Advanced Prostate Cancer. Searching for Optimal Therapy Sequence and Assessing Emerging Treatment Options

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1 Advanced Prostate Cancer Searching for Optimal Therapy Sequence and Assessing Emerging Treatment Options

2 Disclaimer This slide deck in its original and unaltered format is for educational purposes and is current as of December The content and views presented in this educational activity are those of the authors and do not necessarily reflect those of Creative Educational Concepts or the supporter. These materials may discuss therapeutic products that have not been approved by the US Food and Drug Administration and off-label uses of approved products. A qualified healthcare professional should be consulted before using any therapeutic product discussed. Readers should verify all information and data before treating patients or employing any therapies described in this educational activity.

3 Usage Rights This slide deck is provided for educational purposes and slides may be used for personal, noncommercial presentations only as long as content and references remain the same. No part of this slide deck may be published or distributed in print or electronic format without prior written permission from Creative Educational Concepts.

4 Accreditation Physicians: 1.0 AMA PRA Category 1 Credit(s) Pharmacists: 1.0 ACPE contact hour (.10 CEUs) Nurses: 1.0 contact hour Faculty Information: You can find your faculty member s full bio and disclosure in your handout or online at Special Thanks! Supported through an independent educational grant from Astellas and Sanofi, a Genzyme Company. Presented by Creative Educational Concepts, Inc. (CEC)

5 Learning Objectives 1) Review the spectrum of advanced prostate cancer, including castration-resistant prostate cancer (CRPC), the currently available treatment options, unmet clinical needs, and treatment disparities among specific patient populations. 2) Appraise the safety and efficacy of current treatment options for advanced prostate cancer, including CRPC, and rational sequencing strategies for these treatment options across the spectrum of disease. 3) Design individualized treatment plans for advanced prostate cancer as part of an interprofessional healthcare team with a focus on shared decision making. 4) Evaluate the safety and efficacy of emerging treatment options for recurrent advanced prostate cancer, including novel androgen receptor axis-targeting agents.

6 Prostate Cancer Disease States mcspc Localized Disease mcrpc L1 mcrpc L2 mcrpc L2+ Biochemical Recurrence nmcrpc mcspc=metastatic castration-sensitive prostate cancer; nmcrpc=nonmetastatic castration-resistant prostate cancer; mcrpc=metastatic castration-resistant prostate cancer; L=line of treatment.

Prostate Cancer Disease States mcspc Localized Disease mcrpc L1 mcrpc L2 mcrpc L2+ Biochemical Recurrence nmcrpc mcspc=metastatic castration-sensitive

7 Prostate Cancer Disease States mcspc Localized Disease mcrpc L1 mcrpc L2 mcrpc L2+ Biochemical Recurrence nmcrpc mcspc=metastatic castration-sensitive prostate cancer; nmcrpc=nonmetastatic castration-resistant prostate cancer; mcrpc=metastatic castration-resistant prostate cancer; L=line of treatment.

8 Incidence of mpca relative to 2004 Metastatic Prostate Cancer Incidence in US: Age, years < Year of Diagnosis Weiner AB, et al. Prostate Cancer Prostatic Dis

9 DRUG USAGE Metastatic Prostate Cancer Treatment Patterns: Retrospective Analysis of Real-World Data 1 100% 90% 80% 70% 60% 50% 40% 30% 20% Sipuleucel-T Cabazitaxel Enzalutamide Abiraterone acetate Estramustine Mitoxantrone 10% 0% AGE GROUP (years) > > > > Docetaxel The M1 populations reported in clinical trials do not represent real-life patients with M1 disease 2 The treatment guidelines are commonly not followed in everyday practice 1 Flaig TW, et al. Cancer Med. 2016; 2 Flaig TW, et al. Clin Genitourin Cancer

10 mcrpc Therapies With Survival Benefit Agent Year Approved Indication PFS Benefit OS Benefit Docetaxel mcrpc? Yes Sipuleucel-T Asymptomatic or minimally symptomatic mcrpc No Yes Cabazitaxel Post-docetaxel mcrpc Yes Yes Abiraterone 4, and 2012 mcrpc Yes Yes Enzalutamide and 2014 mcrpc Yes Yes Radium Symptomatic bone predominant mcrpc SSRE Yes 1 Tannock IF, et al. N Engl J Med. 2004; 2 Kantoff PW, et al. N Engl J Med. 2010; 3 de Bono JS, et al. Lancet. 2010; 4 de Bono J, et al. N Engl J Med. 2011; 5 Ryan CJ, et al. N Engl J Med. 2013; 6 Scher HI, et al. N Engl J Med. 2012; 7 Parker C, et al. N Engl J Med

