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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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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
  • Transcript

    • 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.
      • Androgen deprivation therapy (ADT) is standard for new M1 prostate cancer since the 1940s.
        • Although over 90% of pts will respond, not all respond well
      • Several questions have been evaluated over the past few decades including :
        • Surgical vs medical gonadal suppression
        • Combined ADT vs monotherapy
        • Gonadal suppression vs peripheral blockade
        • LHRH-agonists vs Antagonist
        • Intermittent AD vs Continuous AD
        • ADT +/- Other
      Background
    • 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.
      • Geller et al 1984 : Tissue DHT levels and clinical response to hormonal therapy in patients with advanced prostate cancer.
        • 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)
        • “ that tissue DHT levels may be a useful marker for predicting the clinical response of PCa to antiandrogen therapy.”
      • Trachtenberg & Walsh 1982: Correlation of prostatic nuclear AR content with duration of response and survival following hormonal therapy in advanced PCa.
        • Total cellular /cytosolic AR content did not correlate with response.
        • “ higher levels of nuclear AR content predicted better response duration (17 m vs 7 m) and survival (24 m vs 14)”
      Potential Predictors of Response to ADT
    • 5. Evidence for a Role of Inherited Genetic Variants in Response to ADT
        • Several studies evaluated whether response to ADT is associated with germline variants (primarily in hormone related genes)
        • 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
        • 334T polymorphism in SLCO1B3 (testosterone transport gene) variant associated with increase in testosterone uptake and shorter time to AI 2
        • Current studies have limited no. of patients with M1 PCa, not all variants detected are functional, lack of data on non-Caucasian populations
      1. Ross et al., J. Clin Oncol. 2008 ;26(6):842-7. 2. Sharifi et al., BJU Int. 2008 ;102(5):617-21
    • 6. ETS Gene Fusions as a Predictor of Response to ADT Gene 1 ( with androgen-sensitive promoter ) Gene 2 (encoding ETS transcripton factor)
      • ~50% of prostate cancers have ETS gene fusions
        • Androgen-sensitive promoter driving overexpression of ETS transcription factor
        • The predominant ETS fusion (80-90%) is TMPRSS2: ERG
      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. Long Term Survival for S8894 Data as of 10/1/2008 Tangen et al, Clin Prostate Cancer, 2003
    • 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. SWOG Study 9346 (INT-0162) n=3040 Patients (1749 Randomized)
      • Endpoints
      • Primary
        • Determine whether survival with IAD is not inferior to survival with CAD
      • Secondary:
        • QOL
        • PSA changes
        • Correlative studies
    • 10. S9346 Study Information
      • Opened: May 15, 1995
      • Closed: September 1, 2008
      • Final Accrual: 3040 eligible patients from: SWOG, ECOG, NCIC, CALGB, EORTC
      • PSA assessments were pre-specified by the study at scheduled intervals: months 1, 4, 6 and 7 of the induction period and monthly thereafter
      • Primary analysis status: Awaiting survival data maturity, expected summer 2011, DSMC has approved all reported analyses
    • 11. S9346: Exploratory Questions
      • What are the predictors of a response to ADT as reflected by PSA
      • Is the absolute PSA value achieved after ADT predictive of survival in patients with M1 prostate cancer ?
      • Is PSA progression while on ADT predictive of overall survival ?
      • In the PSA era, has there been changing trends in survival of patients with new M1 prostate cancer treated with ADT ?
    • 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. 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. 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. 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. 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. Q#3: PSA-Progression Definitions
      • Any increase (rising trend)
      • Increase by ≥ 50% & ≥ 5 ng/mL
      • Increase by ≥ 25% & ≥ 5 ng/mL (PSAWG’99)
      • Increase by ≥ 25% & ≥ 2 ng/mL (PCWG ‘08)
      • Increase by ≥ 25% and ≥ 5 ng/mL OR Increase by ≥ 50% and ≥ 5 ng/mL (based on “PSA response of 50% decrease” -- PSAWG ’99 )
      • For all definitions, PSA-P must be confirmed ≥ 7 days later
    • 18. PSA-P as a Predictor of Overall Survival (Time Varying Analysis, Multivariate Cox Regression)
    • 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. S9346: Germline Genetic Polymorphisms Associated with Response to ADT
      • ~ 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:
        • Targeting genes involved in hormone synthesis/ metabolism & those associated with advanced PCa & mortality
        • Enriching for functional variants
    • 21.
      • 1. Optimize Response to Induction Androgen Deprivation
      • Increase % of patients achieving undetectable PSA at 7 months:
        • ADT therapy + AT-101 (Anti-Bcl2)
        • S0925: ADT therapy +/- IMC-A12 (Anti-IGF)
      Build on S9346 PSA Based Personalize Therapy Hussain et al. J Clin Oncol; 24:3984-3990 2006
    • 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. Sunset-Lake Michigan

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