Predicting Response to Hormonal Therapy and Survival in Men with Metastatic Prostate Cancer Maha Hussain, M.D., FACP Profe...
<ul><li>Androgen deprivation therapy (ADT) is standard for new M1 prostate cancer since the 1940s. </li></ul><ul><ul><li>A...
PCa, prostate cancer; NR, not recorded; PFS, progression-free survival; MS, median survival; a Goserelin + flutamide arm s...
<ul><li>Geller et al 1984 :  Tissue DHT levels and clinical response to hormonal therapy in patients with advanced prostat...
Evidence for a Role of Inherited Genetic Variants in Response to ADT <ul><ul><li>Several studies evaluated whether respons...
ETS Gene Fusions as  a Predictor of Response to ADT Gene 1  ( with androgen-sensitive promoter ) Gene 2  (encoding ETS tra...
Long Term Survival for S8894 Data as of 10/1/2008 Tangen et al, Clin Prostate Cancer, 2003
Clinical Predictors of Survival   Multivariate Proportional Odds Model  (n = 536) Tangen et al, Clin Prostate Cancer, 2003...
SWOG Study 9346  (INT-0162)  n=3040 Patients (1749 Randomized) <ul><li>Endpoints </li></ul><ul><li>Primary </li></ul><ul><...
S9346 Study Information <ul><li>Opened: May 15, 1995  </li></ul><ul><li>Closed:  September 1, 2008 </li></ul><ul><li>Final...
S9346: Exploratory Questions <ul><li>What are the predictors of a response to ADT as reflected by PSA </li></ul><ul><li>Is...
PSA (ng/mL) Patients (%) Q #1:  Patients with Specified PSA Levels During or at the End of 7 Months ADT Induction (n=1395)...
Multivariate Logistic Regression Model  Predicting Lack of  Achieving a PSA  <  4.0 ng/ml  During Induction Adjusted for O...
Q#2: Predictors of Risk of Death  After 7 Months ADT,  n=1,345   Predictor Univariate Hazard Ratio  (95% CI) P-value Bone ...
Multivariate Proportional Hazards Model:  Testing Effect of PSA  <  4 ng/ml or  <  0.2 at Months 6,7  on Subsequent Risk o...
At Risk PSA ≤ 0.2 ng/ml  453  210  63  0.2 < PSA ≤ 4.0  219  77  20 PSA > 4.0  92  17  7 Hussain et al. J Clin Oncol 2006;...
Q#3: PSA-Progression Definitions   <ul><li>Any increase (rising trend) </li></ul><ul><li>Increase by ≥ 50% & ≥ 5 ng/mL </l...
PSA-P as a Predictor of Overall Survival  (Time Varying Analysis, Multivariate Cox Regression)
Landmark Analysis  S9346 Overall Survival by PSA-P at 7 Months (PCWG 08: ≥ 25% & ≥ 2 ng/mL ) 0% 20% 40% 60% 80% 100% 7 31 ...
S9346:  Germline Genetic Polymorphisms Associated  with Response to ADT  <ul><li>~  530  samples will be genotyped to test...
<ul><li>1.  Optimize Response to Induction Androgen Deprivation </li></ul><ul><li>Increase % of patients achieving undetec...
PSA -Based Personalized Therapy 2. Induce a response in suboptimal  PSA – Responders   About 30% of all registered patient...