11 mcrpc Non-Chemotherapy Treatment Options

12 Abiraterone Before Chemotherapy COU-AA-302 Phase 3 Trial: PFS Progression-free Survival (%) Radiographic Progression-free Survival (PFS) Hazard ratio, 0.53 (95% CI, ) P<0.001 Abiraterone-prednisone, 16.5 mo Prednisone alone, 8.3 mo No. of Events Abiraterone-prednisone:271 Prednisone alone: Number at risk Abiraterone prednisone Prednisone alone Time (months) Ryan CJ, et al. N Engl J Med. 2013; Ryan CJ, et al. Lancet Oncol

13 Abiraterone Before Chemotherapy COU-AA-302 Phase 3 Trial: OS Overall Survival (%) Median Overall Survival (OS) Abiraterone acetate plus prednisone 34.7 months (95% CI ) Placebo plus prednisone 30.3 months (95% CI ) HR 0.81 (95% CI ) P= Number at risk Abiraterone acetate plus prednisone Placebo plus prednisone Time (months) Ryan CJ, et al. N Engl J Med. 2013; Ryan CJ, et al. Lancet Oncol

14 Enzalutamide Before Chemotherapy PREVAIL Phase 3 Trial: PFS rpfs (%) Enzalutamide Placebo Median rpfs (95% CI), mo 20 ( ) 5.4 ( ) HR (95% CI); P value 0.32 ( ); P< Patients at risk Enzalutamide Placebo Enzalutamide Placebo mo Beer TM, et al. N Engl J Med. 2014; Beer TM, et al. Eur Urol

15 Enzalutamide Before Chemotherapy PREVAIL Phase 3 Trial: OS OS (%) Patients at risk Enzalutamide Placebo Enzalutamide Placebo Enzalutamide Placebo Median OS (95% CI), mo 35.3 (32.2-NYR) 31.3 ( ) HR (95% CI); P value mo ( ); P= Beer TM, et al. N Engl J Med. 2014; Beer TM, et al. Eur Urol

Maximum PSA Change on Enzalutamide Enzalutamide PSA Decline by Prior Therapy Abiraterone + Docetaxel-Naïve N=36 Prior Therapy Maximum PSA Decrease on Enzalutamide 0-30% 30-50% 50-90% 90-100%

16 Maximum PSA Change on Enzalutamide Enzalutamide PSA Decline by Prior Therapy Abiraterone + Docetaxel-Naïve N=36 Prior Therapy Maximum PSA Decrease on Enzalutamide 0-30% 30-50% 50-90% % Abiraterone + docetaxel-naïve, N=36 27 (75) 24 (67) 21 (58) 8 (22) Prior abiraterone, N=79 47 (59) 22 (28) 14 (18) 2 (3) Prior docetaxel, N=30 16 (53) 13 (43) 9 (30) 4 (13) Prior abiraterone + docetaxel, N= (46) 40 (24) 28 (17) 4 (2) Cheng HH, et al. Prostate Cancer Prostatic Dis

17 Improving Hormonal Therapy Strategies More complete suppression of androgen production Abiraterone More complete blockade of androgen receptor signaling Enzalutamide Apalutamide (ARN-509) Darolutamide (ODM-201) Merseburger AS, et al. Onco Targets Ther. 2016; Francini E, Taplin ME. Cancer

18 Immunotherapy for mcrpc Sipuleucel-T Autologous APCs Cultured With Antigen Fusion Protein Mulders PF, et al. Cancer Immunol Immunother

19 Sipuleucel-T IMPACT Phase 3 Trial: OS FDA approved based on HR of 0.78 Survival curves separated after 6 months Treatment is carried out in 5 weeks Few side effects Placebo Sip-T HR; P N Median OS, mo ;.03 Kantoff PW, et al. N Engl J Med

20 Sipuleucel-T OS by Baseline PSA Survival Benefit May be Better in Patients with Lower Baseline PSA Baseline PSA 22.1 (N=128) > (N=128) > (N=128) >134.1 (N=128) Median OS Sipuleucel-T, mo Median OS Control, mo Difference HR Schellhammer PF, et al. Urology

21 Targeting Bone Metastases Radium-223 a-particles induce dsdna breaks in adjacent tumor cells Short penetration of a emitters (2-10 cell diameters)=highly localized tumor cell killing and minimal damage to surrounding normal tissue Shore ND. Urology

