Updates in Prostate Cancer Treatment 2018

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Muriel Barrett
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1 Updates in Prostate Cancer Treatment 2018 Mountain States Cancer Conference Elaine T. Lam, MD November 3, 2018 Learning Objectives Understand the difference between hormone sensitive and castration resistant prostate cancer. Learn current treatment options for biochemically recurrent prostate cancer and non-metastatic castration resistant cancer. Explore current treatment options for metastatic hormone sensitive cancer and metastatic castration resistant prostate cancer. Question 1

2 Question 2 Overview Epidemiology of prostate cancer and risk stratification Definitive treatment of local disease Biochemical recurrence Treatment of hormone-sensitive prostate cancer Treatment of castrate-resistant prostate cancer Epidemiology Prostate Cancer is the most common non-skin cancer in men in the US. Estimated 164,690 new cases in Accounts for 19% of new cancer cases in men. Third most common cause of cancer death in men (9%). Risk of Prostate Cancer Increases with age Lifetime risk is 1 in 6 for US Caucasians and 1 in 5 US African-Americans living > 75 years Siegel et al. CA Cancer J Clin 2018;68:7-30

Expected patient survival also determines initial workup and treatment recommendation.

3 Risk Stratification and Staging Determined by Gleason score, extent of tumor involvement (exam and imaging), PSA and PSA density. Determines prognosis and initial treatment options. Expected patient survival also determines initial workup and treatment recommendation. Gleason Score Wikipedia Gleason Grading System, accessed 10/12/18 Gleason Score and Recurrence Risk NCCN Guidelines Version Prostate Cancer Epstein et al. Am J Surg Pathol 2016;40:

4 NCCN Risk Groups Localized Very-Low Risk Low Risk Favorable Intermediate Risk Unfavorable Intermediate Risk High Risk Very High Risk Regional Metastatic NCCN Guidelines Version Prostate Cancer Treatment of Local Disease Very-Low and Low Risk Active surveillance Radical prostatectomy External beam radiation therapy Brachytherapy Intermediate Risk Radical prostatectomy External beam radiation therapy with short-term ADT Treatment of Local Disease High Risk External beam radiation therapy with long-term ADT Radical prostatectomy in select cases Regional External beam radiation therapy with long-term ADT

5 Biochemical Recurrence Majority of prostate cancer patients treated for local disease will be cured. Some will relapse and need salvage therapy. Some will relapse after initial and salvage therapy. PSA rise is often the first sign of relapse. PSA rise without detectable cancer on scans is called biochemical recurrence. Treatment of Biochemical Recurrence Relapse after surgery Salvage radiation Relapse after radiation Salvage local therapy if feasible Androgen deprivation therapy Observation Relapse after both surgery and radiation Observation (not curable) Androgen deprivation therapy Focal treatment of oligometastatic disease Novel Imaging Modalities Approved F-18 Sodium Fluoride C-11 Choline Fluciclovine (Axumin) In Clinical Trials C-11 Acetate 68 Ga-PSMA Main utility is to detect metastatic disease in biochemical recurrence (rising PSA after prior surgery and/or radiation) that may not be apparent on routine CT/MRI or bone scan.

18F-Fluciclovine PET (Axumin ) Li et al. J Nucl Med 2018;59:733-739 Hormone-Sensitive vs Castrate- Resistant Prostate Cancer Median survival of relapsed prostate cancer is 5+ years.

6 18F-Fluciclovine PET (Axumin ) Li et al. J Nucl Med 2018;59: Hormone-Sensitive vs Castrate- Resistant Prostate Cancer Median survival of relapsed prostate cancer is 5+ years. Majority of prostate cancers show excellent initial response to androgen deprivation therapy. Development of castrate-resistance develops within a 2-3 years of starting androgen deprivation therapy. Definition of castrate-resistance: despite low testosterone levels, PSA is rising and/or new cancer is detected on scans and/or new clinical symptoms. Treatment of Hormone Sensitive Prostate Cancer

7 Hypothalamic- Pituitary- Gonadal Axis Aragon-Ching et al (picture) Front Biosci 2007;12: LHRH antagonist: Degarelix LHRH agonists: Leuprolide Goserelin Adrenal androgen synthesis inhibitors: Abiraterone acetate Ketoconazole 5-AR Inhibitors: Finasteride Dutasteride Anti-androgens: Bicalutamide Enzalutamide Apalutamide Old Paradigm- Hormone Sensitive Prostate Cancer Biochemical Recurrence/Non-Metastatic HSPC Salvage option whenever possible If no salvage option, observation until radiographic mets, symptoms, or high PSA (preferred option) OR, start androgen deprivation therapy. Metastatic HSPC Androgen deprivation therapy alone Defer addition of other treatments until development of castrate-resistance