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NY Prostate Cancer Conference - M.H. Hussain - Session 5: Predicting response to hormonal therapy and survival in men with metastatic disease

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  • M Hussain: STOP-1, AthensM Hussain 8 Jul 2011 M Hussain 8 Jul 2011
  • M Hussain: STOP-1, AthensM Hussain 8 Jul 2011 M Hussain 8 Jul 2011
  • M Hussain: STOP-1, AthensM Hussain 8 Jul 2011 M Hussain 8 Jul 2011
  • M Hussain: STOP-1, AthensM Hussain 8 Jul 2011 M Hussain 8 Jul 2011
  • NY Prostate Cancer Conference - M.H. Hussain - Session 5: Predicting response to hormonal therapy and survival in men with metastatic disease

    1. 1. Predicting Response to Hormonal Therapy and Survival in Men with Metastatic Prostate Cancer Maha Hussain, M.D., FACP Professor of Medicine & Urology Associate Director For Clinical Research Co-Leader, Prostate Cancer/GU Oncology Program University of Michigan Comprehensive Cancer Center
    2. 2. <ul><li>Androgen deprivation therapy (ADT) is standard for new M1 prostate cancer since the 1940s. </li></ul><ul><ul><li>Although over 90% of pts will respond, not all respond well </li></ul></ul><ul><li>Several questions have been evaluated over the past few decades including : </li></ul><ul><ul><li>Surgical vs medical gonadal suppression </li></ul></ul><ul><ul><li>Combined ADT vs monotherapy </li></ul></ul><ul><ul><li>Gonadal suppression vs peripheral blockade </li></ul></ul><ul><ul><li>LHRH-agonists vs Antagonist </li></ul></ul><ul><ul><li>Intermittent AD vs Continuous AD </li></ul></ul><ul><ul><li>ADT +/- Other </li></ul></ul>Background
    3. 3. PCa, prostate cancer; NR, not recorded; PFS, progression-free survival; MS, median survival; a Goserelin + flutamide arm superior in subjective and objective PFS, OS and rate of cancer deaths Selected Randomized Studies of Combined AD vs Monotherapy in M1 PCa Crawford ED et al. N Engl J Med 1989;321:419–24 Keuppens F et al. Cancer 1993;72(12 suppl):3863–9 Tyrrell C et al. Cancer 1993;72(12 suppl):3878–9 Eisenberger M et al. N Engl J Med 1998;339:1036–42 Author Treatment n PFS (months) OS (months) p Crawford, 1989 Leuprolide + placebo Leuprolide + flutamide 300 303 13.9 16.5 28.3 35.6 0.03 (PFS) 0.03 (OS) Keuppens, 1993 Orchidectomy Goserelin + flutamide a 163 161 Diff (subj) 8.1 Diff (obj) 11.0 Diff (ms) 7 Diff (c) 15 0.009 (PFS) 0.05 (OS) Tyrrell, 1993 Goserelin Goserelin + flutamide 282 287 NR NR 37.7 42.4 0.08 (PFS) 0.14 (OS) Eisenberger, 1998 Orchidectomy + placebo Orchidectomy + flutamide 687 700 18.6 20.4 29.9 33.5 0.26 (PFS) 0.16 (OS)
    4. 4. <ul><li>Geller et al 1984 : Tissue DHT levels and clinical response to hormonal therapy in patients with advanced prostate cancer. </li></ul><ul><ul><li>Higher tumor DHT levels (above 2.5 ng/g) predicted for better response : Average disease-free interval of 24 months vs 9.75 months (P < 0.001) </li></ul></ul><ul><ul><li>“ that tissue DHT levels may be a useful marker for predicting the clinical response of PCa to antiandrogen therapy.” </li></ul></ul><ul><li>Trachtenberg & Walsh 1982: Correlation of prostatic nuclear AR content with duration of response and survival following hormonal therapy in advanced PCa. </li></ul><ul><ul><li>Total cellular /cytosolic AR content did not correlate with response. </li></ul></ul><ul><ul><li>“ higher levels of nuclear AR content predicted better response duration (17 m vs 7 m) and survival (24 m vs 14)” </li></ul></ul>Potential Predictors of Response to ADT
