New Treatment Options for Prostate Cancer Moderator: Jeremy P. Goldberg, President, JPG Healthcare LLC Panelists: Philip Kantoff, MD, Director, Lank Center for Genitourinary Oncology, Dana- Farber Cancer Institute Richard Heyman, CEO, Seragon (ex-ceo Aragon) Marco Gottardis, PhD, VP and Prostate Cancer Disease Area Stronghold Leader, Oncology Therapeutic Area, Janssen Research & Development, LLC Brian Richard Gaynor, MD, VP, Product Development/Medical Affairs, Eli Lilly and Company Marianne Sadar, PhD, Distinguished Scientist, BC Cancer Agency. Professor of Pathology and Laboratory Medicine, University of British Columbia 1
New Treatment Options for Prostate Cancer Richard Gaynor, M.D. Sr. Vice President Oncology Clinical Development and Medical Affairs Lilly Oncology 2
Drug Development in Prostate Cancer Genetic Changes Pathway inhibitors Immunotherapeutic approaches Clinical status
Clinically Relevant Genomic Alterations in Prostate Cancer Gene Alteration Type Frequency (%) Potential Treatment Hypotheses ETS transcription factors Rearrangement 50 Indirect targeting of ETS gene fusions through PARP or DNAPK inhibitors Androgen receptor Mutation Amplification 50 50 PTEN Loss 50 PI3K pathway inhibitors J Clin Oncol 31:1866-1873. 2013 by American Society of Clinical Oncology Androgen synthesis inhibitors, next-generation androgen receptor antagonists RB1 Loss 25 to 60 Role in disease progression and castrate resistance with potential for targeting PIK3CA Amplification Mutation MYC Amplification 9 40 10 5 PI3K pathway inhibitors Potential for targeting Neuroendocrine prostate cancer AURKA Amplification 5 Aurora kinase inhibitors, co-occurs with MYC in 40% of neuroendocrine prostate cancers AKT Mutation 1 to 2 AKT inhibitors RAF KRAS Rearrangement Mutation Mutation Rearrangement 1 to 2 RAF inhibitors 1 RAF, MEK, or PI3K inhibitors NOTE: Summarizes alterations in prostate cancer that have a treatment hypothesis currently being explored preclinically or in clinical trials. The most common alterations with a treatment hypothesis involve ETS rearrangements, androgen receptor, and PTEN loss. With only a limited number of samples assessed, a majority of these alterations are not necessarily mutually exclusive. Abbreviation: PI3K, phosphatidylinositide 3-kinase.
Pathway-guided Treatment in Prostate Cancer J Clin Oncol 31:1866-1873. 2013 by American Society of Clinical Oncology
Translating Genomics for Prostate Cancer Trials J Clin Oncol 31:1866-1873. 2013 by American Society of Clinical Oncology
The Changing Treatment Landscape of Prostate Cancer Philip Kantoff, MD Dana-Farber Cancer Institute Harvard Medical School March 4 5, 2014 Conrad New York
Prostate Cancer: The Old Treatment Paradigm Therapies after LHRH agonists anti-androgens etc. Post Chemo A Hormone Sensitive B C Castration Resistant 1 2 3 4 CRPC
The Treatment Landscape in 2014 Standard Androgen Deprivation Therapy Denosumab, Zoledronic Acid Radium-223 Enzalutamide Local Therapy Androgen Deprivation Therapies After LHRH Agonists and Antiandrogens Abiraterone Chemotherapy Death Postchemotherapy Sipuleucel-T Docetaxel Cabazitaxel
Immunotherapy AR-Targeting Therapies Chemotherapy Bone Targeted Agents
ANDROGEN SIGNALING BLOCKERS 11
Androgen Dependent Cell CRPC
mhspc-lower PSA Nadir: Better Outcome With ADT (Proportion of CRPC Cells in Population?) Hussain M, et al. J Clin Oncol, 2006
Mechanisms of Resistance To Primary Androgen Deprivation Therapy Adaptive mechanisms by which hormone sensitive cells reprogram in response to ADT Androgen receptor mediated mechanisms Ligand and AR independent mechanisms Alternative molecular signaling pathways Clonal selection (ex: neuroendocrine differentiation) Ligand dependency despite low ligand availability
Examples of AR Mediated Mechanisms AR mutations and amplification AR reprogramming
Androgen Receptor Reprogramming Wang Q, et al. Cell. 2009;138(2):245-256.
