Charles B. Huggins. Despite regressions of great magnitude, it is obvious that there are many failures of endocrine therapy to control the disease.
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1 New Concepts in ADT Leonard G. Gomella, MD Chairman, Department of Urology President Society of Urologic Oncology Sidney Kimmel Cancer Center Thomas Jefferson University Hospital
2 Charles B. Huggins Nobel Prize winner who established the fact that prostate cancer could be treated by hormonal treatment in the 1940 s He also alluded to what we now call Castration Resistant Prostate Cancer (CRPC) Despite regressions of great magnitude, it is obvious that there are many failures of endocrine therapy to control the disease. Nobel Lecture December 13, 1966 Huggins, 1966.
3 The ADT Con*nuum in Advanced Prostate Cancer Start of ADT LHRH agonist/ antagonist If PSA rising check testosterone Low PSA, low testosterone, no symptoms (GOOD!!) Add an*- androgen pill If testosterone not very low consider changing LHRH agent Stay on therapy Good response Stay on therapy Con*nued rising PSA Other Second line therapy PSA rising with low testosterone: CRPC (castrate resistant prostate cancer) Advanced Therapy for CRPC: Chemo Provenge Xtandi Xofigo Zy*ga ADT is con*nued to keep testosterone as low as possible throughout
4 CRPC Prostate Cancer: Adapting to Castrate Environment Hormone Therapy selective pressure AR AC P Sumo CoACT T MUTATION gain of function Crosstalk AR Sig Path Post-translational Modifications of AR AR SPLICE VARIANTS COFACTOR PERTURBATION CoAct gain CoR loss/ dismissal INTRACRINE ANDROGEN SYNTHESIS Amplification\ Overexpression AR Alterations of Steroid Transporters adaptation RESTORED AR ACTIVITY (rising PSA) RECURRENT TUMOR DEVELOPMENT CRPC Knudsen KE, et al. Trends Endocrinol Metab. 2010;21(5):
5 Sources of Androgen Production Androgens are produced at 3 sites: - Testes - Adrenal gland - Prostate tumor cells (NEW DISCOVERY!)
6 Sources of Androgen Production LHRH Agents Anti-Androgens Androgen pathway blockers help block here
7 New Treatment for CRPC Based on Translational Discoveries PC responds to castration by synthesizing androgens from weaker androgens and/or cholesterol Androgen receptor (AR) responds to castration with molecular and biochemical alterations that cause hypersensitivity to low levels of androgens Progressing PC with low/castrate levels of testosterone is STILL sensitive to androgens ADT STILL A CORE PRINCIPLE
8 SHOULD WE BE USING THE TERM TERTIARY HORMONAL THERAPY BASED ON NEW ANDROGEN RECEPTOR PATHWAY AGENTS?
9 The ADT Con*nuum in Advanced Prostate Cancer Start of ADT LHRH agonist/ antagonist Good response Stay on theray Secondary Hormone Therapy Non Hormonal for CRPC: Chemo Provenge Xofigo Ter9ary CRPC Hormonal Therapy Abiraterone Enzalutamide ADT is con*nued to keep testosterone as low as possible throughout
10 New Concepts in ADT NEWER ARS AGENTS FOR CRPC Abiraterone acetate APPROVED Enzalutamide APPROVED Investigational PREVENT/LIMIT CRPC Intermittent Hormonal Therapy Bipolar Androgen Therapy OPTIMIZE CHOICE OF ADT ARV-7 HSD3B1 gene
11 Newer AR-Pathway Agents APPROVED Abiraterone acetate (approval 2011, 2012) Enzalutamide (approval 2012, 2014) INVESTIGATIONAL TAK700 (development ended) TOK001 (galeterone, multifunctional ARB) ARN 509 (Apalutamide) (ARB) ODM-201 (ARB plus mutant AR) others
12 Androgen receptor targeted therapies in castration-resistant prostate cancer: Bench to clinic International Journal of Urology Volume 23, Issue 8, pages , 14 JUN 2016 DOI: /iju
13 European Urology, Volume 67 Issue 3, March
14 1 Dramatic Androgen Reductions With Abiraterone ng/dl Start of treatment Lower limit of sensitivity 10 Testosterone (by LC-MS/MS) 20 Days No rise at progression At progression nmol/l Start of treatment Androstenedione Days No rise at progression At progression DHEA Estradiol nmol/l No rise at progression ρmol/l Start of treatment At progression Days Days post treatment Data on file.
