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Targeting castration-resistant prostate cancer

Targeting castration-resistant prostate cancer. Androgen deprivative Therapy WHY? HOW? WHEN?. Prostate cells are physiologically dependent on androgens to stimulate growth , function and proliferation .

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Targeting castration-resistant prostate cancer

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  1. Targeting castration-resistant prostate cancer

  2. Androgendeprivative Therapy WHY? HOW? WHEN?

  3. Prostate cells are physiologicallydependent on androgenstostimulategrowth, function and proliferation. Testosterone, althoughnottumorigenic, isessentialfor the growth and perpetuationoftumourcells (Berman DM, Rodriguez R, Veltri RW. Development, molecularbiology and physiologyof the prostate. In: Wein AJ, et al (eds). Campbell-WalshUrology. 10th edn. Elsevier 2012, pp. 2533-69). If prostate cells are deprivedofandrogenicstimulation, theyundergoapoptosis .

  4. Charles Brenton Huggins Nobel Prize 1966 He found out that castration or estrogen administration led to glandular atrophy, which could be reversed by re-administration of androgen. In 1941 the beneficial effect of androgen ablation on metastatic prostate cancer was realised when Huggins and Clarence Hodges treated patients by either castration or estrogen therapy.

  5. Any treatment thatresultsultimately in suppressionofandrogenactivityisreferredtoasAndrogenDeprivationTherapy (ADT).

  6. ADT can be achieved by: Suppressing the secretion of testicular androgens Bilateral Orchiectomy Long acting LHRH agonists or antagonists Inhibiting the action of circulating androgens at the level of their receptor using competing compounds Non steroidal antiandrogens Steroidal antiandrogens In addition, these two methods can be combined to achieve what is known as complete (or maximal or total) androgenblockade (CAB). New Dugsforcastrationresistance prostate cancer Abiraterone – Taestosteronesynthesis inhibition at the adrenal level as inside the cancer cells (intracrine mechanism) Enzalutamide- a novel antiandrogen with higher receptor affinity than bicalutamide

  7. Castration levels • < 50 ng/dl (1.7 nmol/l) • Conventionalvaluetodefineeffectivecastration (established more than 40 years ago) • < 20 ng/dl (1 nmol/l) • Contemporary and more appropriate definitionofcastration1, 2, 3 1) Oefelein MG et al Urology 2000; 56: 1021. 2) Morote J et al BJU Int 2009; 103:332. 332. 3) Pickels T et al BJU Int 2012; 110: E500

  8. Long-acting LHRH agonists are currently the main forms of ADT MAB Uncertain clinical advantage , incremental costs of therapy LHRH antagonists are an alternative to LHRH agonists . Probably agonists have less side effects in particular cardiovascular effects Non -steroidal antiandrogenmonotherapy is less effective than LHRH analogues . Its use in advanced prostate cancer is not indicated Intermittent MAB – Should be considered only in selected patients. Recent studies do not shows advantages in quality of life for intermittent treatment

  9. Timing Localizeddisease Immediate therapyonly in high risktumors Locallyadvanced N- AdjuvantradiotherapyN+ Immediate therapy in presenceof >2 positive nodes Expectant management is optional in presenceof ≤2 positive nodes BCR Evaluationofprognosticfactors Metastaticdisease Immediate therapy in symptomaticpatients Deferredtherapy (optional) only in asymptomaticpatientswith limitedmetastaticdisease and importantcomorbidity

  10. CASTRATION RESISTANT PROSTATE CANCER (CRPC) Prostate cancer becomes refractory to ADT Mechanisms Increased expression of AR Increased expression of enzymes that synthesize androgens Utilization of other pathways to activate AR

  11. HORMONE REFRACTORY PROSTATE CANCER HRPC Androgen Deprivation Chemotherapy Therapies After LHRH Agonists and Anti-androgens Death Local Therapy Postchemotherapy Tumor Volume & Activity Asymptomatic Symptomatic Nonmetastatic Metastatic Castration Sensitive Castration Resistant Time

  12. Disease progression CASTRATE RESISTANT PROSTATE CANCER CRPC Castration threshold Stimulation of Tumor Growth Testosterone serum levels (ng/dl) tumor burden (PSA levels) 150 100 AndrogenDepletion/Blockade 50 Serum testosterone 20 0 time De Bono ESMO Educational Program, Genitourinary Cancers 2010 modified

  13. “….In metastatichormone-resistant/refractoryprostate cancer, tumor growth is no longer sensitive toandrogen….” “mCRPC remains androgen-sensitive despite castrate levels of testosterone...” Intracrinesteroidogenesismay permit tumors to circumvent low levels of circulating androgens.