8 New Paradigm- Hormone Sensitive Prostate Cancer Biochemical Recurrence/Non-Metastatic HSPC Salvage option whenever possible Observation is still an option until mets or sx OR, start androgen deprivation therapy especially if rapid doubling time < 4 months. Metastatic HSPC Upfront combination therapy with ADT in combination with 6 cycles of docetaxel OR ADT in combination with abiraterone acetate Upfront combination therapy for metastatic hormone sensitive PCA Androgen deprivation therapy + abiraterone acetate LATITUDE study STAMPEDE study- abiraterone arm Androgen deprivation therapy + 6 cycles of docetaxel CHAARTED study STAMPEDE study- docetaxel arm LATITUDE Phase 3 study comparing upfront therapy with ADT alone vs ADT + abiraterone acetate in metastatic hormonesensitive prostate cancer 1199 men with node positive or metastatic prostate cancer randomized. Primary endpoint = overall survival Secondary endpoints = time to castrate-resistant progression, PSA progression, time to pain progression, time to initiation of chemotherapy. Fizazi et al. N Engl J Med 2017;377:

9 STAMPEDE- ABIRATERONE Multiple arm study in men with high risk and metastatic prostate cancer men with high risk non-metastatic, node positive, or metastatic prostate cancer. Compared ADT alone vs ADT + abiraterone acetate arms. Primary endpoint = overall survival Secondary endpoints = failure-free survival, PSA recurrence James et al. N Engl J Med 2017;377: Sydes et al. Ann Oncol 2018;29: CHAARTED Phase 3 study comparing upfront therapy with ADT alone vs ADT + docetaxel in metastatic hormone-sensitive prostate cancer 790 men with metastatic prostate cancer randomized. Primary endpoint = overall survival Secondary endpoints = progression-free survival, PSA progression Sweeney et al. N Engl J Med 2015;373: Kyriakopoulos et al. J Clin Oncol 2018;36: STAMPEDE- DOCETAXEL Multiple arm study in men with high risk and metastatic prostate cancer men with high risk non-metastatic, node positive, or metastatic prostate cancer. Compared ADT alone vs ADT + docetaxel arms. Primary endpoint = overall survival Secondary endpoints = failure-free survival, PSA recurrence James et al. Lancet 2016;387:

10 Treatment of Castrate- Resistant Prostate Cancer Old Paradigm- Castrate-Resistant Prostate Cancer Biochemical Recurrence/Non-Metastatic CRPC Continue androgen deprivation therapy Add on sequential secondary hormonal therapy or chemotherapy Metastatic CRPC Continue androgen deprivation therapy Add on sequential secondary hormonal therapy or chemotherapy Sipuleucel-T Enzalutamide Cabazitaxel Abiraterone acetate Radium 223 Docetaxel Clinical Trials New Paradigm- Castrate- Resistant Prostate Cancer Biochemical Recurrence/Non-Metastatic CRPC Continue androgen deprivation therapy Add on enzalutamide or apalutamide at development of castrate resistance Apalutamide (SPARTAN) Enzalutamide (PROSPER) Metastatic CRPC Continue androgen deprivation therapy Add on sequential secondary hormonal therapy or chemotherapy

11 SPARTAN Phase 3 study with 2:1 randomization to apalutamide 240mg/day or placebo 1207 men with M0 CRPC at high risk of developing metastasis (defined as PSA DT 10 months during continuous androgen deprivation therapy) 332 sites in 26 countries Primary endpoint = metastasis-free survival Secondary endpoints = time to metastasis, PFS, time to symptom progression, OS, time to initiating chemo Smith et al. N Engl J Med 2018;378: PROSPER Phase 3 study with 2:1 randomization to enzalutamide 160mg/day or placebo 1401 men with M0 CRPC at high risk of developing metastasis (defined as PSA DT 10 months and PSA 2) Primary endpoint = metastasis-free survival Secondary endpoints = OS, time to pain progression, PSA response, time to chemo, functional status deterioration, quality of life Hussain et al, N Engl J Med 2018; 378: Summary of Current Approach to Recurrent/Metastatic PCA Local therapy and salvage therapy when possible. Observation OR start ADT for non-metastatic, biochemical disease if no local salvage option and PSA DT < 4 months. Add apalutamide or enzalutamide for non-metastatic CRPC. Start ADT in combination with either abiraterone or docetaxel chemotherapy for metastatic hormone-sensitive, prostate cancer. Add on sequential secondary agents for CRPC.

12 Clinical Trials In Development Immunotherapy Targeted treatments for cancers with genomic alterations Combination therapies Use of new imaging techniques for diagnosis and potential treatment

Prostate Cancer. Dr. Andres Wiernik 2017

Prostate Cancer. Dr. Andres Wiernik 2017 Prostate Cancer Dr. Andres Wiernik 2017 Objectives YES!!! 1. Epidemiology 2. Biology or Natural History of Prostate Cancer 3. Treatment NO!!! 1. Prostate Cancer Screening - controversies Which is the most