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Carcinoma prostatico - Dott. N. Fossati

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Carcinoma prostatico: deprivazione androgenica e terapie di II livello (abiraterone, enzalutamide) nella forma metastatica
resistente alla castrazione chimica - Dott. N. Fossati

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Carcinoma prostatico - Dott. N. Fossati

  1. 1. Carcinoma prostatico: deprivazione androgenica e terapie di II livello (abiraterone, enzalutamide) nella forma metastatica resistente alla castrazione chimica Nicola Fossati Urological Research Institute Università Vita-Salute San Raffaele San Raffaele Scientific Institute Milan, Italy
  2. 2. Valerio G, 62 year old, no symptoms First PSA assessment : 110 ng/ml Prostate biopsy: Gleason 5+4 in all cores (cT3) CT scan: no visceral mets Bone scan: Clinical case (back in 2013…)
  3. 3. Clinical case (back in 2013…) 0 10 20 30 40 50 60 70 80 90 100 110 120 May Jun Jul Oct Jan Apr Jul Oct Jan Jan Feb PSA degarelix 5 ng/ml 6 ng/ml 12 ng/ml Bone scan: almost complete resolution of all lesions Testosterone: 25 ng/dL
  4. 4. Castration-Resistant PCa: Definition ü Castrate serum testosterone <50ng/dL or 1.7nmol/L plus either ü Biochemical progression: Three consecutive rises in PSA 1 week apart resulting in two 50% increases over the nadir, with PSA > 2 ng/mL or ü Radiological progression: The appearance of 2 or more new bone lesions on bone scan or enlargement of a soft tissue lesion using RECIST (Response Evaluation Criteria in Solid Tumors). Symptomatic progression alone must be questioned and subject to further investigation and is not sufficient to diagnose CRPC EAU Guidelines on Prostate Cancer 2017
  5. 5. Castration resistant PCa In men with M0 CRPC, baseline PSA level, PSA velocity and PSA-DT have been associated with time to first bone metastasis, bone metastasis-free and OS. PCa Radiographic Assessments for Detection of Advanced Recurrence (RADAR) group: a bone scan and a CT scan when the PSA reached 2 ng/mL and if this was negative it should be repeated when the PSA reached 5 ng/mL and again after every doubling of the PSA based on PSA testing every three months for asymptomatic men. EAU GUIDELINES: Do not treat M0 CRPC patients outside clinical trial
  6. 6. THE PAST: 2005 Hormone therapy ADT + Docetaxel Metastatic CRPC Asymptomatic / symptomatic (failed ADT) Hormone naive Medical Oncologist
  7. 7. THE PRESENT: 2018 Hormone therapy ADT + Docetaxel ADT+ Abiraterone ADT + Enzalutamide ADT + Sipuleucel-T ADT + Radium 223 ADT + Cabazitaxel Metastatic CRPC Asymptomatic / symptomatic (failed ADT) Hormone naive Medical Oncologist + Urologist + Nuclear medicine All these compounds have shown to improve survival of men with mCRPC in large Phase 3 Trials and have been approved in this setting
  8. 8. Metastatic CRPC: first and second line therapies First-line therapy Docetaxel Enzalutamide Abiraterone Sipuleucel-T Radium-223 Second-line therapy (dependent on previous treatment) Cabazitaxel Radium-223 Abiraterone Enzalutamide Docetaxel ADT^ MAB^
  9. 9. Phase 3 clinical trials in mCRPC
  10. 10. CRPC: should we stop ADT? ü In the absence of prospective data, the modest potential benefits of a continuing castration outweigh the minimal risk of treatment ü In addition, all subsequent treatments have been studied in men with ongoing androgen suppression and therefore it should be continued indefinitely in these patients EAU Guidelines on Prostate Cancer 2017
