FDA Approvals for Treatment of Castration Resistant Prostate ...

FDA Approvals for Systemic Treatment of Prostate Cancer in 2018 William R Berry MD Prostate Oncology Duke Cancer Center Cary New FDA approvals for the treatment of prostate cancer in 2018 Apalutamide, February 14 Enzalutamide, July 13 Abiraterone acetate, February 7 Apa and Enza are non-steroidal anti-androgens

Bind directly to ligand binding domain of androgen receptor (AR) Prevent AR translocation from cytoplasm to nucleus Prevent AR binding to DNA Prevent AR mediated transcription Both agents were approved for a specific prostate cancer clinical state non metastatic castration resistant disease Enzalutamide previously FDA approved for metastatic castration resistant disease Abiraterone acetate (with prednisone)

Approved in combination with prednisone for highrisk castration-sensitive metastatic prostate cancer Androgen biosynthesis inhibitor that inhibits CYP17, a bifunctional enzyme that includes 17alpha hydroxylase and C17,20-lyase activity CYP17 is needed for the synthesis of androgens Since Abiraterone works at the enzyme level, it blocks androgen synthesis in the testes, adrenals, and prostate cancer tissue Prostate Cancer Clinical States Model Anatomic stage Localized and confined to prostate Localized and advanced or high risk PSA only evidence of disease after primary therapy Metastatic

Castration sensitive or resistant disease Prostate Cancer Clinical States Localized PC Rising PSA only

Castration sensitive Castration resistant Hormone sensitive metastatic disease Newly diagnosed-localized disease Newly diagnosed-locally advanced and/or high risk localized disease T3a,T3b,T4 or Gleason 8 or higher

Newly diagnosed, with metastases present at diagnosis Previously diagnosed, with metastases developing in non-castrate setting Castration resistant metastatic disease (mCRPC) Asymptomatic or minimally symptomatic Symptomatic This state can be further divided by types of therapy previously received for mCRPC Newly Diagnosed Localized Disease Newly diagnosed and localized to gland

Very low, low, or intermediate risk Projected 2020 incidence 259,715 84% of newly diagnosed cases Projected 2020 prevalence 2,075,945 Projected all cause mortality in this clinical state 10,915 (5%) Projected annual progression to later clinical state 5% weighted average for all localized disease Locally Advanced Disease

High risk localized disease Extend beyond prostate capsule with any Gleason score or Gleason 8 or higher T3a-extends through the capsule T3b-invades seminal vesicles T4-invades adjacent organs such as bladder or rectum N1-pelvic nodal disease Projected 2020 incidence 37,300 12% of newly diagnosed cases

Projected 2020 prevalence 237,515 Projected 2020 all cause mortality while in this clinical state 13,920 Projected annual progression to a later clinical state 5% weighted average for all localized disease Rising PSA after Primary Therapy

Castration sensitive Rising PSA after treatment of localized disease Non-castrate levels of testosterone Projected 2020 incidence 98,800 Projected 2020 prevalence 528,770 Annual all cause mortality in this clinical state 6% Annual progression to more advanced clinical state 11% Castration resistant (nmCRPC) Rising PSA while on androgen deprivation therapy Castrate levels of testosterone Projected 2020 incidence

58,960 Projected 2020 prevalence 112,065 Annual all cause mortality in this clinical state 16% Annual progression to more advanced clinical state 34% Newly Diagnosed Metastatic Disease, Castration Sensitive by Definition Metastases detectable by some form of imaging at time of original diagnosis Projected 2020 incidence 13,575 5% of newly diagnosed patients

Projected 2020 prevalence 41,495 Projected 2020 all cause mortality 6,565 Annual progression to more advanced clinical state 14% Annual all cause mortality in this clinical state 16% Metastatic Castration Resistant Disease

Asymptomatic or minimally symptomatic (no narcotics for pain) Projected 2020 incidence 20,255 Projected 2020 prevalence 8320 Projected 2020 all cause mortality 2785 Symptomatic Projected 2020 incidence 58,340 Projected 2020 prevalence

68,370 Definition of Castration Resistant NCCN and PCWG2 define CRPC as: Castrate level of testosterone (<50 ng/dL) Disease progression despite ADT demonstrated by radiographic evidence or rising PSA values Term evolved from HRPC/AIPC based on new information on biology of resistance to androgen deprivation therapies Many tumors remain sensitive to novel AR antagonists or androgen synthesis inhibitors Amplifications and mutations in AR develop Synthesis of androgenic precursors increases Not truly hormone refractory