  14. Enzyme expression of the main steroidogenesis enzymes in CPRC vs primary tumor

  15. CRPC expresses more AR than benign prostatic tissue and hormone-naïve prostate cancers in immunohistochemical studies While absent in hormonally untreated prostate cancer, in≈ 30% of CRPC, AR amplification is reported As a consequence, even very low levels of intracellular testosterone and/or DHT might cause androgen signalling and AR –regulated transcription

  16. Abiraterone Acetate: An Androgen Biosynthesis Inhibitor

  17. Abiraterone Acetate plus Pdn vs Placebo plus Pdn in Docetaxel progressive mCRPC pts. Results of the phase III Randomized Study AA-301. (147 sites in 13 countries; USA, Europe, Australia, Canada) TREAT UNT I L PROGRESS ION • 1195 pts with progressive mCRPC • Failed 1 or 2 CT Regimens, one of which contained Docetaxel • Randomised 2:1 • Stratification by: • ECOG PS (0-1 vs. 2) • Worst pain over previous 24 hours (BPI short form; 0-3 [absent] vs. 4-10 [present]) • Prior CT (1 vs. 2) • Type of progression (PSA only vs. Rx PD with or without PSA PD) Abiraterone acetate 1000 mg daily Prednisone 5mg twice daily Placebo daily Prednisone 5mg twice daily Primary endpoint: OS (25% improvement; HR 0.8) de Bono et al. Ann Oncol 2010: Abstract LBA5 (Oral presentation at ESMO) Scher et al. J Clin Oncol 2011; 29(7S):Abstract 4 (Oral presentation at ASCO GU )

  18. Abiraterone Acetate: Improved OS in mCRPC Hazard ratio = 0.646 (0.54-0.77) P < 0.0001 100 Abiraterone acetate: 14.8 months (95% CI, 14.1-15.4) 80 60 Survival (%) Placebo: 10.9 months (95% CI, 10.2-12.0) 40 20 AA Placebo 0 0 3 6 9 12 15 18 21 Time to Death (Months) AA 797 736 657 520 282 68 2 0 Placebo 398 355 306 210 105 30 3 0 de Bono et al. Ann Oncol 2010: Abstract LBA5 (Oral presentation at ESMO) Scher et al. J Clin Oncol 2011; 29(7S):Abstract 4 (Oral presentation at ASCO GU )

  19. Study 301. second pre-planned analysis (775 Events): median OS Increase from 3.9 to 4.6 Months 100 HR (95% CI): 0.74 (0.638-0.859) P < 0.0001 80 AA median OS (95% CI):15.8 mos (14.82-17.02) 60 Survival (%) 40 Placebo median OS (95% CI): 11.2 mos (10.41-13.14) 20 Placebo AA 0 0 6 12 18 24 30 Time to Death (Months) AA 797 657 473 273 15 0 183 398 306 6 0 Placebo 100 Scher et al. J Clin Oncol 2012; 29 (suppl): Abs A4517 (oral presentation)

  20. Abiraterone Acetate - Study 301: OS Benefit across Patient Subgroups 0.5 0.75 1 1.5 Favors AA Favors placebo

  21. Abiraterone (COU-301) : Tempo al primo SRE

  22. Phase III Trial of Abiraterone Acetate in asymptomatic or mildly symptomatic metastatic chemotherapy-naïve CRPC Treat until progression R A Abiraterone acetate 1000mg Prednisone 5mg BID Primary end point: NDOM • 1000 patients with asymptomatic or mildly • 25% improvement in symptomatic radiologic progression-freesurvival metastatic CRPC• Chemotherapy naïve I Z • 50% improvement in overall PlaceboPrednisone 5mg BID E D1:1 survival Stratified by: ECOG performance status (0 vs 1) Accrual completed 4/2009 www.clinicaltrials.gov Identifier: NCT00887198