15 Enzalutamide T 1 Inhibits Binding of Androgens to AR T AR 1Enzalutamide inhibits AR testosterone binding 2 cytoplasm Inhibits Nuclear Translocation of AR 2 Enzalutamide receptor inhibi*on blocks the ac*va*onal change induced by AR testosterone binding 3 nucleus Inhibits Inhibits Association Association Of Of AR AR with with DNA DNA AR 3 Enzalutamide inhibits AR testosterone nuclear transloca*on and DNA transcrip*on
16 Peer CME.com 2/3/2016
17 Phase 2 Trial of Galeterone in the Treatment of CRPC (ARMOR2)
18 ClinicalTrials.gov Iden*fier: NCT
19 ARN-509 Apalutamide Next-generation AR inhibitor Phase II - 47 patients CRPC M1 Recommended dose = 240 mg/d Fatigue grade 3 (2%) GI grade 1-2 No epilepsy reported PSA Response (decrease >50%) % Variation PSA weeks 24 weeks Smith MR, et al. J Clin Oncol. 2013;31(Suppl 6): Abstract 7.
20 A Study of Apalutamide (ARN- 509) in Men With Non- Metasta*c Castra*on- Resistant Prostate Cancer (SPARTAN) ClinicalTrials.gov Iden*fier: NCT
21 ODM-201 Has a Unique Profile for ODM-201 enzalutamide 19%* ODM main metabolite 3% ** ARN %* Compound AR affinity Ki (nm) Antagonism WT AR IC50 (nm) Proliferation VCaP IC50 (nm) enzalutamide ARN ODM *Clegg et al, Cancer Research 2012; Forster at al,, Prostate 2011 ** Rat autoradiography (QWBA) confirms brain/plasma ratio of 14C-ODM-201 related radioactivity was , indicating negligible penetration to the brain ORM (main metabolite) No CYP inhibition or induction with therapeutic doses Fizazi K, et al. Eur J Cancer. 2013;49(Suppl 2): Abstract E
22 Efficacy and Safety Study of BAY (ODM- 201) in Men With High- risk Non- metasta*c Castra*on- resistant Prostate Cancer (ARAMIS) ClinicalTrials.gov Iden*fier: NCT
23
24 New Concepts in ADT NEWER ARS AGENTS FOR CRPC Abiraterone acetate APPROVED Enzalutamide APPROVED Investigational PREVENT/LIMIT CRPC Intermittent Hormonal Therapy Bipolar Androgen Therapy OPTIMIZE CHOICE OF ADT ARV-7 HSD3B1 gene
25 What about new data in IHT?
26 What we have learned about IHT Level I evidence supports the oncologic equivalence of IHT compared with continuous androgen blockade in men with biochemical failure. Compared with CHT, IHT demonstrates improved QOL and fewer side effects. Patient selection for IHT is important to maintain good oncologic results. Monitoring of PSA response and duration of offtreatment intervals allow for stratification of patients by risk of progression. Klotz and Toren Current Oncology 19:2012
27 What we have learned about IHT Both SWOG 9346 and PR7 were non-inferiority trials. The non-inferiority result of the PR7 trial showed < 8% survival difference The SWOG 9346 produced an statistically inconclusive result (HR: 1.1; CI: ), with the upper limit being above the pre-specified 90% upper limit of 1.2. Other Benefits: Bone protection, protection against metabolic syndrome, decrease in treatment costs. EAU Prostate cancer guidelines 2012
28 After Dason S., et al CJU February 2014
29 2015 IHT Major Review References: 10,510 Published: 2000 to articles from15 trials (6856 patients) No significant difference between IHT and CHT overall survival cancer-specific survival progression-free survival Minimal difference in self-reported QOL Most trials observed improved physical and sexual functioning with IHT JAMAOncol.2015;1(9):
30 JAMAOncol.2015;1(9):
31 EAU-Guidelines Intermittent Androgen Blockade The best population to consider for IAD has still to be fully characterized. However, the most important factor seems to be the patient s response to the first cycle of IAD, e.g. the PSA level response.... should be the standard of care for those relapsing after radiotherapy Heidenreich A.et al : European Urology 53 (