  11. 11. Metastatic CRPC: first and second line therapies ADT^ MAB^ First-line therapy Second-line therapy If a men progressed to mCRPCa on ADT, should bicalutamide being added (MAB) prior to first line therapy? Commonly done in clinical practice Never been shown to improve patient survival of men progressing on ADT EAU Guidelines on Prostate Cancer 2017
  12. 12. Metastatic CRPC: first and second line therapies First-line therapy Docetaxel Enzalutamide Abiraterone Sipuleucel-T Radium-223 ADT^ MAB^
  13. 13. “First line Metastatic CRPC”: Inclusion criteria Drug (Study) Treatment arms Patients Docetaxel (TAX 327) Docetaxel (3 weeks( + pred vs mito + pred CRPC. Visceral M+ Chemotherapy naïve 45% were symptomatic Enzalutamide (PREVAIL) Enza vs placebo CRPC Chemotherapy naïve 10% Visceral M+ Asymptomatic or mildly symptomatic Abiraterone (CU-11-302) Abi + pred vs placebo + pred Progressive CRPC Chemotherapy naïve Asymptomatic or midly symptomatic No known visceral M+ Sipuleucel – T (IMPACT) Sipuleucel – T vs control arm CRPC Chemotherapy naïve. No visceral M+ Asymptomatic or mildly symptomatic Radium 223 (ALSYMPCA) Radium 223 + BSC vs placebo + BSC Symptomatic CRPC >= 2 bone mets No known visceral M+ Post doxetacel or unfit to docetaxel (>40% of recruited patients)
  14. 14. Most important prognostic factors in mCRPC ü Symptoms and performance status ü Visceral disease ü Time of response to ADT ü PSADT
  15. 15. Docetaxel ü Docetaxel inhibits depolymerization of the microtubule while polymerization continues to occur ü This results in the disruption of cellular activities including cell-cycle arrest and inhibition of mitosis Mackler NJ et al. Nat Clin Pract Urol 2005;2: 92–100
  16. 16. Docetaxel: TAX-327 ü TAX-327: first trial showing a survival benefit of chemotherapy in the context of CRPC (OS: primary endpoint) ü The median survival was 18.9 months vs. 16.4 months in the group of patients who received mitoxantrone/prednisone (p=0.009), the pain response was 35% vs. 22% ü Up to 10 cycles of treatment were planned Tannock et al. NEJM 2004;351:1502-12
  17. 17. Cabazitaxel plus Prednisone: FIRSTANA ü Cabazitaxel (CBZ) is a tubulin-binding taxane drug ü Cabazitaxel has significantly more effective suppression of microtubule dynamics, rapid intracellular uptake, and prolonged drug retention ü Additionally, the drug has antitumour activity in models resistant to paclitaxel and docetaxel ü FIRSTANA trial de Bono et al. Lancet 2010;376:1147-54
  18. 18. Cabazitaxel vs. docetaxel in chemotherapy naïve patients ü 1,168 Chemotherapy naïve patients ü Inclusion criteria ü ECOG performance status 0-2 ü Effective castration ü Disease progression ü Primary endpoint: OS ü Patients randomized in a 1:1:1: fashion to: ü Cabazitaxel 20 mg/m2 ü Cabazitaxel 25 mg/m2 ü Docetaxel 75 mg/m2 Oudard et al. J Clin Oncol 2017; in press
  19. 19. Cabazitaxel vs. docetaxel in chemotherapy naïve patients Oudard et al. J Clin Oncol 2017; in press
  20. 20. Cabazitaxel vs. docetaxel in chemotherapy naïve patients Oudard et al. J Clin Oncol 2017; in press 41,2 34,4 25,2 60,1 47,8 31,7 46 32,6 33,9 0 10 20 30 40 50 60 70 Grade ≥3 TEAE Serious TEAE TEAE leading to treatment discontinuation C20 C25 D75
