Second line hormone therapies. Dr Lisa Pickering Consultant Medical Oncologist ESMO Preceptorship Singapore PDF Free Download

Second line hormone therapies Dr Lisa Pickering Consultant Medical Oncologist ESMO Preceptorship Singapore 2017

Disclosures Institutional Research Support/P.I. Employee Consultant Major Stockholder Speakers Bureau Honoraria Scientific Advisory Board Novartis, Pfizer, Pierre Fabre N/A Astellas, BMS, EUSA Pharma, Ipsen, Janssen, MSD, Novartis, Pfizer N/A BMS, EUSA Pharma, Novartis, Pfizer Astellas, Ipsen, Janssen, MSD, Pfizer Astellas, EUSA Pharma, Ipsen, Janssen, MSD, Novartis, Pfizer, Sanofi

Second line hormone therapies The biology of castration-resistance Hormone therapies in clinical practice Abiraterone acetate Enzalutamide Pre and post docetaxel Next steps: Predicting response and resistance Novel agents

Tumor volume & activity Current treatment landscape Abi 302 Enza PREVAIL Radium ALSYMPCA Abi 301 Enza AFFIRM Cabazitaxel TROPIC Radium ALSYMPCA Docetaxel chemo

Phase III CRPC Trials Showing OS Benefit Drug Prior Therapy Symptom Improvement/D elay Control OS Median Δ (Months) HR Docetaxel Chemo-naïve + MTX 2.4 0.76 Sipuleucel-T +/- chemo - Placebo 4.1 0.78 Cabazitaxel Post-docetaxel +/- MTX 2.4 0.70 Abiraterone Post-docetaxel + Prednisone 4.6 0.74 Enzalutamide Post-docetaxel + Placebo 4.8 0.63 Radium-223 +/- chemo + Placebo 3.6 0.70 Abiraterone Chemo-naïve + Prednisone 4.4 0.81 Enzalutamide Chemo-naïve + Placebo 2 0.70 Courtesy of Arun Azad

Androgens and prostate cancer Prostate cancer is driven by androgen receptor signaling Testosterone stimulation Normal prostate cell Prostate cancer cell This provides targets for blocking testosterone production and / or receptor

Testosterone suppression Testosterone Level Patients on LHRH analogues will achieve castrate levels of circulating testosterone (< 50ng/dl, < 2.0nM)

Aim of second line hormone treatment Prostate cancer cell Dihydrotestosterone Heat-shock protein Cytoplasm Nucleus Coactivator Androgen-response element AR Prostate cancer cell in CRPC Androgen deprivation Amplified AR Mutated AR therapy alone is insufficient Coactivator Cytokines to prevent growth of prostate cancer Other ligands PTEN Prostate cancer is deemed Pathways involving AR Hormone refractory Castration resistant Neuropeptides Bad Growth factors Bcl-2 So what is happening biologically that additional Pathways bypassing AR hormone therapies need to overcome? PI3K Akt Overexpression of Bcl-2 Neuroendocrine-like cells

Biology of castration resistant prostate cancer CRPC Prostate cancer cell Prostate cancer cell in CRPC Dihydrotestosterone Heat-shock protein Cytoplasm Nucleus AR Amplified AR Pathways involving AR Mutated AR Coactivator Cytokines Growth factors Other ligands PTEN Bad PI3K Akt Coactivator Bcl-2 Androgen-response element Pathways bypassing AR Overexpression of Bcl-2 Neuropeptides Neuroendocrine-like cells

One of the other issues in CRPC: Multiple sources of androgens Historic view Endocrine Gonadal Adrenal Testosterone AR Endocrine Gonadal Current view Microenvironment Intracrine Testosterone Adrenal AR Intracrine production Steroid metabolism Danila DC et al. J Clin Oncol. 2010;28:52(suppl). Abstract 4635

Castration-resistant not hormone-resistant High levels of intratumoural androgens and persistent AR signalling despite castration Androgens in prostate tissue Metastatic tissue samples (3 sites of metastasis from 4 patients) were acquired from patients with castrate testosterone levels DHT, dihydrotestosterone; T, testosterone CRPC pts have a rising PSA at progression PSA is an androgen regulated gene related to AR transcription Mostaghel et al. Urol Oncol 2009; 27(3): 251-257

Probability of survival This is why its important to maintain castrate testosterone levels after progression (ie to continue on ADT) Retrospective analysis (N = 341) showed that stopping medical castration was predictive of shorter survival 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 No orchidectomy, hormone therapy discontinued prior to study entry Orchidectomy plus continued hormonal therapy 0 6 12 Mos Recommendation: Patients requiring second line hormone therapy should continue androgen suppression after progression on ADT Taylor CD, et al. J Clin Oncol. 1993;11:2167-2172.