Ligand and AR independent Mechanisms Clinical Observations Alternative molecular signaling pathways Largely not known Evolution of AR and PSA negative cells Acquisition of neuroendocrine differentiation
Importance of Persistent Ligand in CRPC Genetic evidence-ar-mutated or amplified AR (Taplin and others) Probably low frequency events Persistent AR expression and expression of androgen regulated genes androgen signature (Chen et al, Stanbrough et al) including genes involved in conversion of precursors to T and DHT (Balk et al and Nelson et al) Persistent intratumoral ligand -T or DHT or precursors Intratumoral conversion Persistent androgen in CRPC tissue (Geller, Mohler, Montgomery, Nelson)
FDA Approved Androgen Signaling Pathway Inhibitors CYP 17, 20 lyase inhibitors-androgen biosynthesis inhibitors Abiraterone acetate Antiandrogens-block AR action Enzalutamide (MDV3100)
Abiraterone in mcrpc Pre- and Post-Chemotherapy* mcrpc Pre-chemotherapy mcrpc 1 st Line Chemotherapy mcrpc Post-chemotherapy COU-AA-302 Co-Primary Endpoints: OS, rpfs COU-AA-301 Primary Endpoint: OS *FDA approved indications
Enzalutamide in mcrpc Pre- and Post-Chemotherapy mcrpc Pre-chemotherapy mcrpc 1 st Line Chemotherapy mcrpc Post-chemotherapy PREVAIL Co-Primary Endpoints: OS and rpfs AFFIRM Primary Endpoint: OS
Conclusions Understanding the persistence of the androgen signaling pathway in CRPC has been transformative Multiple agents with varied mechanisms extend survival and delay progression Cross resistance occurs between agents Active agents against similar targets (eg. Orterenol) have failed to meet endpoint
Questions What is the optimal sequencing and/or combination of agents? Can we develop predictive biomarkers of efficacy? Can we cure patients by using these drugs earlier in the treatment paradigm (adjuvantly)? How much further can we get by extinguishing the AR pathway completely?
IMMUNOTHERAPY 24
Sipuleucel-T (Provenge)
Sipuleucel-T: Presumed Mechanism of Action Antigen (PAP- GMCSF) is exposed to an Antigen Presenting Cell (APC) APC takes up the antigen Antigen is processed and presented on surface of the APC Fully activated, the APC is now sipuleucel-t and is collected INFUSE PATIENT T-cells proliferate and attack cancer cells sipuleucel-t activates T-cells in the body
Vaccines-Questions While this was a breakthrough in terms of validating a new MOA and validating the principles of immunotherapy, the acceptance and adoption has been very slow: Cumbersome administration Controversial MOA-does it really work the way we thought? Few PSA declines No measurable prolongation in TTP (NB-time to first progression) Other agents with more straightforward MOAs have been developed Cost and initially uncertainty of reimbursement
Will Vaccines Survive? Challenges Takes a long time to have a clinical effect Adjuvant treatments (chemotherapy/hormonal therapy in breast and colon CA) are similar but easier to understand Antiresorptive agents-tangible clinical readout although very modest The Future Vaccine development may develop more robust effects in short term-unlikely in short term in light of MOA Need more efficient production procedures Combining with other agents seems better approach Active hormonal agents or chemotherapy Checkpoint inhibitors Vaccines will have a role in the future 28
Immunotherapy-Looking ahead What will the role of checkpoint blockade be? Ipilimumab PD-1, PDL-1 Will CAR-T cells emerge as a viable therapy? 29
BONE TARGETING-RADIUM-223 30
Radium-223 Targets Bone Metastases Radium-223 acts as a calcium mimic Naturally targets new bone growth in and around bone metastases Radium-223 is excreted by the small intestine Ca Sr Ba Ra
Radium-223 Targets Bone Metastases Range of alpha-particle Radium-223 Bone surface Alpha-particles induce double-strand DNA breaks in adjacent tumour cells 1 Short penetration of alpha emitters (2-10 cell diameters) = highly localized tumour cell killing and minimal damage to surrounding normal tissue Perez Conrad et NY, al. Principles March 4 and 5, 2014 Practice of Radiation Oncology. 5th ed. Lippincott Williams & Wilkins; 2007:103.
ALSYMPCA Phase III Study Design PATIENTS Confirmed symptomatic CRPC 2 bone metastases No known visceral metastases or >3 cm nodes Post-docetaxel or unfit for docetaxel or refusing docetaxel STRATIFICATION Total ALP: < 220 U/L vs 220 Bisphosphonates: Yes vs No Prior docetaxel: Yes vs No R A N D O M I Z E D 2:1 N = 922 TREATMENT 6 injections at 4-week intervals Radium-223 (50 kbq/kg) + Best standard of care Placebo (saline) + Best standard of care
Radium 223-Conclusions Radium-223: Significantly prolonged median OS Significantly prolonged median time to first SRE by 5.5 months Benefit to pre and post chemotherapy patients
Radium-223: Radium 223-Questions Rare declines in PSA Given over 6 months Optimal timing Can it be used earlier successfully and safely Can it be successfully combines with other agents
The Future-Targets How far will precision medicine get us in prostate cancer? What are other viable targets and can they successfully be drugged? 36
The Future-Endpoints What endpoints will be acceptable in the future? OS benefit will become harder to achieve because of multiple approved drugs and will take longer to read out What is the meaning of PFS in prostate cancer? Some agents prolong PFS and not OS and vice versa What is the meaning of MFS in prostate cancer? Does this translate into clinical benefit to the patient? 37
Phase III Study of ARN-509 in Men With Non-Metastatic CRPC (SPARTAN) Patients with non-metastatic CRPC with high-risk disease Enrollment Goal N = 1200 R A N D O M I Z E D 2:1 ARN-509 240 mg daily Placebo Daily Endpoints Primary: Metastasisfree survival Key Secondary: OS rpfs Time to chemo
The Future-Endpoints What endpoints will be acceptable in the future? OS benefit will become harder to achieve because of multiple approved drugs and take longer to read out What is the meaning of PFS in prostate cancer? Some agents prolong PFS and not OS and vice versa What is the meaning of MFS in prostate cancer? Does this translate into clinical benefit to the patient? What meaningful intermediate endpoints that translate into clinical benefit can we develop? CURE SHOULD BE OUR GOAL 39