32 Metastatic Prostate Cancer: CHT versus IHT EAU Is now positive on IHT Ø Not investigational despite empirical cut points IHT used only with castration agents; motivated pt LHRH antagonists might be valid ; CAB is standard Initial induction must be at least 6-7 months IHT ok if PSA<4 in metastatic Defined threshold for re-start: for metastatic Strict follow up every 3-6 months, T/PSA same lab
33 Metastatic Prostate Cancer: CCHT versus IHT ESMO Mixed Ø Continuous ADT is recommended as first-line treatment of metastatic, hormone-naïve disease Ø IHT recommended for men with biochemical relapse after radical RT starting ADT
34 Metastatic Prostate Cancer: CHT versus IHT NCCN positive Ø Can consider for M0/M1 to reduce toxicity (NEW) Ø 3 meta analysis failed to show any survival difference Ø IHT not inferior Ø Study demonstrating increased death in IHT balanced by more non prostate cancer deaths in CHT arm Ø Unplanned analysis Gl 8-10 longer OS with CHT (8y vs 6.8y): Consider CHT Ø QOL better with IHT
35 NCCN 2016 IHT Strategy Ø Initial Induction with standard ADT for 7 mos Ø Risk Stratify based on Serum PSA after 7 mos Low =PSA <0.2ng/ml (Med survival =75mos.) Intermed= PSA ng/ml (Med survival=44 mos) High = PSA>4ng/ml (Med survival =13 mos) Ø Asymptomatic patients after 7 mos of ADT Remain on CAB Ø Symptoms related to ADT Low-Intermediate risk-consider IAD
36 IHT: 2016 Bottom Line Individual studies can be confusing Option after RT failure Option in selected M1 patients after ADT induction (good PSA response) Use in M0 less clear but accepted No data yet on IHT after up front chemo (CHARRTED Trial) Comprehensive metaanalysis of 15 trials No difference in OS/CSS/PFS QOL may be better
37 Introducing Bipolar Androgen Therapy Rapid cycling from supraphysiologic to near-castrate serum T: bipolar androgen therapy (BAT). 16 CRPC: testosterone cypionate (400 mg IM); day 1 of 28) and etoposide (100 mg/d; days 1-14 After three cycles, those with a declining PSA continued on IHT (monotherapy). 4 men > 1 year therapy 10/10 had PSA reductions w/iht after BAT BAT may restore sensitivity to ADTs Sci Transl Med 7 January 2015 Vol. 7, Issue 269, p. 269ra2
38 Bipolar Androgen Therapy for Men With Androgen Ablation Naïve Prostate Cancer: Results From the Phase II BATMAN Study The primary endpoint met, with 17/29 men (59%, PSA <4 ng/ml at 18 months. Improved QOL The Prostate 76: (2016)
39 New Concepts in ADT NEWER ARS AGENTS FOR CRPC Abiraterone acetate APPROVED Enzalutamide APPROVED Investigational PREVENT/LIMIT CRPC Intermittent Hormonal Therapy Bipolar Androgen Therapy OPTIMIZE CHOICE OF ADT ARV-7 HSD3B1 gene
40 AR targeted therapies in castration-resistant prostate cancer: Bench to clinic International Journal of Urology Volume 23, Issue 8, pages , 14 JUN 2016 DOI: /iju.13137
41 Molecular Profiling Precision/Personalized Therapy AR-V7: an androgen receptor splice variant expressed about 20-fold higher in patients with CRPC If present, may indicate resistance to abiraterone or enzalutamide May allow more targeted therapies Antonarakis ES, et al. J Clin Oncol. 2014;32(5s): Abstract Antonarakis ES, et al. N Engl J Med. 2014;371(11):
42 Progression-Free Survival (Enzalutamide) HR = 8,5 (95% CI: ) Antonarakis E et al. N Engl J Med. 2014;371(11):
43 Progression-Free Survival (Abiraterone) HR = 16.5 (95% CI: ) Antonarakis E et al. N Engl J Med. 2014;371(11):
44 Outcomes: AR-V7 Conversions Outcome AR- V7(- ) AR- V7(- ) (n=36) AR- V7(- ) AR- V7(+) (n=6) AR- V7(+) AR- V7(+) (n=16) PSA response 68% (95% CI, 52-81%) 17% (95% CI, 4-58%) 0% (95% CI, 0-19%) PSA progression- free survival 6.1 months (95% CI, 5.9 mo- NR) 3.0 months (95% CI, 2.3 mo- NR) 1.4 months (95% CI, 0.9 mo- 2.6 mo) Progression- free survival 6.5 months (95% CI, 6.1 mo- NR) 3.2 months (95% CI, 3.1 mo- NR) 2.1 months (95% CI, 1.9 mo- 3.1 mo) Antonarakis E et al. N Engl J Med. 2014;371(11):