Tumor volume & activity Current treatment landscape Abi 302 Enza PREVAIL Radium ALSYMPCA Abi 301 Enza AFFIRM Cabazitaxel TROPIC Radium ALSYMPCA Docetaxel chemo

Abiraterone Acetate: an androgen biosynthesis inhibitor that inhibits all three sources of androgens Testes Adrenal gland Prostate tumour cells

COU-AA-302: Phase III RCT pre-docetaxel of abiraterone + pred vs pred alone Randomised 1:1 Patients with mcrpc progressing on ADT No prior chemo No visceral mets (N = 1088) Abiraterone 1000 mg PO daily + pred 5mg bd (n = 546) Placebo PO daily + pred 5mg bd (n = 542) Co-primary endpoint: OS and rpfs (central review) Key secondary endpoints: time to PSA progression, time to cytotoxic chemo, time to opiate use, time to PS deterioration Ryan et al. NEJM 2013; Lancet 2015

COU-AA-302: Overall survival favours abiraterone + pred AA plus pred 34 7 months [95% CI 32 7 36 8] vs Placebo plus pred 30 3 months [28 7 33 3]; HR 0 81 [95% CI 0 70 0 93]; p=0 0033) 3.3 months improved OS with abiraterone and 19% reduction in risk of death Ryan et al. NEJM 2013; Lancet 2015

Subjects Without Progression or Death (%) Ryan et al. NEJM 2013; Lancet 2015 COU-AA-302: rpfs also favours abiraterone 100 80 Abiraterone (median, mos): 16.5 Prednisone (median, mos): 8.3 HR (95% CI): 0.53 (0.45-0.62) p Value: < 0.0001 60 40 20 0 0 Abiraterone Prednisone 3 6 9 12 15 18 21 24 27 30 33 36 Months From Randomization Abiraterone Prednisone 546 542 485 406 389 244 311 176 240 133 195 99 157 78 131 62 117 45 66 20 20 7 4 0 0 0 IA3 data. rpfs assessed by investigator review at prespecified IA.

Physiologic consequences of abiraterone Attard et al, J Clin Oncol, 2008; Ryan et al, J Clin Oncol 2010; Attard et al, JCEM 2012 Low-dose glucocorticoid replacement minimises mineralocorticoid-related toxicity by suppressing ACTH drive

Abiraterone Acetate: Safety Profile NB: Toxicities similar for pre- and post-docetaxel patients Ryan CJ, et al. Lancet Oncol. 2015;16:152-160.

Enzalutamide: mechanism of action Pure AR antagonist Greater binding to AR Prevents translocation of AR to nucleus Prevents co-activator recruitment overcomes resistance to bicalutamide in vitro 1. Tran, Science 2009; 2. Higano CS, et al. ASCO GU 2011; 3. Scher HI, et al. Lancet. 2010

PREVAIL: phase III RCT of enzalutamide in CRPC pre-docetaxel Randomised 1:1 Patients with mpc progressing on ADT (N = 1717) Enzalutamide 160 mg PO daily (n = 872) Placebo PO daily (n = 845) Co-primary endpoint: OS and PFS Key secondary endpoints: soft tissue response, time to PSA progression, time to cytotoxic chemo, time to first SRE Beer et al. NEJM 2014

PREVAIL: rpfs and OS both favour enzalutamide over placebo Radiographic PFS Overall survival 81% reduction in risk of rpfs 12mth rpfs rate 65% v 14% p < 0.001 29% reduction in risk of death 32.4 v 30.2 mths p < 0.001 Beer et al. NEJM 2014

PREVAIL: Enzalutamide Safety NB: Toxicities similar for pre- and post-docetaxel patients Beer et al. NEJM 2014

Posterior Reversible Encephalopathy Syndrome (PRES) PRES is a neurological disorder which can present with rapidly evolving symptoms including seizure, headache, lethargy, confusion, blindness, and other visual and neurological disturbances, with or without associated hypertension Diagnosis of PRES requires confirmation by brain imaging, preferably MRI Enzalutamide should be discontinued

Is there still a role for bicalutamide in patients failing 1 st line ADT? TERRAIN RCT Ph II PFS Clear PFS benefit for enzalutamide so probably not unless other seond line optionms not available

Summary: Hormone therapy in CRPC Abiraterone and enzalutamide are both associated with improved overall survival & radiographic PFS Both have beneficial PROs. Good HRQoL & welltolerated with some differences in toxicity. Enzalutamide used in patients with visceral metastases as well as bone and lymph node Anecdotally abiraterone has activity in these pts 1A 1B

Tumor volume & activity Current treatment landscape Abi 302 Enza PREVAIL Radium ALSYMPCA Abi 301 Enza AFFIRM Cabazitaxel TROPIC Radium ALSYMPCA Docetaxel chemo