  21. 21. Docetaxel combined studies 1. Scher HI et al. J Clin Oncol 2010 2. Kelly WK et al. J Clin Oncol 2010 3. Small E et al. ASCO GU 2009 4. Sternberg C et al. Annals Oncol 2009 Design Results Docetaxel DN-1011 Negative Docetaxel Bevacizumab2 Negative Docetaxel GVAX3 Negative Docetaxel Oblimersen4 Negative Docetaxel Atrasentan5 Negative Docetaxel Zibotentan Negative Docetaxel Aflibercept7 Negative Docetaxel Lenalidomide Negative Docetaxel Dasatinib8 Negative 5. University of Michigan press release (April 2011) 6. Nelson JB et al. J Clin Oncol 2011 7. Tannock I et al. J Clin Oncol 2013 8. Araujo JC. ASCO GU 2013 Constant failure
  22. 22. Abiraterone Acetate (Zytiga) AA is a selective inhibitor of androgen biosynthesis that potently blocks cytochrome P450 c17, a critical enzyme in testosterone synthesis Cholesterol Pregnenolone Progesterone Corticosterone 17α-OH- pregnenolone DHEA Androstenedione 17α –OH- progesterone Cortisol CYP17 C17,20-lyase CYP17 17α-hydroxylase Aldosterone Deoxy- corticosterone DHT 5α-reductase 11-Deoxy- cortisol Desmolase X X ACTH Loop Renin-Angiotensin Abiraterone Testosterone ++
  23. 23. Abiraterone Acetate: COU-AA-302 Ryan CJ, et al. N Engl J Med 2013;368:138–48. ü Phase 3 multicenter, randomized, double-blind, placebo-controlled study ü Stratification by ECOG performance status 0 vs 1 AA 1000 mg daily Prednisone 5 mg BID (Actual n = 546) Co-Primary: • rPFS by central review • OS Secondary: • Time to opiate use (cancer-related pain) • Time to initiation of chemotherapy • Time to ECOG-PS deterioration • TTPP Efficacy end points Placebo daily Prednisone 5 mg BID (Actual n = 542) R A N D O M I Z E D 1:1 Progressive chemo- naïve mCRPC patients (Planned N = 1088) Asymptomatic or mildly symptomatic without visceral mets Patients
  24. 24. Abiraterone Acetate: COU-AA-302 Ryan et al, Lancet Oncol 2015; 16: 152–60 ü At a median follow-up of 49.2 months (IQR 47.0–51.8), Overall, 365 (67%) patients in the abiraterone acetate group and 435 (80%) in the placebo group received subsequent treatment with one or more approved agents. ü Median overall survival was significantly longer in the abiraterone acetate group than in the placebo group (34.7 months [95% CI 32.7–36.8] vs 30.3 months [28.7–33.3]; hazard ratio 0.81 [95% CI 0.70–0.93]; p=0.0033).
  25. 25. Enzalutamide (xtandi) ü Enzalutamide is a second-generation AR antagonist with significantly more potent binding to the AR than the first-generation antagonists ü Enzalutamide-bound AR mostly remains cytoplasmic, whereas the older drugs actually cause nuclear translocation Hurtwitz et al. Oncology 2013
  26. 26. Beer et al. N Engl J Med 2014;371:424-33 Enzalutamide: PREVAIL ü Double-blind, phase 3 randomized trials: 1717 patients (10% visceral mets) assigned to receive either ENZA (160 mg) or placebo once daily ü The rate of progression-free survival at 12 months was 65 vs. 14% for ENZA and placebo (81% RR; HR: 0.19; 95% CI: 0.15-0.23; P<0.001) ü 626 patients (72%) in the ENZA group and 532 patients (63%) in the placebo group were alive at the data-cutoff date (29% RR; HR: 0.71; P<0.001)
  27. 27. Beer et al, Eur urol, 2016 ü Longer term analysis with additional 20 months of follow-up for rPFS, 9 months for OS, and 4 months for safety (up to the pre-specified number of deaths) ü Enzalutamide reduced the risk of radiographic progression or death by 68% (p<0.001) and the risk of death by 23% (p=0.0002). ü Median investigator assessed rPFS: 54 mo vs 20 mo Median OS was 35.3 mo vs 31.3 mo in the placebo arm. Most common AE: fatigue, back pain, constipation, arthralgia.
