Urological Cancer Organisation

1. Predicting Subsequent Response to Hormone Therapy Following First-line Androgen Deprivation in Advanced Prostate Cancer S. Turner H. Gurney V. Gebski M. Helmer J. Pohlan M. Cardimone H. Woo M. Drummond A. Brooks Urological CancerOrganisation

2. The problem • 80-90% response rates to first-line AD • 15-30% second-line response (includes anti-androgen withdrawal) • all prostate cancers become ‘hormone refractory’ • increasing options for systemic therapy • limited information about likelihood of subsequent hormone response • Fujikawa et al : 22 patients on flutamide as second-line; bCR on first-line predicted for CR on 2nd line European Urology. 37(2): 218-22, 2000

3. Androgen Independence • androgen receptors • AR gene amplification • ‘promiscuous’ AR • up-regulation of AR expression • regulation of apoptosis • EGFR  endothelin • caspases  HSPs • IGF-I  IAPs Hengartner M.O. Nature 407: 770, 2000

4. Study objectives • to identify clinical parameters that predict for subsequent response to hormone manipulation • to develop a simple clinical algorithm for management following first-line hormones

5. Patients and eligibility • 108 men with proven prostate cancer • 41 (39%) initial radical treatment • managed through a multidisciplinary prostate cancer clinic • PSA response to first-line androgen deprivation • at least one trial of further hormone therapy • regular PSAs available

6. Methods and definitions • data collected retrospectively • PSA ‘response’: > 50% fall from baseline • ‘complete response’: PSA < 4ng/ml • PSA progression: PSA rise triggering change in therapy • multivariate logistic regression analysis of possible predictive factors

7. Potential predictors ofsubsequent response • clinical features at presentation • PSA • Gleason score • demonstrated metastatic disease • ‘curative’ management • features of first-line therapy • type of hormone therapy • duration, rapidity and ‘completeness’ of response

8. Results:features of first-line therapy • type of hormone therapy % • median duration of response 16.7 months (5.0 -102.8) • MAB 14.3 months (5.0 - 95) • castration 18.8 months (5.3 - 102.8)

9. Results:subsequent hormone response • up to 4 successive responses • 9 non-responders to second-line responded to third line included in ‘subsequent responders’ • overall response rate 44% • RR to AA withdrawal 53% • median duration of response 7.8 months (range 0 - 49.4 months)

10. Type of second-line hormone therapy %

11. Predictors of subsequent response

12. Predictors of subsequent response

13. Duration of response: first-line versus subsequent hormone therapy Duration second-line (months) Duration first-line (months)

14. Algorithm for managementfollowing first-line hormones response < 4/12? yes no MAB 1st line? MAB 1st line? EBRT as required yes yes no no withdraw AA symptomatic? withdraw AA add AA progression? yes no progression? bone pain only? observe or experimental yes no chemotherapy or experimental Sr-89, Sm-153

15. Conclusions • antiandrogen withdrawal is a common event • men are less likely to exhibit a useful further response if: (a) slow response to first-line (b) single agent employed initially • recommend this group be observed closely in order to initiate alternative therapies in timely manner