COU-AA-301: Phase III RCT post-docetaxel of abiraterone + pred v pred alone Randomised 2:1 Progressing mcrpc Failed 1 or 2 chemo Regimens of which 1 contained docetaxel (N = 1195) Abiraterone 1000 mg PO daily + pred 5mg bd (n = 797) Placebo PO daily + pred 5mg bd (n = 398) Primary endpoint: OS Key secondary endpoints: time to PSA progression, rpfs, PSA response de Bono et al. NEJM 2011

COU-AA-301: Updated analysis of OS shows benefit for abiraterone Median OS Benefit: 4.6 Months Median duration of follow-up: 20.2 months Median duration of treatment: AA, 8 months vs placebo, 4 months Fizazi, Lancet Oncology 2012

AFFIRM: phase III RCT of enzalutamide v placebo in CRPC after docetaxel Randomized 2:1 Patients with mcrpc progressing on docetaxel (N = 1199) Enzalutamide 160 mg PO daily (n = 800) Placebo PO daily (n = 399) Primary endpoint: OS Key secondary endpoints: PSA response, radiographic PFS, time to PSA progression Scher HI, et al. NEJM 2012

Survival (%) AFFIRM: OS improvement with enzalutamide in CRPC Enzalutamide Placebo 100 90 80 70 60 50 40 30 20 10 0 HR: 0.631 (95% CI: 0.529-0.752; P < 0.0001) 37% reduction in risk of death Placebo: 13.6 mos (95% CI: 11.3-15.8) Enzalutamide: 18.3 mos (95% CI: 17.3-NYR) 0 3 6 9 12 15 18 21 24 Duration of OS (Mos) 800 399 Median OS Benefit: 4.8 months 775 376 701 317 627 263 400 167 211 81 72 33 7 3 0 0 Scher HI, et al. NEJM 2012

AFFIRM: Progression free survival also favours enzalutamide over placebo Radiographic PFS PSA progression Improved patient-reported outcomes; toxicity and QoL Scher HI et al. N Engl J Med 2012;367:1187-1197 Scher H et al, NEJM 2012

Hormone therapy in CRPC postdocetaxel Abiraterone with prednisolone and enzalutamide both associated with improved overall survival Improved PFS Improved patient-reported outcomes Both well tolerated but differences in toxicity profiles Personal perspective: I use both but have preferences in certain patients

Second line hormone therapy in CRPC: Drug characteristics Abiraterone Enzalutamide Prednisone required yes no Drug interactions (CYP) yes yes Lowers seizure threshold no yes Potential liver toxicity yes less Risk for hypertension yes yes Risk for CV events, AF yes yes Choice cannot be dictated by efficacy: Therefore choice is based on differential toxicity: Abiraterone if seizure-prone, frail, high risk for falls Enzalutamide if significant CV risk factors, contraindications to steroids Initial choice important

mcrpc: Abiraterone following disease progression on enzalutamide and viceversa. Low response rates Abiraterone response after prior treatment with enzalutamide 1 Enzalutamide versus docetaxel in men with CRPC progressing after abiraterone 1. Loriot Y, et al. Ann Oncol 2013;24:1807-1812. 2. Suzman DL, et al. Prostate. 2014; 74:1278-1285.

PSA (ng/ml) A few words about resistance 1. Promiscuous AR Steroid precursors upstream of P450c17 may be androgenic ie may bind and activate mutated AR Decrease ACTH driven synthesis of steroids upstream of CYP17* by adding low dose dex Abiraterone Acetate 120 Dexamethasone 100 Dexamethasone 80 60 40 20 0-600 -400-200 0 200 400 Days on Study 2. AR splice variants: Isoforms of AR (eg Arv7) that lack the ligand-binding domain & are constitutively active Implicated in resistance to abi and enza But not taxanes

Ligand-independent receptor activation & bypass pathways: future directions Minimal actvity with agents targeting HER2 to date-?? Need to completely ablate androgens first. PI3K/ AKT inhibitors in PTEN lost patients in early development Drugs promoting apoptosis are in development ie. an antibody to survivin (antiapoptotic protein)

Conclusions and future directions Androgens and AR signaling remain critically important throughout the disease Abiraterone & enzalutamide target the AR axis Both have demonstrated improved patient-reported outcomes for patients at various stages of CRPC Both have led to a survival advantage for patients at various stages of CRPC (pre & post docetaxel) Future work involves: Enhancing our understanding of the mechanisms of resistance to these drugs Targeting other signalling pathways involved in CRPC Investigating optimal combinations & schedules with chemotherapy & other novel agents

Thank you

Second line hormone therapies. Dr Lisa Pickering Consultant Medical Oncologist ESMO Preceptorship Singapore 2017