  28. 28. Sipuleucel-T: IMPACT (Provenge) Autologous vaccine consisting of antigen-presenting cells that are exposed to the fusion protein prostatic acid phosphatase and GCSF, and then re-infused in the patient Kantoff et al. NEJM 2010;363;5:411
  29. 29. Sipuleucel-T: IMPACT Kantoff et al. NEJM 2010;363;5:411 † Primary endpoint: overall survival Secondary endpoint: Time to objective disease progression PSA was not an endpoint measure †
  30. 30. Sipuleucel-T: IMPACT ü Median survival with sipuleucel-T was 25.8 months compared with 21.7 months with placebo ü Only patients with good performance status, asymptomatic or mildly symptomatic osseous metastases, and absence of visceral metastases were included in the trial Kantoff et al. NEJM 2010;363;5:411
  31. 31. Sipuleucel-T: Limitations ü Extremely expensive!!! ü (Currently) available only in the U.S. Attard et al. The Lancet 2015; in press IT SEEMS THAT THOSE WHO BENEFIT YTHE MOST FROM IT ARE PATEINTS IN THE EARLY mCRPC PHASE
  32. 32. Radium-223: ALSYMPCA ü Radium-223 mimics calcium, forming complexes with the bone mineral hydroxyapatite at areas of increased bone turnover, such as bone metastases ü The short-range of alpha particles emitted by Radium-223 limits the damage to the surrounding normal tissue ü Radium-223 emits alpha particles that cause double-strand DNA breaks in the adjacent cells, resulting in antitumor activity Parker et al. NEJM 2013;369:213-23 Henriksen et al. Cancer Res 2002
  33. 33. Radium-223: ALSYMPCA Parker et al. NEJM 2013;369:213-23 Primary endpoint: OS Secondary endpoints: time to first SRE, time to total ALP progression, total ALP response, total ALP normalization, time to PSA progression, safety and QoL Placebo + best standard of care FOLLOW-UP PHASETREATMENT PHASE 6 injections at 4-week intervals Stratification factors •Total ALP < 220 U/L vs. ≥ 220 U/L •Bisphosphonate use (Yes vs. No) •Prior docetaxel (Yes vs. No) Key inclusion criteria •Confirmed symptomatic CRPC •≥ 2 bone metastases •No known visceral metastases •Post-docetaxel or unfit for docetaxel Randomization 2:1 Radium 223 + best standard of caren=921 mCRPC No visceral mets
  34. 34. Radium-223: ALSYMPCA ü 921 patients assigned to radium-223 or placebo ü Radium-223 significantly improved overall survival compared to placebo (14.9 vs. 11.3 mo, respectively) ü Radium-223 was also associated with low myelosuppression rates and fewer adverse events compared to placebo Parker et al. NEJM 2013;369:213-23
  35. 35. Management of castration-resistant PCa EAU Guidelines on Prostate Cancer 2017
  36. 36. Metastatic CRPC: which drug to be given first? First-line therapy Docetaxel if: 1. Asymptomatic and symptomatic fit for chemo 2. Bone and or visceral mets 3. Rapidly progressing disease and short ADT response Enzalutamide if: 1. Asymptomatic and midly symptomatic 2. Bone and visceral mets Sipuleucel-T 1. Asymptomatic and midly symptomatic 2. Bone mets only Radium-223 1. Symptomatic 2. Bone mets only (>= 2) ADT^ MAB^ Abiraterone if: 1. Asymptomatic and midly symptomatic 2. Bone mets only