22 Radium-223 ALSYMPCA Phase 3 Trial Symptomatic CRPC 2 bone metastases No known visceral metastases or >3- cm nodes Post-docetaxel or unfit for docetaxel or refusing docetaxel N=921 2:1 ARM A Radium-223 (50 kbq/kg) + Best standard of care 6 injections at 4-week intervals ARM B Placebo + Best standard of care Stratifications: Total ALP: <220 U/L vs 220 U/L; Bisphosphonates: Yes vs No; Prior docetaxel: Yes vs No. Parker C, et al. N Engl J Med

23 Radium-223 ALSYMPCA Phase 3 Trial: OS Parker C, et al. N Engl J Med Placebo Radium-223 HR; P N Median OS, mo ; <.001

24 mcrpc Chemotherapy Treatment Options

Docetaxel TAX 327 Phase 3 Trial: OS Median OS: 18.9 vs 16.5 mo HR=0.76 (CI: 0.62-0.

01) 31 (P=.07) 22 PSA response 45 (P=.005) 45 (P<.

25 Docetaxel TAX 327 Phase 3 Trial: OS Median OS: 18.9 vs 16.5 mo HR=0.76 (CI: ) P=.009 Outcome, % DOC Q3W (N=296) DOC Q1W (N=297) M Pain response 35 (P=.01) 31 (P=.07) 22 PSA response 45 (P=.005) 45 (P<.001) 32% QoL response (FACT-P) 22 (P=.009) 23 (P=.005) 13 Objective response Tannock IF, et al. N Engl J Med

Mitoxantrone Prednisone Cabazitaxel Prednisone N 377 378 MR; P Median OS, mo

26 Cabazitaxel TROPIC Phase 3 Trial: PFS and OS Patients with Progressive Disease During or After Docetaxel Treatment PFS OS Mitoxantrone Cabazitaxel Mitoxantrone Prednisone Cabazitaxel Prednisone N MR; P Median OS, mo ; <.0001 Median PFS, mo ; <.0001 de Bono JS, et al. Lancet

Cabazitaxel vs Docetaxel FIRSTANA Phase 3 Trial Chemotherapy -Naïve mcrpc N=1168 ARM A Cabazitaxel 25 mg/m 2 Prednisone ARM B Cabazitaxel 20 mg/m 2 Prednisone ARM C Docetaxel Prednisone Until

27 Cabazitaxel vs Docetaxel FIRSTANA Phase 3 Trial Chemotherapy -Naïve mcrpc N=1168 ARM A Cabazitaxel 25 mg/m 2 Prednisone ARM B Cabazitaxel 20 mg/m 2 Prednisone ARM C Docetaxel Prednisone Until progression or unacceptable toxicity Primary Endpoint: OS C20 and C25 did not demonstrate superiority for OS Among secondary endpoints, only tumor responses were significantly superior for C25 AEs were less frequent in C20 for most categories Sartor AO, et al. ASCO

28 Docetaxel Post-Abiraterone N PSA decline >50%, % PR, % Median Time to PSA Progression, mo Median OS, mo Chemo Cycles Mezynski (All Patients) (2-12) Mezynski (ABI Refractory ) (2-10) Aggarwal (All Patients) Azad (ABI Responders) NR (113) Azad (ABI Non-Responders) NR (1-10) Mezynski J, et al. Ann Oncol. 2012; Aggarwal RR, et al. Clin Genitourin Cancer. 2014; Aggarwal RR, et al. J Clin Oncol. 2012; Azad A, et al. J Clin Oncol

29 Chemotherapy in mcrpc Summary Docetaxel remains the standard first-line chemotherapy Docetaxel is active in patients previously treated with abiraterone and enzalutamide Cabazitaxel is the standard second-line chemotherapy Cabazitaxel yields similar OS when compared to docetaxel as first line chemotherapy Cabazitaxel 20 mg/m 2 dosing yields equivalent survival to the higher dose with less toxicity

30 mcspc ADT + Chemotherapy

31 ADT + Docetaxel CHAARTED Phase 3 Trial N=790; median age of 63 years Stratification: Extent of Mets: high vs low Age: 70 vs <70 years ECOG PS: 0-1 vs 2 CAB >30 days: yes vs no SRE prevention: yes vs no Prior adjuvant ADT: 12 vs >12 months ARM A: ADT + docetaxel 75 mg/m 2 every 21 days for a maximum of 6 cycles Evaluate Q3W while on docetaxel and at week 24, then every 12 weeks Follow for TTP and OS ARM B: ADT-only Evaluate every 12 weeks Chemotherapy at investigators discretion at progression Primary endpoint: OS ADT allowed up to 120 days prior to randomization Intermittent ADT dosing was not allowed Standard dexamethasone premedication, but no daily prednisone Sweeney CJ, et al. N Engl J Med

