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How to Sequence the many novel agents for CRPC Charles J Ryan, MD

How to Sequence the many novel agents for CRPC Charles J Ryan, MD Professor of Clinical Medicine and Urology Helen Diller Family Comprehensive Cancer Center University of California, San Francisco. The Challenge of this “Abundance”. What to give ? What to give when?

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How to Sequence the many novel agents for CRPC Charles J Ryan, MD

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  1. How to Sequence the many novel agents for CRPC Charles J Ryan, MD Professor of Clinical Medicine and Urology Helen Diller Family Comprehensive Cancer Center University of California, San Francisco

  2. The Challenge of this “Abundance” • What to give? • What to give when? • What is the impact of prior treatment? • What can guide us?

  3. Therapeutic Goals in mCRPC Delay, Prevent, Preserve, Survive Pain PSA Progression Tumor/Bone Progression ECOG PS Decline Death Baseline Chemotherapy 24-48 months Adapted from HalabiS. J ClinOncol. 2009;27: 2766-2771. ECOG PS= Eastern Cooperative Oncology Group Performance Status.

  4. What Anti-Tumor Therapies are Available? • Immunotherapy • Sipuleucel T • AR directed therapies • Abiraterone • Enzalutamide • Chemotherapy • Docetaxel • Cabazitaxel • Mitoxantrone • Radioisotope • Alpharadin

  5. Immunotherapy • Consensus • SOC in pre-chemotherapy indolent low volume disease. • Uptake slower than anticipated. • Patients enthusiastic about receiving it • Challenge • Patients want “remission” and they don’t get it from Sipuleucel-T. • Cost/Perception • Opportunity • Earlier metastatic detection may increase use. • “Remission induction”

  6. Survival “Delta” may peak b/w 2-3 years: Ideal time to use may be “EARLY CRPC” Sipuleucel T Sipul T 1*Kaplan-Meier estimates with 95% confidence interval and number at risk. †(Percent Sipuleucel-T – percent control)/percent control.

  7. Targeting AR in mCRPC • Consensus • SOC in pre-chemotherapy • Many patients get abi who would not have gotten chemotherapy • Both asymptomatic and symptomatic patients. • No comparison data of AbivsEnz • Challenge • Primary resistance – • Opportunity • Regulatory space created by “Abiraterone/Enzalutamide refractory, chemotherapy naive”? • Combination studies underway

  8. The Persistent Relevance of Androgens – The Biological Foundation of Secondary Hormonal Therapy Intratumor Androgen Production/conversion/sequestration AR Amplification (30%) CRPC Persistent Serum Androgens (e.g. adrenals)

  9. Enzalutamide and Abiraterone – Different points, one Pathway Signaling Event Aberration Drugs Intervention Abiraterone Orteronel Ketoconazole Intracrine Production SCC Inhibitors CYP 17 Inihibitors Androgen Production Androgen Transport/Circulation/Uptake Block Transport Polymorphisms Pre -Receptor 5-Alpha Reductase inhibitors Conversion to DHT Amplified 5 Alpha Reductase Enzalutamide ARN-509 Tok-001 Novel AR Inhibitors Amplified AR Splice Variant AR AR Binding Receptor

  10. Two very active agents EnzalutamideVs Placebo Abiraterone/Pred vs Prednisone Ryan et al, NEJM 2012 Beer et al, Proc GU ASCO 2014

  11. Baseline Features: Prevail and 302 Ryan et al, Proc ASCO 2012, LBA4518 Beer et al, Proc GU ASCO 2014

  12. Abiraterone Doubled the Maximal Decline in PSA (≥ 50%) Relative to Prednisone Alone Placebo + Prednisone Abiraterone + Prednisone 100 75 50 25 Maximal Decline From Baseline (%) 0 -25 -50 -75 -100 • 29% of patients on the prednisone control arm had a decline in PSA by ≥ 50% • 69% of patients on the abiraterone arm had a decline in PSA by ≥ 50% IA3 data. A negative percent indicates a decline in PSA. A positive percent indicates that the subject never has a decline in PSA.

  13. Ryan Proc GU ASCO 2013 Is “Sequencing” of Abiraterone and Enzalutamide Worth it? PSA declines are common on ENZ post ABI Sustained declines and clinical benefit <20% Sandhu GU ASCO 2014 Noonen et al Proc ESMO 2012 Post EnzAbi response rate =11% PSA PFS= 15 weeks

  14. Combination Phase III: Alliance: A031201 - PI Michael Morris Arm A: Enzalutamide Arm B: Enzalutamide Abiraterone Prednisone Stratification factor: prior chemo Total of 616 deaths, log-rank statistic 90% power (one sided type I error rate of 0.025) to detect HR of 0.77 in favor of arm B

  15. Chemotherapy • Consensus • Overall use declining? • Still very useful in aggressive disease/symptom control and visceral metastases • More “debulking” pre Enzalutamide or Abi? • Challenge • Perception • Urology practices • Still no viable combinations. • Opportunity • Cabazitaxel front line. • combinations? • Novel delivery?

  16. Treatments for CRPCby Symptoms and Presence of Visceral Disease *Mild symptoms. Mohler JL, et al. J NatlComprCancNetw. 2013;11:1471-1479.

  17. Ryan Proc GU ASCO 2013 Be aware of Phenotypic Change…. Resistance with Phenotypic Change: e.g. Neuro-endocrine Primary Resistance(Non-response) Acquired Resistance: (compensatory /adaptive) ASI or ART Therapy Response Death Non-PC Cause CRPC ASI= Androgen Synthesis Inhibitor ART = AR Targeted Therapy

  18. Docetaxel Probably as effective post Abiraterone/Enza Maximal PSA Decline on Docetaxel Following Prior Abiraterone Therapy AggarwalProc ASCO 2012

  19. Radio-Isotopes • Consensus • OS advantage is real • Alsympca trial was in very ill patients – in whom docetaxel had failed or would be too toxic. • Challenge • Clinical data is lacking from the phase III trial. • How to “use” it once you have started. • No real data on integrated/subsequent use of other active therapies (abi and enzaetc) • Opportunity • May be easily combine-able with Abiraterone/Enzalutamide and chemotherapy

  20. ALSYMPCA Overall Survival (Updated Analysis) 100 90 80 70 60 Radium-223 Dichloride, n = 614 Median OS: 14.9 months 50 % Placebo, n = 307 Median OS: 11.3 months 40 30 20 HR = 0.695 95% CI, 0.581, 0.832P = 0.00007 10 0 May 2013, Radium-223 was FDA approved for patients with castrate- resistant prostate cancer who have bone metastases and no known visceral metastases Parker C, et al. NEJM. 2013; 369(3):213-223.

  21. ALSYMPCA: Adverse Events • At 1.5 years after the final injection, there were no reports of AML, MDS, or primary bone cancer • Aplastic anemia was reported in 1 patient in the radium-223 arm (consideteredtreatement-related) • Primary cancers in other organs were identified in 2 Radium-223 treated patients and 3 placebo-treated patients (deem not study-drug related by investigators) Parker C, et al. N Engl J Med. 2013;369(3):213-223. Nilsson S, et al. J ClinOncol. 2014;32(suppl 4): Abstract 9.

  22. Summary Map of CRPC therapies http://www.onclive.com/publications/obtn/2012/december-2012/sequencing-of-novel-prostate-cancer-agents-is-a-work-in-progress/2

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