  37. 37. Clinical case (back in 2008…) 0 10 20 30 40 50 60 70 80 90 100 110 120 May Jun Jul Oct Jan Apr Jul Oct Jan Jan Feb PSA degarelix 5 ng/ml 6 ng/ml 12 ng/ml NO SYMPTOMS Bone scan: 3 new lesions in the lumbar vertebrae CT Scan: no visceral mets Testosterone: 25 ng/dL WHICH DRUG IS INDICATED? 1. DOCETAXEL 2. ABIRATERONE 3. ENZALUTAMIDE 4. RADIUM 223 5. SIPULEUCEL T
  38. 38. Clinical case (back in 2013…) 0 10 20 30 40 50 60 70 80 90 100 110 120 May Jun Jul Oct Jan Apr Jul Oct Jan Jan Feb Apr Jul Oct Jan PSA degarelix 12 ng/ml Started abiraterone Testosterone: 25 ng/dL Change treatment in case of at least two of three criteria : ü PSA progression, ü radiographic progression ü clinical deterioration 14 ng/ml NO SYMPTOMS Bone scan: Stable CT Scan: Retroperitoneal thoracic lymphadenopaties with a short diameter axis >2.5 mm
  39. 39. Metastatic CRPC: first and second line therapies First-line therapy Docetaxel Enzalutamide Abiraterone Sipuleucel-T Radium-223 Second-line therapy (dependent on previous treatment) Cabazitaxel Radium-223 Abiraterone Enzalutamide Docetaxel ADT^ MAB^
  40. 40. Abiraterone Acetate: COU-AA-301 ü 1195 patients with progressive mCRPC who failed docetaxel-based chemotherapy ü Overall survival was significantly improved from 10.9 mo in the placebo arm to 14.8 mo in the AA/P arm (p<0.001) ü All secondary end points were met and all end points demonstrated a significantly improved benefit for the AA/P group de Bono et al. NEJM 2011;364;21:1995-2005
  41. 41. Enzalutamide: AFFIRM ü 1199 patients with CRPC after chemotherapy assigned to ENZ or placebo ü Median overall survival: 18.4 mo vs. 13.6 mo (p<0.0001) in the ENZ vs. placebo groups, with a 37% reduction in relative risk for death ü All secondary end points were met with a statistically significant benefit in the ENZ arm Scher et al. NEJM 2012;367:1187-97
  42. 42. Cabazitaxel plus Prednisone: TROPIC de Bono et al. Lancet 2010;376:1147-54 Overall survival Progression-free survival ü Median overall survival of 15.1 mo in the CBZ/P vs. 12.7 mo in the mitoxantrone/prednisone group
  43. 43. Post docetaxel Metastatic CRPC
  44. 44. Clinical case (back in 2013…) 0 10 20 30 40 50 60 70 80 90 100 110 120 May Jun Jul Oct Jan Apr Jul Oct Jan Jan Feb Apr Jul Oct Jan PSA degarelix 12 ng/ml Started abiraterone Testosterone: 25 ng/dL 14 ng/ml Started docetaxel NO SYMPTOMS Bone scan: Stable CT Scan: Multiple retroperitoneal thoracic lymphadenopaties with a short diameter axis >3 cm
  45. 45. HOW TO FOLLOW OUR PATIENTS? BASELINE EXAMINATIONS FOLLOW-UP HIstory and clinical examination as well as baseline bloods (PSA, FBC, renal function, LFTs, ALP), bone scan and CT of chest abdomen and pelvis 1. Regular review and repeat blood profile every 2-3 months 2. Bone scintigraphy and CT scans at least every 6 months even in the absence of a clinical indication
  46. 46. Carcinoma prostatico: deprivazione androgenica e terapie di II livello (abiraterone, enzalutamide) nella forma metastatica resistente alla castrazione chimica Nicola Fossati Urological Research Institute Università Vita-Salute San Raffaele San Raffaele Scientific Institute Milan, Italy

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