2020 Spring Oncology Conference
Evolving Options in Metastatic Prostate Cancer
Learning Objectives • Implement guideline-recommended treatment strategies for patients with nonmetastatic castrate-resistant prostate cancer (CRPC) • Formulate personalized management strategies for patients with metastatic CRPC based on patient preferences and efficacy and safety of novel agents • Apply strategies to identify and manage AEs associated with novel therapies for CRPC 3 AE = adverse event.
Prostate Cancer in 2020 • Estimated for 2020 ‒ 191,930 new cases ‒ 33,330 deaths ‒ Incidence and mortality rates have declined ‒ 10-year overall survival (OS): 98% • Risk factors ‒ Advancing age ‒ African ancestry Image: Histology slide showing prostate cancer. Courtesy of the National Cancer Institute. ‒ Family history Photographer: Otis Brawley, ‒ Genetic mutations American Cancer Society. www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/annual-cancer-facts-and- 4 figures/2020/cancer-facts-and-figures-2020.pdf. Accessed Mar 24, 2020.
Advances in Treatment Approvals Apalutamide (next- generation ARSI) Darolutamide Enzalutamide (next- Docetaxel for nmCRPC Cabazitaxel (next-generation ARSI) generation ARSI) Radium-223 (taxane) (novel taxane) postdocetaxel for nmCRPC (radiopharmaceutical) 2004 2010 2011 2012 2013 2014 2018 2019 Sipuleucel-T Abiraterone (next- Abiraterone Enzalutamide Enzalutamide (immunotherapy) generation ARSI) predocetaxel predocetaxel Enzalutamide for mHSPC postdocetaxel for nmCRPC mHSPC = metastatic hormone-sensitive prostate cancer; nmCRPC = nonmetastatic castrate-resistant prostate cancer. Komura K, et al. Int J Urol . 2018;25:220-231; US Food and Drug Administration. www.fda.gov/newsevents/newsroom/pressannouncements/ucm596768.htm. Accessed Mar 24, 2020; US Food and Drug Administration. www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=210951. Accessed Mar 24, 2020. US Food and Drug Administration. www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-darolutamide-non-metastatic-castration-resistant-prostate-cancer. Accessed Mar 24, 2020; US Food and Drug Administration. www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-enzalutamide- 5 metastatic-castration-sensitive-prostate-cancer. Accessed Mar 24, 2020.
CHAARTED: ADT + Docetaxel in mHSPC All Patients OS Benefit by Volume of Disease 100 • High volume: 17 months • Low volume: no benefit 80 OS (%) 60 ADT + docetaxel: (median OS, 57.6 months) 40 ADT alone (n = 393): Death with ADT + docetaxel (n = 397): 20 (median OS, 44.0 months) HR, 0.61 (95% CI, 0.47-0.80) P <.001 0 12 24 36 48 60 72 0 84 Number at Risk ADT + docetaxel 397 333 189 89 46 5 2 0 ADT alone 393 318 168 71 27 3 1 0 Median follow-up: 28.9 months ADT = androgen deprivation therapy; CI = confidence interval; HR = hazard ratio; PSA = prostate-specific antigen. 6 Sweeney CJ, et al. N Engl J Med . 2015;373:737-746.
STAMPEDE, Arm C: ADT and Docetaxel in HSPC Median OS (Months) 5-Year Survival (%) 70% 60% Median OS Metastatic 45 Months 63% 50% 60 Months 50% 40% 55% 30% Median OS 39% 71 Months 20% 81 Months 10% 0 10 20 30 40 50 60 70 80 90 0% 5-Year Survival (Metastatic) 5-Year Survival ADT Alone ADT + Docetaxel ADT Alone ADT + Docetaxel ADT alone: n = 1184 ADT + docetaxel: n = 592 Median follow-up: 43 months 7 James ND, et al. Lancet . 2016;387:1163-1177.
Phase 3 Trials of ADT + Abiraterone in mHSPC LATITUDE STAMPEDE, Arm G N = 1199: ADT + abiraterone + prednisone vs ADT + placebo N = 960: ADT + abiraterone + prednisolone vs ADT alone 100 80 100 ADT + abiraterone 80 60 rPFS (%) PFS (%) 60 Abiraterone 40 40 ADT Placebo HR, 0.47 (95% CI, 0.39-0.55) 20 20 P <.001 HR, 0.29 (95% CI, 0.25-0.34) 0 P <.001 0 8 16 24 32 40 0 0 6 12 18 24 30 36 42 48 54 Months Months PFS = progression-free survival; rPFS = radiographic progression-free survival. 8 Fizazi K, et al. N Engl J Med. 2017;377:352-360; James ND, et al. N Engl J Med . 2017;377:338-351.