32 CHAARTED Phase 3 Trial Primary Endpoint: OS Sweeney CJ, et al. N Engl J Med

33 CHAARTED Phase 3 Trial OS by Disease Volume For high-volume metastatic disease, there is a 17-month improvement in median OS from 32.2 months to 49.2 months Sweeney CJ, et al. N Engl J Med

34 CHAARTED Phase 3 Trial Subgroup Analysis: HR for Death Subgroup No. of Patients Hazard Ratio (95% CI) All patients Age 790 <70 yr 612 >70 yr 178 ECOG performance-status score 0 1 or 2 Race White Other or unknown Volume of metastases Low High Type of metastases Visceral metastases with or without bone metastases High-volume disease with bone metastases alone Gleason score <8 >8 Sweeney CJ, et al. N Engl J Med ( ) 0.68 ( ) 0.43 ( ) 0.71 ( ) 0.42 ( ) 0.62 ( ) 0.32 ( ) 0.60 ( ) 0.60 ( ) 0.52 ( ) 0.64 ( ) ( ) ( ) ADT plus Docetaxel Better ADT Alone Better

35 SOC ± Docetaxel ± Zoledronic Acid STAMPEDE Phase 3 Trial N=2,962 M+ (n=1,817; 61%) N+/X M0 (n=448; 15%) N0M0 (n=697; 24%) Median age of 65 years 2:1:1:1 SOC-only SOC + ZA SOC + Doc Primary endpoint: OS ZA: 4 mg for six Q3W cycles, then Q4W until two years Doc: 75 mg/m 2 for six Q3W cycles with prednisolone 10 mg daily Randomly assigned between Oct 5, 2005 and March 31, 2013 James ND, et al. Lancet SOC + ZA + Doc

36 STAMPEDE Phase 3 Trial FFS and OS Median OS: 71 months for SOC-only or SOC + ZA 81 months for SOC + Doc 76 months for SOC + ZA + Doc James ND, et al. Lancet

37 STAMPEDE Phase 3 Trial Treatment Effect by Metastatic Status: OS SOC vs SOC + ZA Metastasis status M0 M1 Overall SOC-only SOC + ZA Hazard ratio HR (95% CI) 65/ /724 31/ / ( ) 0.93 ( ) 0.94 ( ) Favors SOC + ZA Favors SOC SOC vs SOC + Doc Metastasis status M0 M1 Overall 65/ /724 31/ / ( ) 0.76 ( ) 0.78 ( ) Favors SOC + Doc Favors SOC SOC vs SOC + ZA + Doc Metastasis status M0 65/460 M1 350/724 Overall 29/ / Favors SOC + ZA + Doc Favors SOC 0.98 ( ) 0.79 ( ) 0.82 ( ) James ND, et al. Lancet

38 mcspc Management Summary Data from two large prospective trials demonstrate clear evidence of the survival benefit of ADT + docetaxel, which should now be considered the standard of care. Select patients should be managed with ADT alone, based on their comorbidities and performance status. Sweeney CJ, et al. N Engl J Med. 2015; James ND, et al. Lancet

39 Advanced Prostate Cancer Treatment Options and Sequencing

40 mcspc Therapy ADT ADT + docetaxel Strongly consider in the setting of high-volume disease Clinical trial Valenca LB, et al. Cancer Treat Rev

41 mcrpc 1 st -Line Therapy Sipuleucel-T In the setting of minimally symptomatic, low disease burden Enzalutamide or abiraterone Docetaxel In the setting of symptomatic or visceral metastasis Radium-223 In the setting of extensive, symptomatic bone disease, or if unfit for docetaxel Clinical trial Valenca LB, et al. Cancer Treat Rev

42 mcrpc 2 nd -Line Therapy: Post-Docetaxel Enzalutamide or abiraterone Cabazitaxel Radium-223 In the setting of extensive, symptomatic bone disease Sipuleucel-T In the setting of slowly progressive disease Clinical trial Valenca LB, et al. Cancer Treat Rev

43 mcrpc 2 nd -Line Therapy: Post-AR-Targeted Agents Docetaxel Enzalutamide or abiraterone Radium-223 In the setting of extensive, symptomatic bone disease Sipuleucel-T In the setting of minimally symptomatic, low disease burden Clinical trial Valenca LB, et al. Cancer Treat Rev

