1. Continuous versus Intermittent Androgen Deprivation Therapy for Prostate Cancer Robert Dreicer, M.D., M.S., FACP, FASCO Chair Dept of Solid Tumor Oncology Taussig Cancer Institute Cleveland Clinic Professor of Medicine Cleveland Clinic Lerner College of Medicine

2. A Brief ADT for the Management of Advanced Prostate Cancer Despite 70 + years of understanding the clinical benefit of ADT in advanced prostate cancer, the “optimal” timing of initiating therapy remains unclear VA Cooperative group studies (VACURG)  After 9 years all men with metastatic disease in the control arm ( orchiectomy vs. delayed treatment) received ADT, thus interpreted as early vs. late treatment: no difference in survival, however palliative end points not recorded

3. Intermittent Androgen Suppression for Rising PSA Level after Radiotherapy Pts with a PSA > 3 more than 1 year after primary or salvage EBRT for localized prostate cancer Intermittent rx was given in 8-month cycles, with non-treatment periods determined according to the PSA level The primary end point was OS Secondary end points included QOL, time to castration-resistant disease, duration of non- treatment intervals. Crook, JM, et al. n engl j med 367;10 2012

4. Intermittent Androgen Suppression for Rising PSA Level after Radiotherapy 1386 pts were randomized with a median follow-up of 6.9 years In the intermittent-therapy group, full testosterone recovery occurred in 35% of patients, and testosterone recovery to the trial-entry threshold occurred in 79% Crook, JM, et al. n engl j med 367;10 2012

5. Intermittent Androgen Suppression for Rising PSA Level after Radiotherapy Median overall survival was 8.8 years in the intermittent-therapy group versus 9.1 years in the continuous-therapy group (hazard ratio for death, 1.02; 95% confidence interval, 0.86 to 1.21) Intermittent therapy provided potential benefits with respect to physical function, fatigue, urinary problems, hot flashes, libido, and erectile function Crook, JM, et al. n engl j med 367;10 2012

7. Intermittent versus Continuous Androgen Deprivation in Prostate Cancer 3040 metastatic patients were enrolled, of whom 1535 were included in the analysis The median follow-up period was 9.8 years Median survival was 5.8 years in the continuous- therapy group and 5.1 years in the intermittent- therapy group (HR ratio for death with IT, 1.10; 90% confidence interval, 0.99 to 1.23) IT was associated with better erectile function and mental health respectively) at month 3 but not thereafter Hussain M, et al. N Engl J Med 368;14 2013

8. Hussain M, et al. N ENGL J MED 368;14 2013

9. minimal disease was disease confined to the spine, pelvic bones, or lymph nodes

10. Commentary The Canadian study is silent on the critical question i.e. early ADT SWOG intergroup study is statistically inconclusive, but certainly non an endorsement of routine use of IT The recent initial report of E 3805 will impact to some extent on management, as it consisted of continuous ADT