    5. 5. Evidence for a Role of Inherited Genetic Variants in Response to ADT <ul><ul><li>Several studies evaluated whether response to ADT is associated with germline variants (primarily in hormone related genes) </li></ul></ul><ul><ul><li>Inherited variants in CYP19A1 (cytochrome P450), HSD3B1 (enzymes for synthesis of steroid hormones, including progesterone and aldosterone), & HSD17B4 (enzyme involved in peroxisomal fatty acid oxidation) are associated with longer TTP on ADT . However, none of the variants detected result in amino acid sequence changes or are known to be functional in the activity of the gene 1 </li></ul></ul><ul><ul><li>334T polymorphism in SLCO1B3 (testosterone transport gene) variant associated with increase in testosterone uptake and shorter time to AI 2 </li></ul></ul><ul><ul><li>Current studies have limited no. of patients with M1 PCa, not all variants detected are functional, lack of data on non-Caucasian populations </li></ul></ul>1. Ross et al., J. Clin Oncol. 2008 ;26(6):842-7. 2. Sharifi et al., BJU Int. 2008 ;102(5):617-21
    6. 6. ETS Gene Fusions as a Predictor of Response to ADT Gene 1 ( with androgen-sensitive promoter ) Gene 2 (encoding ETS transcripton factor) <ul><li>~50% of prostate cancers have ETS gene fusions </li></ul><ul><ul><li>Androgen-sensitive promoter driving overexpression of ETS transcription factor </li></ul></ul><ul><ul><li>The predominant ETS fusion (80-90%) is TMPRSS2: ERG </li></ul></ul>Karnes et al : The ability of biomarkers to predict systemic progression in men with high-risk prostate cancer treated surgically is dependent on ERG status. Cancer Res 2010
    7. 7. Long Term Survival for S8894 Data as of 10/1/2008 Tangen et al, Clin Prostate Cancer, 2003
    8. 8. Clinical Predictors of Survival Multivariate Proportional Odds Model (n = 536) Tangen et al, Clin Prostate Cancer, 2003 Variable Estimated DR (95% CI) р Value Flutamide vs. Placebo 0.72 (0.47, 1.12) 0.14 Extensive vs. Minimal Disease 2.90 (1.78, 4.73) <0.0001 Performance Status (2/3 vs. 0/1) 1.22 (0.63,2.36) 0.56 Bone Pain (Yes vs. No) 2.61 (1.66, 4.12) <0.0001 Race (Black vs. Others) 1.19 (0.67, 2.10) 0.56 Gleason Score <7 1.0 (reference) - 7 1.84 (0.94, 3.60 0.076 >7 3.79 (2.00, 7.18) <0.0001 Log (PSA) 1.18 (1.03, 1.34) 0.016 Age 1.02 (1.00, 1.05) 0.082
    9. 9. SWOG Study 9346 (INT-0162) n=3040 Patients (1749 Randomized) <ul><li>Endpoints </li></ul><ul><li>Primary </li></ul><ul><ul><li>Determine whether survival with IAD is not inferior to survival with CAD </li></ul></ul><ul><li>Secondary: </li></ul><ul><ul><li>QOL </li></ul></ul><ul><ul><li>PSA changes </li></ul></ul><ul><ul><li>Correlative studies </li></ul></ul>
    10. 10. S9346 Study Information <ul><li>Opened: May 15, 1995 </li></ul><ul><li>Closed: September 1, 2008 </li></ul><ul><li>Final Accrual: 3040 eligible patients from: SWOG, ECOG, NCIC, CALGB, EORTC </li></ul><ul><li>PSA assessments were pre-specified by the study at scheduled intervals: months 1, 4, 6 and 7 of the induction period and monthly thereafter </li></ul><ul><li>Primary analysis status: Awaiting survival data maturity, expected summer 2011, DSMC has approved all reported analyses </li></ul>
    11. 11. S9346: Exploratory Questions <ul><li>What are the predictors of a response to ADT as reflected by PSA </li></ul><ul><li>Is the absolute PSA value achieved after ADT predictive of survival in patients with M1 prostate cancer ? </li></ul><ul><li>Is PSA progression while on ADT predictive of overall survival ? </li></ul><ul><li>In the PSA era, has there been changing trends in survival of patients with new M1 prostate cancer treated with ADT ? </li></ul>
    12. 12. PSA (ng/mL) Patients (%) Q #1: Patients with Specified PSA Levels During or at the End of 7 Months ADT Induction (n=1395) Hussain M et al. J Clin Oncol 2006;24:3984–90
    13. 13. Multivariate Logistic Regression Model Predicting Lack of Achieving a PSA < 4.0 ng/ml During Induction Adjusted for Other Variables in the Model (n=1395) The results are similar for achieving PSA ≤ 4.0 ng/ml at any time during induction Significant (p<0.05) univariate predictors with < 15% missing are included in this model Lack of PSA ≤ 4.0 ng/ml at Months 6 &7 Predictor Odds Ratio (95% CI) P-value Age at Study Entry in 5 Year increments 0.93 (0.86, 1.00) 0.048 Prestudy PSA in 50 unit increments 1.02 (1.01, 1.03) <0.0001 Performance Status 2,3 vs. 0,1 1.88 (1.09, 3.25) 0.023 Gleason sum ≥ 8 1.97 (1.49, 2.60) <0.0001 Bone Pain Present 2.25 (1.70, 2.99) <0.0001