44 mcrpc 3 rd - and 4 th -Line Therapy Chemotherapy Enzalutamide or abiraterone Radium-223 Clinical trial Valenca LB, et al. Cancer Treat Rev

45 mcrpc Treatment Selection By Clinical Features Clinical Feature Bone predominance Visceral metastases Sipuleucel-T Enzalutamide Abiraterone Docetaxel Cabazitaxel Radium- 223 = = = = = = = = Galloping disease = = = Low performance status = Pain = = = = = There are many other clinical features of tumor and patients that influence therapy decisions Courtesy of Tomasz M. Beer, MD. More likely to prescribe Less likely to prescribe = No effect on prescribing Contraindicated

46 mcrpc Treatment Selection By Prior Therapy and Tumor Histology Clinical Feature Prior enzalutamide or abiraterone Prior docetaxel Small cell histology Anaplastic histology Sipuleucel-T Enzalutamide Abiraterone Docetaxel Cabazitaxel Radium- 223 = = = = = * =*** =*** ** = *Cisplatin-containing chemotherapy is indicated; **docetaxel with cisplatin considered; ***AR expression may influence decision More likely to prescribe Less likely to prescribe Courtesy of Tomasz M. Beer, MD. = No effect on prescribing Contraindicated

47 Sequencing Therapy Abiraterone and Enzalutamide Prior Docetaxel N Abiraterone after enzalutamide PSA Decline 30%, % PSA Decline 50%, % Median TTP, mo Median PFS, mo Noonan Y NR 3.5 Loriot Y NR 2.7 Enzalutamide after abiraterone Schrader Y * - Bianchini Y Badrising Y Cheng Y Azad Y Cheng N Azad N *Responders PSA=prostate specific antigen; TTP=time to progression; PFS=progression-free survival; mo=months. Noonan KL, et al. Ann Oncol. 2013; Loriot Y, et al. Ann Oncol. 2013; Schrader AJ, et al. Eur Urol. 2014; Bianchini D, et al. Eur J Cancer. 2014; Badrising S, et al. Cancer. 2014; Cheng HH, et al. J Clin Oncol. 2014; Azad AA, et al. Eur Urol

48 Sequencing Therapy (cont.) Abiraterone and Enzalutamide Enza then Abi Abi then Enza Log Rank Test, P=.081 Miyake H, et al. Clin Genitourin Cancer. 2016; Maughan BL, et al. Prostate

49 Sequencing Therapy Docetaxel After Abiraterone N PSA decline >50%, % PR, % Median Time to PSA Progression, mo Median OS, mo Chemo Cycles Mezynski (All Patients) (2-12) Mezynski (ABI Refractory ) (2-10) Aggarwal (All Patients) Azad (ABI Responders) NR (113) Azad (ABI Non-Responders) NR (1-10) Mezynski J, et al. Ann Oncol. 2012; Aggarwal RR, et al. Clin Genitourin Cancer. 2014; Aggarwal RR, et al. J Clin Oncol. 2012; Azad AA, et al. J Clin Oncol

50 Sequencing Therapy Cabazitaxel After Abiraterone/Enzalutamide N Prior Docetaxel Prior AA or ENZA PSA Decline 50%, % ORR, % Median PFS, mo Median OS, mo Pezaro 37 Y Y Sella 24 Y Y Saad 26 Y Y AA=abiraterone; ENZA=enzalutamide; PSA=prostrate serum antigen; ORR=objective response rate; PFS=progression-free survival; OS=overall survival. Pezaro CJ, et al. Eur Urol. 2014; Sella A, et al. Clin Genitourin Cancer. 2014; Saad F, et al. J Clin Oncol

51 Predictive Biomarkers Are Needed!

52 Advanced Prostate Cancer Integrative Clinical Genomics Robinson D, et al. Cell

53 Somatic and Germline Aberrations Integrative mcrpc Landscape Analysis Robinson D, et al. Cell

54 Emerging Biomarkers Clinical Utility None in routine clinical use yet Allocation to investigational trials DDR deficiency Double stranded break repair defects BRCA1, BRCA2, ATM, others DNA mismatch repair deficiency microsatellite instability, hypermutated phenotype, MLH, MSH, and others PI3K pathway Raf kinases AR defects Amplification Resistance mutations Splice variants AR-V7

55 Enzalutamide-Resistant mcrpc Evidence of Anti-PD-1 Activity Patients with evidence of progression on enzalutamide were treated with pembrolizumab 200 mg IV every 3 weeks for 4 doses Pembrolizumab was added to standard dose enzalutamide 5 of 27 (19%) patients had a confirmed PSA response 3 of 5 had measurable disease with at least a PR by radiographic assessment 4 of 19 (21%) patients had stable disease > 6 months (range weeks) None of the 5 responders have relapsed Median PFS was 34 weeks There have been seven Grade 3 or higher iraes Graff JN, et al. Oncotarget. 2016; Graff JN, et al. ESMO 2016.