  23. Abiraterone Delays Progression in Patients with Chemotherapy-Naïve CRPC

  24. Simvastatin suppresses biochemical recurrence (BCR) incastrated mice bearing LNCaP xenografts. Simvastatin suppresses intratumoral and serum steroid accumulation in castrated mice bearing LNCaP xenografts

  25. ENZALUTAMIDE 3. Blocks DNA binding and activation 1. Blocks AR binding AR 2. Impairs nuclear translocation 2–3 fold lower affinity than DHT Cytoplasm Nucleus • Blocks androgen (dihydrotestosterone) binding to the AR. • 2. Impairs the movement of the complex formed when androgen binds to the AR into the nucleus of the cell (nuclear translocation). • 3. Inhibits the binding of the androgen–AR complexto DNA. DHT Enzalutamide Enzalutamide Enzalutamide

  26. Enzalutamide reduced risk of death by 29%

  27. 113 patients abiraterone-to-enzalutamide sequence and 85 enzalutamide-to-abiraterone sequence No statistical difference in overall survival The combined PSA progression-free survival was significantly longer in the abiraterone-to-enzalutamide than in the enzalutamide-to-abiraterone1 This may possibly be attributable to higher PSA response rates and longer PSA-PFS to second-line ENZA compared to ABI (i.e., ENZA retains activity after ABI but not vice versa).

  28. Large Part of ResistanceMechanism in Prostate Cancer due to AR events AR-mediated Mechanisms of“Castration Resistance” in P.Ca Sensitivity to other ligands1 Hypersensitivity to low levels of ligand1 • Non-androgen ligands • Steroids • Anti-androgens Overamplification of the AR or increased 5α-reductase enzyme levels may result in hypersensitivity of AR to low levels of androgens AR point mutations1 CRPC • Single amino-acid substitutions, e.g. • Codon 730 valine methionine2 • Codon 89 leucine valine1 AR splice variants1 • Transcription of non-AR mRNAinto AR peptides, e.g. • ARDLBD variant includes90–120 bp insertion from a non-AR gene • A3 variant appears to constitutivelytarget Akt • A23 variant has a 23-amino-acidinsertion and impairs AR nuclear localisation AR AR over-expression1 Prostate cancer pts feature overexpression of AR independent of ligand levels • Dutt & Gao. Future Oncol 2009;5:1403–13.; Newmark et al. Proc Natl Acad Sci USA 1992;89:6319–23.

  29. the generation of ARv567es is especially sensitive to suppression of intratumoral androgens, suggesting growth of these tumors is associated with generation of AR variants in the presence of castrate levels of androgen

  30. Detection of AR-V7 in CTCs from men with metastatic CRPC is not associated with primary resistance to taxane chemotherapy. In AR-V7-positive men, taxanes appear to be more efficacious than enzalutamide or abiraterone therapy, whereas in AR-V7-negative men, taxanes and enzalutamide or abiraterone may have comparable efficacy. In AR-V7-positive patients, PSA responses were higher in taxane-treated vs enzalutamide- or abiraterone-treated men (41% vs 0%; P < .001), and PSA PFS and PFS were significantly longer in taxane-treated men (HR, 0.19 [95% CI, 0.07-0.52] for PSA PFS, P = .001; HR, 0.21 [95% CI, 0.07-0.59] for PFS, P = .003).

  31. BIOLOGIC CLASSIFICATION OFPROSTATE CANCER ENDOCRINE-DRIVEN PHASE MICROENVIRONMENT-DEPENDENT PHASE (ENDOCRINE-TO-PARACRINE TRANSITION) TUMOR CELL AUTONOMOUS PHASE

  32. Grazie per l’attenzione

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