    14. 14. Q#2: Predictors of Risk of Death After 7 Months ADT, n=1,345 Predictor Univariate Hazard Ratio (95% CI) P-value Bone Pain Present 1.91 (1.63, 2.24) <.0001 Performance Status 2,3 vs. 0,1 1.83 (1.39, 2.41) <.0001 Gleason Sum 8 or higher 1.58 (1.34, 1.87) <.0001 Weight Change 1.57 (1.31, 1.88) <.0001 Positive Distant Nodes 1.34 (1.03, 1.73) 0.027 Prestudy PSA in 50 unit increments 1.01 (1.00, 1.01) 0.0024 Any PSA < 4ng/ml 0.26 (0.22, 0.31) <.0001 PSA < 4ng/ml at Months 6&7 0.20 (0.17, 0.23) <.0001 Any PSA < 0.2 ng/ml 0.34 (0.29, 0.40) <.0001 Any PSA < 0.2 ng/ml at Months 6&7 0.30 (0.26, 0.36) <.0001
    15. 15. Multivariate Proportional Hazards Model: Testing Effect of PSA < 4 ng/ml or < 0.2 at Months 6,7 on Subsequent Risk of Death (Estimates and p-values adjusted for other variables in the model) # comparison of these two estimates with a Wald chi-square, p <0.0001. Significant (p<0.05) univariate predictors with < 15% missing included in model Predictor Hazard Ratio (95% CI) P-value Performance Status 2 vs 0,1 1.86 (1.34, 2.60) <0.001 Bone Pain Present 1.50 (1.25, 1.80) <0.0001 Gleason sum ≥8 1.35 (1.13, 1.62) 0.001 Prestudy PSA in 50 unit increments 0.99 (0.99, 1.00) 0.005 0.2 < PSA < 4 ng/ml at Months 6 & 7 0.30 # (0.24, 0.38) <0.0001 PSA ≤ 0.2 ng/ml at Months 6&7 0.17 # (0.13, 0.21) <0.0001
    16. 16. At Risk PSA ≤ 0.2 ng/ml 453 210 63 0.2 < PSA ≤ 4.0 219 77 20 PSA > 4.0 92 17 7 Hussain et al. J Clin Oncol 2006;24:3984–90 Overall Survival by By PSA Status at End of 7 month ADT Induction 0% 20% 40% 60% 80% 100% 0 24 48 72 96 120 Months After End of Induction PSA ≤ 0.2 0.2 < PSA ≤ 4.0 PSA > 4.0 At Risk 602 360 383 Deaths 199 166 322 Median in Months 75 44 13 P < .0001
    17. 17. Q#3: PSA-Progression Definitions <ul><li>Any increase (rising trend) </li></ul><ul><li>Increase by ≥ 50% & ≥ 5 ng/mL </li></ul><ul><li>Increase by ≥ 25% & ≥ 5 ng/mL (PSAWG’99) </li></ul><ul><li>Increase by ≥ 25% & ≥ 2 ng/mL (PCWG ‘08) </li></ul><ul><li>Increase by ≥ 25% and ≥ 5 ng/mL OR Increase by ≥ 50% and ≥ 5 ng/mL (based on “PSA response of 50% decrease” -- PSAWG ’99 ) </li></ul><ul><li>For all definitions, PSA-P must be confirmed ≥ 7 days later </li></ul>
    18. 18. PSA-P as a Predictor of Overall Survival (Time Varying Analysis, Multivariate Cox Regression)
    19. 19. Landmark Analysis S9346 Overall Survival by PSA-P at 7 Months (PCWG 08: ≥ 25% & ≥ 2 ng/mL ) 0% 20% 40% 60% 80% 100% 7 31 55 79 103 127 151 Months After Registration No PSA Progression PSA Progression N 829 200 Events 465 191 Median in months 44 (51) 10 (17) P<.0001
    20. 20. S9346: Germline Genetic Polymorphisms Associated with Response to ADT <ul><li>~ 530 samples will be genotyped to test associations between achieving a serum PSA of less than 4 ng/ml after 7 months of induction ADT & inherited variability in a set of candidate genes: </li></ul><ul><ul><li>Targeting genes involved in hormone synthesis/ metabolism & those associated with advanced PCa & mortality </li></ul></ul><ul><ul><li>Enriching for functional variants </li></ul></ul>
    21. 21. <ul><li>1. Optimize Response to Induction Androgen Deprivation </li></ul><ul><li>Increase % of patients achieving undetectable PSA at 7 months: </li></ul><ul><ul><li>ADT therapy + AT-101 (Anti-Bcl2) </li></ul></ul><ul><ul><li>S0925: ADT therapy +/- IMC-A12 (Anti-IGF) </li></ul></ul>Build on S9346 PSA Based Personalize Therapy Hussain et al. J Clin Oncol; 24:3984-3990 2006
    22. 22. PSA -Based Personalized Therapy 2. Induce a response in suboptimal PSA – Responders About 30% of all registered patients to S9346 had a PSA > 4 at 7 months BUT not rising S1014: Abiraterone acetate for patients not achieving a PSA  4 ng/mL after 7 months of CAD
    23. 23. Sunset-Lake Michigan

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