56 Responder 1 Responder 1 Baseline Week 24 Baseline Week 24 Responder 3 Responder 3 Baseline Week 24 Baseline Week 24 Responder 5 Responder 5 Baseline Week 12 Baseline Week 12

57 Proportion of Patients Olaparib in DDR-Deficient CRPC TOPARP-A Phase 2 Trial: rpfs Radiologic Progression-free Survival 1.00 P<.001 by log-rank test 0.75 Biomarker-positive, median: 9.8 mo Biomarker-negative, median: 2.7 mo Months since Trial Entry Mateo J, et al. N Engl J Med

58 Proportion of Patients Olaparib in DDR-Deficient CRPC TOPARP-A Phase 2 Trial: OS Overall Survival 1.00 P=.05 by log-rank test 0.75 Biomarker-positive, median: 13.8 mo Biomarker-negative, median: 7.5 mo Months since Trial Entry Mateo J, et al. N Engl J Med

59 Androgen Receptor Splice Variants The Androgen Receptor and its Ligand-Independent Variants Nakazawa M, et al. Horm Cancer

60 AR-V7-expressing CRPC Response to Treatment Study Antonarakis, et al. Steinestel, et al. Therapeutic Prevalence of AR- V7 (%) PSA response in AR-V7 + vs AR-V7 Patients (%) Abiraterone 19% 0% vs 68% (P<.01) Enzalutamide 39% 0% vs 53% (P<.01) Abiraterone or enzalutamide 64% 7% vs 63% (P=.01) Todenhofer, et al. Abiraterone 11% 0% vs 42% (P=.01) Antonarakis, et al. Docetaxel or cabazitaxel 46% 41% vs 65% (P=.19) Onstenck, et al. Cabazitaxel 55% 8% vs 22% (P=.07) Bryce AH, Antonarakis ES. Int J Urol

61 AR-V7 Summary AR-V7 warrants further evaluation as a potential predictive biomarker May be associated with primary and acquired resistance Potential to select patients who may not benefit from AR-targeted therapy May help guide future sequencing of agents Could fuel development of N-terminal domain inhibitors A prospective, randomized control trial is necessary to validate AR-V7 as a predictive biomarker AR-V7 predictive potential prior to docetaxel should be explored

62 Personalizing Therapy Today Examples Clinical features of disease presentation Sites of disease (bone predominant vs visceral) Pace of disease Presence or absence of significant symptoms Patient health status Performance status Co-morbidities relevant to tolerability of treatment Therapy history Prior enzalutamide or abiraterone Prior chemotherapy Tumor histology Small cell carcinoma Neuroendocrine/anaplastic Molecular features?

63 Advanced Prostate Cancer To Personalize Therapy We Need Multiple therapy options Cognizance of disease heterogeneity Disease presentation and behavior Host and tumor response to treatment The ability to identify functionally distinct disease states that map to specific treatments A selection of active treatments Application of treatments not generally used in prostate cancer

64 Concluding Remarks With patient and tumor heterogeneity and 6 approved agents, there are opportunities to individual treatment selection and sequencing. There is not a single, correct sequence. Patient and tumor factors, prior treatment history, as well as patient and physician preferences drive treatment sequencing today.

65 Concluding Remarks (cont.) Biomarkers that robustly define resistance and response to therapy have the potential to improve on our current approach. Validation of emerging biomarkers would, for the first time, yield individualized, molecularly defined treatment sequences that might include: PARP inhibitors and/or platinum agents for DDR deficiency Checkpoint inhibitors in MMR deficiency Early chemotherapy in AR-V7 overexpressed disease Others

Sequencing Strategies in Metastatic Castration Resistant Prostate Cancer (MCRPC)

Sequencing Strategies in Metastatic Castration Resistant Prostate Cancer (MCRPC) Amit Bahl Consultant Oncologist Bristol Cancer Institute Clinical Director Spire Specialist Care Centre UK Disclosures Advisory