inhibición del Src Src permanece sobreexpresado en células tumorales de Cáncer de Próstata La función normal del Osteoclasto depende de quinasa Src La inhibición del Src inhibe: Proliferación de células tumorales Proliferación de Osteoclastos Actividad y Osteólisis de Osteoclastos

Dasatinib: Estudios Fase II No Qtp previa Maximum Tumor Size Change From Baseline (%) 5 4 3 2 1-1 -2-3 -4-5 Tumor Size (by RECIST) Maximum untx Change From Baseline (%) 16 14 12 1 8 6 4 2-2 -4-6 -8-1 Urine N-Telopeptide Bisphosphonate No bisphosphonate Maximum PSA Change From Baseline (%) 2 15 1 5-5 -1-15 PSA Maximum BAP Change From Baseline (%) 1 8 6 4 2-2 -4-6 -8 Bone Alkaline Phosphatase Bisphosphonate No bisphosphonate Yu EY, Clin Cancer Res. 29;15:7421-7428.

Dasatinib: Estudio Fase III Patients with metastatic CRPC and evidence of progression (Planned N = 15) Docetaxel + Prednisone + Placebo daily Docetaxel + Prednisone + Dasatinib 1 mg/day PO Primary endpoint: OS Secondary endpoints: untx, time to first SRE, pain intensity, time to PSA progression, tumor response rate, PFS, safety/tolerability ClinicalTrials.gov. NCT744497

Estrategias Dirigidas a Enfermedad Ósea Prevención de fractura en Estadios Tempranos Bifosfonatos y Denosumab cada 6 meses Retardar la aparición de Metástasis Óseas Denosumab aumenta SLE (no uso estándart) Tratamiento de Metástasis Óseas en Carcinoma de Próstata Hormono Resistente Tratamiento de Metástasis Óseas en Carcinoma de Próstata Hormono Sensible Denosumab? Nuevos Agentes

Eventos Óseos: Consecuencias Clínicas Eventos Óseos Consecuencias Clínicas Fracturas Patológicas Compresión Medular Uso de Radioterapia Cirugía de Metásis Óseas Hipercalcemia Cambio en tratamiento Sistémico Dolor Óseo Uso de Analgésicos Calidad de Vida Menor Sobrevida

Parmidronato Eligibility Criteria Prostate cancer with confirmed skeletal metastases Bone pain secondary to bone metastases No previous bisphosphonate R A N D O M I Z E D Pamidronate 9 mg q3w x 9 (n = 169) Placebo q3w x 9 (n = 181) SRE (Study Wk 27), n (%) Pamidronate Placebo Any SRE 42 (25) 46 (25) Radiation to bone (pain relief) 25 (15) 29 (16) Vertebral fracture 11 (7) 1 (6) Spinal cord compression 5 (3) 3 (2) Surgery to bone 5 (3) 6 (3) Small EJ, J Clin Oncol. 23;21:4277-4284.

Ácido Zoledrónico Eligibility Criteria Patients with prostate cancer Castration resistant Bone metastases (N = 643) R A N D O M I Z E D Zoledronic acid 4 mg q3w (n = 214) Zoledronic acid 4 mg q3w (initially 8 mg) (n = 221) Placebo q3w (n = 28) Patients in 8-mg arm reduced to 4 mg because of renal toxicity Primary outcome: proportion of patients having 1 SRE Secondary outcomes: time to first on-study SRE, proportion of patients with SREs, and time to disease progression Saad F, J Natl Cancer Inst. 22;94:1458-1468.

Ácido Zoledrónico Eventos Óseos 1 Percent Without Event 8 6 4 2 Median, Days P Value ZOL 4 mg 488.9 Placebo 321 12 24 Days 36 48 6 72 SREs: ZOL 4 mg 38%; placebo 49% (P =.28) 11% absolute risk reduction in 1 SRE Pain/analgesia scores increased less with ZOL No improvement in tumor progression, QoL, OS Saad F, ASCO 23. Abstract 1523. Saad F, et al. J Natl Cancer Inst. 24;96:879-882.

Denosumab vs Ácido Zoledrónico Patients with CRPC and bone metastases, and no current or past IV bisphosphonate treatment (N = 191) Denosumab 12 mg SC + Placebo IV* q4w (n = 95) Zoledronic acid 4 mg IV* + Placebo SC q4w (n = 951) Calcium and vitamin D supplemented in both treatment groups Primary endpoint: time to first on-study SRE (fracture, radiation or surgery to bone, spinal cord compression) *Per protocol and zoledronic acid 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. Fizazi K, Lancet. 211;377:813-822.

Denosumab vs Ácido Zoledrónico Tiempo al Primer Evento Óseo Proportion of Subjects Without SRE 1..75.5.25 HR:.82 (95% CI:.71-.95; P =.2, noninferiority; P =.8, superiority) Denosumab Zoledronic acid KM Estimate of Median Mos 2.7 17.1 18% Risk reduction 3 6 9 12 15 18 21 24 27 Patients at Risk, n Study Mo Fizazi K, Lancet. 211;377:813-822.

Denosumab vs Ácido Zoledrónico Efectos Adversos Subject Incidence, n (%) Zoledronic Acid (n = 945) Denosumab (n = 943) Infectious adverse events 375 (39.7) 42 (42.6) Infectious serious adverse events 18 (11.4) 13 (13.8) Acute-phase reactions (first 3 days) 168 (17.8) 79 (8.4) Renal adverse events* 153 (16.2) 139 (14.7) Cumulative rate of ONJ 12 (1.3) 22 (2.3) Yr 1 5 (.5) 1 (1.1) Yr 2 8 (.8) 22 (2.3) Hypocalcemia 55 (5.8) 121 (12.8) New primary malignancy 1 (1.1) 18 (1.9) Fizazi K, Lancet. 211;377:813-822.

Algoritmo Terapéutico Maintain castration serum levels of testosterone and use denosumab or zoledronic acid with vitamin D and calcium if bone metastases are present No Symptomatic Visceral disease Yes Sipuleucel-T Secondary hormone therapy Antiandrogen Antiandrogen withdrawal Ketoconazole or abiraterone acetate (level 2B) Steroids DES or other estrogen Clinical trial Mottet N, Eur Urol. 211;59:572-583. NCCN. Clinical practice guidelines in oncology: prostate cancer. v.1.212. Yap TA, et al. Nat Rev Clin Oncol. 211; 8:597-61. Docetaxel Mitoxantrone Abiraterone acetate Palliative radiotherapy or radionuclide (radium-223?) for symptomatic bone metastases Clinical trial Abiraterone acetate Cabazitaxel Salvage chemotherapy Docetaxel rechallenge Mitoxantrone Secondary hormone therapy Sipuleucel-T Enzalutamide Clinical trial

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