45 Implications CRPC patients with detectable AR-V7 in CTCs could be steered away from receiving AR-targeting drugs and could be offered alternative treatments New availability of a blood-based biomarker for AR-V7 detection could allow development of novel ARN-terminal domain inhibitors Antonarakis E et al. N Engl J Med. 2014;371(11):
46 New Genomic ADT Predictor HSD3B1 gene involved in DHT metabolism Inheritance of the HSD3B1 variant allele associated with resistance to ADT When abnormal, the gene causes prostate cancer cells to generate more self androgens when treated with ADT An inherited variant in the HSD3B1 gene may indicate which who benefits from ADT or not Homozygous variant (fast enzyme) have the worst outcomes and men who are homozygous wild-type (slow enzyme) to have the best outcomes, with heterozygotes potentially having an intermediate course August Hearn, et al. Lancet Oncology. In press.
47 Overall Survival According to HSD3B1 Genotype year OS wt/wt 82% wt/mt 74% mt/mt 58% 10 year OS wt/wt 55% wt/mt 35% mt/mt 0% Overall Survival (%) Homozygous Wild-Type 20 Heterozygous 0 P=0.006 Homozygous Variant No. at Risk Wild-Type Heterozygous Homozygous Variant Nima Sharifi Years Hearn, et al. Lancet Oncology. In press.
48 Mayo Clinic Cohort (with Manish Kohli and Don Tindall) Homozygous wild-type: median 1.8 years Heterozygous: median 1.4 years Homozygous variant: median 0.8 years P=0.049 P = Nima Sharifi Hearn, et al. Lancet Oncology. In press.
49 Adult Scrabble... Rearrange the letters to spell out an important part of the human body which is even more useful when erect. P N E S I If you said SPINE you are correct
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52 ODM-201 (AR Inhibitor) Phase I: PSA Response By Dose By Prior Chemotherapy 100 mg 200 mg 300 mg 500 mg P 700 mg o P o s t A B I s t A B I No chemotherapy Chemotherapy Fizazi K, et al. Lancet Oncol. 2014;15(9):
53 ODM-201: Phase II PSA Response at 12 Weeks Chemo-/ CYP17i-naïve Post-chemo/ CYP17i-naive Post-CYP17i Response rate in 65% of patients Response rate 86% at 700 mg bid Response rate in 32% of patients 30% response rate in 20% of patients *Data truncated at +25% Fizazi K, et al. Lancet Oncol. 2014;15(9):
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61 SKCC Multidisciplinary Approach to Prostate Cancer Care Gomella LG, et al. J Oncology Pract. 2010;6(6):e5-e10.
62 Conclusions Many new oral androgen-receptor based therapies have shown survival benefits in prostate cancer Well tolerated and may be applied to a wide variety of patients An understanding of the FDA approval and patient eligibility criteria critical to their appropriate use Sequencing will take several years to establish The diverse mechanisms of action of all the new CRPC therapies allow for significant patient selection and clinician input on treatment choice Coordination of care essential to optimize outcomes
63 Androgen receptor targeted therapies in castration-resistant prostate cancer: Bench to clinic International Journal of Urology Volume 23, Issue 8, pages , 14 JUN 2016 DOI: /iju
64 Endocr Relat Cancer Aug 31
Institut Gustave Roussy, University of Paris Sud, Villejuif, France. Queen Elizabeth Hospital, Birmingham, United Kingdom
An open-label, phase I/II safety, pharmacokinetic, and proof-of concept study of ODM-201 in patients with progressive metastatic castration-resistant prostate cancer (CRPC) K Fizazi 1, P Bono 2, R J Jones
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