Rationale Design of Combination Therapy in Prostate Cancer: Targeting the AR and PI3K pathways Brett S Carver, MD Assistant Attending, Department of Surgery/Urology
Prostate Cancer Therapeutics: A Changed Landscape As Six Phase 3 Trials Show a Survival Benefit TARGETING AR Clinically Localized Disease Noncastrate Castration resistant Diagnoses: 217,730 Deaths: 32,050 Rising PSA Clinical Metastases: Noncastrate Non- Metastatic CRPC Castration Resistant Metastatic Pre- Provenge 2010 Castration Resistant Metastatic 1 st -Line Docetaxel 2004 Castration Resistant Metastatic Post- Cabazitaxel 2010 Abiraterone 2010 Alpharadin 2011 Abiraterone 2012 Alpharadin 2011 MDV3100 2012 Modified from Scher and Heller. Urology. 2000.
Mechanisms of Resistance to AR inhibition
The Survival Benefits Were Shown Across the Clinical Spectrum of Castration Resistant Disease Trial/ Agent Approved IMPACT (Provenge vaccine) 2010 TAX327 (Docetaxel) 2004 TROPIC (Cabazitaxel) 2010 COU-AA-301 (Abiraterone acetate) 2011 No. Disease state Comparator 512 Pre-chemo Asymptomatic 1006 First-line 755 ALYMPTA 922 Post-Chemo Symptoms 1195 Post-Docetaxel Pre and Post Symptomatic Hazard Ratio Survival (Months) P value Placebo 0.775 25.8 vs. 21.7 0.032 Mitoxantrone Prednisone Mitoxantrone Prednisone Placebo Prednisone 0.76 18.9 vs. 16.5 0.009 0.70 15.1 vs. 12.7 <0.0001 0.646 14.8 vs. 10.9 <0.0001 Placebo.695 14.0 vs. 11,2 0.00085 MDV3100 1199 Post-Docetaxel Placebo 0.631 18.4 vs. 13.6 <0.0001
MSKCC Prostate Cancer Genomics Project http://cbio.mskcc.org/cancergenomics CGH: 232 (195 non-flat) mrna: 156 mirna: 113 DNA seq: 160 (103 matched normal) All platforms: 103 Taylor, Cancer Cell 2010
Activation of the PI3K pathway is enriched in castrate resistant metastatic CaP Attractive therapeutic target BKM120 (Novartis) BEZ235 (Novartis) MK2206 (Merck) AZD8055 (AstraZenaca) RAD001* (Novartis) Taylor, Cancer Cell 2010
Evaluating novel targeted therapies in the context of specific genetic events: Utility of GEM mouse models T0 T35 Castrate PB-MYC
Inhibition of the PI3K pathway blocks cell proliferation in Pten loss prostate cancer AR target gene expression in Pten lox//lox mice Carver, Cancer Cell 2011
Feedback regulation of the PI3K pathway Rapamycin Untreated AKTi BT-474 xenograft 1400 Untreated Chandarlapaty, Cancer Cell 2011 O'Reilly, Cancer Research 2006 P-INSR, P-IGF-1R Untreated Mean tumor volume (mm 3 ) 1200 1000 800 600 400 Lapatinib 150mg/kg TIW AKTi-1/2 100mg/kg TIW Combination AKTi 200 0 15 25 35 day
Inhibition of the PI3K promotes AR activity in a HER2/3 (RTK) dependent manner Carver, Cancer Cell 2011
Inhibition of AR results in activation of PI3K signaling through dysregulation of the AKT phosphatase PHLPP FKBP5 serves as a scaffold for PHLPP and AKT interaction Carver, Cancer Cell 2011
Pten loss is associated with a repressed AR gene signature prtk Array: Pten-/-:WT prostate prtk Fold Change ERBB2 0.6 ERBB3 0.6 IGF-1R 0.8 EPHA7 0.4 MET 0.5 Carver, Cancer Cell 2011
PI3K AR feedback regulation in human prostate cancer Carver, Cancer Cell 2011 AR responsive gene sets are repressed in PTEN loss prostate cancers by GSEA
A Phase I/II Study of Gefitinib and Everolimus in Castration Resistant Prostate Cancer: Disappointing Clinical Activity of mtor Inhibition in CRPC 700 PSA 600 STOP Everolimus 500 PSA (ng/ml) 400 300 START Everolimus 200 100 0 6/1/2005 7/1/2005 8/1/2005 9/1/2005 10/1/2005 11/1/2005 12/1/2005 PI: Rathkopf Also observed with IGF1R/Temsirolimus and AKT inhibitor.
Rationale for combined PI3K and AR inhibition in prostate cancer: Targeting oncogenic feedback pathways Carver, Cancer Cell 2011
Therapeutic benefit of mtorc1 and ER inhibition in Breast Cancer X Creighton, Breast Cancer Res 2010 724 patients with hormone-receptor positive advanced breast cancer who had recurrence or progression while receiving previous therapy with a nonsteroidal aromatase inhibitor in the adjuvant setting or to treat advanced disease Baselga BOLERO 2, NEJM 2012
Moving Forward Reciprocal feedback regulation of PI3K and AR pathways necessitates combination therapy Development of clinical trials evaluating PI3K/AR inhibition, tissue validation studies PSA may not be a useful endpoint SU2C clinical trial evaluating ARN509 + everolimus in patients with castrate resistant prostate cancer Dissecting out which nodes of the PI3K pathway are critical for inhibition Defining the impact of concomitant genetic alterations on response to PI3K/AR pathway inhibition BKM120 (Novartis) BEZ235 (Novartis) MK2206 (Merck) INK128 (Intellikine) RAD001* (Novartis)
Sawyers Lab Caren Chapinski John Wongvipat Haley Hieronymus Yu Chen Rosen Lab Sarat Chandarlapaty Animal Imaging Carl Le Jason Koutcher Clinical Trials Dana Rathkopf Howard Scher