Some Agents Used in Advanced Settings Are Now Being Used in Earlier Disease rPFS: significant TITAN Phase 3 ADT + apalutamide vs improvement in both low- Study ADT + placebo in and high-volume disease (N >1050) mHSPC ( P <.001) with apalutamide PFS: significant improvement in both low- ARCHES Phase 3 ADT + enzalutamide vs and high-volume disease Study ADT + placebo in ( P <.001) with (N = 1150) mHSPC enzalutamide Armstrong AJ, et al. J Clin Oncol. 2019;37(7 suppl):Abstract 687; Chi KN et al. J Clin Oncol . 2019;37(15 suppl):Abstract 5003; US Food and Drug Administration. www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-enzalutamide-metastatic-castration-sensitive-prostate- 9 cancer. Accessed Mar 24, 2020.
2019 NCCN Guidelines for mHSPC • Based on results of clinical trials, for patients with mHSPC, consider adding to ADT: ‒ Docetaxel 75 mg/m 2 every 3 weeks for 6 cycles • Patients with high-volume disease derive greater benefit ‒ Abiraterone acetate + steroid ‒ Apalutamide ‒ Enzalutamide NCCN = National Comprehensive Cancer Network. 10 NCCN Guidelines. Prostate cancer. www.nccn.org/professionals/physician_gls/pdf/prostate.pdf. Accessed Mar 24, 2020.
Castrate-Resistant Prostate Cancer • Disease progression despite castrate levels of testosterone (<50 ng/mL) • Heterogeneous — can be symptomatic or asymptomatic, with or without metastases • Affects 10% to 20% of men with prostate cancer within 5 years of diagnosis ‒ Before recent therapeutic advances, ≥50% of these patients would have died within 3 years • Natural history can involve progressive decline in health-related QoL • Metastasis-free survival (MFS) is a new, reasonable endpoint for both clinical trials and clinical discussions with patients QoL = quality of life. Anantharaman A, et al. Expert Rev Anticancer Ther . 2017;17:625-633; Beaver JA, et al. N Engl J Med . 2018;378:2458-2460; Nussbaum N, et al. 11 Prostate Cancer Prostatic Dis . 2016;19:111-121.
Typical Progression of CRPC Rising PSA mHSPC despite castrate Criterion 1: levels of Rising Identification of testosterone PSA metastases Both criteria met Localized/locally Biochemical Start Definitive mCRPC advanced ADT recurrence therapy prostate cancer Criterion 2: Rising PSA Identification of despite castrate metastases levels of testosterone nmCRPC 12 Adapted with permission from Anantharaman A, et al. Expert Rev Anticancer Ther . 2017;17:625-633.
Nonmetastatic CRPC • CRPC with no clinical or radiologic evidence of metastases • Newer imaging techniques have greater sensitivity (eg, 18 F-fluorocholine or PSMA-targeted PET) ‒ May reveal metastases earlier • PSA testing every 4 to 6 months is advised • Treatment is recommended for men with PSADT ≤10 months • Until recently, no approved drugs were available for nmCRPC Image from Singh A, et al. PET Clin . 2017;12:193-203. PET = positron emission tomography; PSADT = prostate-specific antigen doubling time; PSMA = prostate-specific membrane antigen. Anantaraman A, et al. Expert Rev Anticancer Ther . 2017;17:625-633; Virgo KS, et al. J Clin Oncol . 2017;35:1952-1964; Zimmerman ME, et al. 13 Clin Adv Hematol Oncol . 2019;17:455-463.
Case Study 1: Earl, 69 Years Old • Earl has mild COPD and occasional arrhythmias ‒ No family history of cancer • He underwent radiotherapy for localized prostate cancer 4 years ago • Earl experienced biochemical recurrence as evidenced by increasing PSA • Because of previous radiotherapy, he was not considered a candidate for surgery • He was started on ADT 1 year ago 14
Case Study (cont’d): Earl’s Test Results • PSA increased from 6 ng/mL to 14 ng/mL, with PSADT of 8 months ‒ Testosterone level: 23 ng/dL ‒ No evidence of metastases on CT or bone scan, no bone pain ‒ No lymph node masses detected • Now diagnosed with nmCRPC 15
Factors to Consider When Selecting Therapies Patient Disease Treatment • Preferences • Metastatic? • Toxicity profile • Medical history, – To bone? • Possible drug-drug comorbidities, medications interactions – Visceral? • Treatment and response • Effects on pain, QoL • Disease volume history – Low or high? • Practitioner experience • Symptoms and preference • Risk level/aggressiveness • Overall condition and performance status Basch E, et al. J Clin Oncol . 2014;32:3436-3448; Crawford ED, et al. J Urol . 2015;194:1537-1547; Nussbaum N, et al. Prostate Cancer Prostatic 16 Dis . 2016;19:111-121; Zarrabi K, et al. J Hematol Oncol . 2019;12:89.
Shared Decision-Making • Especially important for complex diseases such as CRPC • Endorsed by all major guidelines • Patients and clinicians collaborate on treatment selection • May enhance adherence to therapies • May improve outcomes: Greater adherence → better treatment responses Fennimore LA, Ginex PK. Nurs Clin North Am . 2017;52:115-131; Makarov DV, et al. www.auanet.org/guidelines/shared-decision-making. 17 Accessed Mar 24, 2020.
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