NCCN=National Comprehensive Cancer Network; PCWG2=Prostate Cancer Clinical Trials Working Group 2; HRPC=hormone-refractory prostate cancer; AIPC=androgen-independent prostate cancer; AR=androgen receptor. Hotte SJ et al. Current Oncology. 2010;17:S72-S79; NCCN. Prostate Cancer. NCCN Clinical Practice Guidelines in Oncology. V1.2015; Scher HI et al. J Clin Oncol. 2008;26:1148-1159; Mottet N et al. Eur Urol. 2011;59:572-583; Bellmunt J et al. Ther Adv Med Oncol. 2010;2:189-207; Aggarwal R et al.Oncologist. 2011;16:264-275; Antonarakis ES et al. Clinical Oncol News. 2011;30-45. 11 Progression to mCRPC Is Rapid 46% of men with nmCRPC will develop metastases within 2 years Time to Onset of Metastases in Men With CRPC Probability of

Bone Metastases 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 0 12 24

36 Months Since Randomization 48 60 Data are from the placebo arm (n=331) of a randomized, controlled study to evaluate the effects of atrasentan on time to disease progression in men who had progressive CRPC and no radiographic evidence of bone metastases. Smith MR et al. Cancer. 2011;117:2077-2085. 12 Higher absolute value of PSA and more rapid PSA doubling times correlate with more rapid development of metastases

Proportion of Patients Time to Bone Metastases or Death Stratified by PSA and PSADT Years Since Random Assignment Years Since Random Assignment Data are from the placebo arm (n=201) of a randomized, double-blind, controlled study to evaluate the effects of zoledronic acid on time to first bone metastases in men with prostate cancer. PSADT=prostate-specific antigen doubling time. Smith MR et al. J Clin Oncol. 2005;23:2918-2925. 13

Metastatic Disease Is Often Occult Over 30% of men thought to have nonmetastatic CRPC were found to have metastatic disease when screened via imaging for a recent clinical trial Leading Cause of Screening Failures Patients (N=2577) Detection of metastatic disease 818 (32%) Data represent screening failures of patients trying to enroll in the phase 3 study comparing zibotentan with placebo. Of the

2577 patients, 818 who were presumed to have nonmetastatic CRPC actually had metastatic disease and did not qualify for the study. Yu EY et al. J Urol. 2012;188:103-109. 14 PROSPER PROSPER was a double blind randomized phase III clinical trial Eligible men had castration resistant prostate cancer PSA doubling time 10 months or less No imaging evidence of metastatic disease (technetium bone scans and CT scans) Enzalutamide 160 mg vs placebo Randomized 2:1 in favor of enzalutamide 1401 men were enrolled Primary endpoint was metastasis free survival

Time from initiation of therapy to radiographic progression or death Secondary endpoints . Time to PSA progression PSA response rate Time to initiation of a new therapy Quality of life assessments

Safety Overall survival METAMM. Hussain M et al. N Engl J Med 2018;378:2465-2474 KaplanMeier Est to the First Use of Subsequent Antineoplastic Therapy. Hussain M et al. N Engl J Med 2018;378:2465-2474 Demographic and Clinical Characteristics of the Patients at Baseline. Hussain M et al. N Engl J Med 2018;378:24652474

Primary and Secondary End Points. Hussain M et al. N Engl J Med 2018;378:2465-2474 SPARTAN SPARTAN was a double blind randomized phase III clinical trial Eligible men had castration resistant prostate cancer

PSA doubling time 10 months or less No imaging evidence of metastatic disease (technetium bone scans and CT scans) Apalutamide 240 mg daily versus placebo Randomized 2:1 in favor of apalutamide 1207 patients were enrolled Primary endpoint was metastasis free survival Time from initiation of therapy to radiographic progression or death Secondary endpoints

Time to symptomatic progression Overall survival Time to initiation of cytotoxic chemotherapy Metastasis-free Survival. Smith MR et al. N Engl J Med 2018;378:14081418 Prespecified Secondary and Exploratory Efficacy End Points. Smith MR et al. N Engl J Med 2018;378:1408-1418 Demographic and Disease Characteristics at Baseline. Smith MR et al. N Engl J Med 2018;378:1408-1418

Prespecified Secondary and Exploratory End Points. Smith MR et al. N Engl J Med 2018;378:1408-1418 Adverse Events. Smith MR et al. N Engl J Med 2018;378:1408-1418 Abiraterone acetate (with prednisone) was FDA approved for treatment of high risk castration sensitive metastatic prostate cancer Based on LATITUDE, a phase III placebo controlled trial

Abiraterone acetate with 5 mg prednisone daily versus 2 placebos All patients received LHRH agonist or bilateral orchiectomy 1199 patients randomized 1:1 Primary endpoints Overall survival Radiographic progression free survival Secondary endpoints

Time to next symptomatic skeletal related event Time to PSA progression Time to next therapy Time to initiation of cytotoxic chemotherapy Time to pain progression KaplanMeier Estimates of the Two Primary End Points. Fizazi K et al. N Engl J Med 2017;377:352-360.

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