1. Several randomized controlled trials have consistently shown that the addition of neoadjuvant hormonal therapy (NHT) to external beam radiotherapy (EBRT) improves outcomes for men with intermediate-risk or high-risk localized prostate cancer. 2. The optimal timing and duration of NHT is still unclear, but most evidence suggests that 2-3 months of NHT combined with EBRT is adequate for intermediate-risk patients. Longer adjuvant hormonal therapy may benefit high-risk patients. 3. While the sequence of NHT relative to EBRT may impact outcomes, short-term NHT combined with EBRT appears beneficial overall based on multiple randomized trials.

1. Neadjuvant Hormonal Therapy in Men Being Treated with Radiotherapy for Localized Prostate Cancer Mack Roach III, MD Professor, Radiation Oncology & Urology University of California, San Francisco UCSF/Mt. Zion NCI-Designated Comprehensive Cancer Center San Francisco, California

3. All Patients Pilepich et al. Proc Am Soc Clin Oncol . 2003;22:381(Abs1530). 0.0053 22% 13% 17% 9% Prostate Cancer Death 0.0043 38% 71% 47% 76% Absolute Survival <0.0001 22% 44% 36% 62% NED Survival <0.0001 39% 29% 25% 15% Distant Failure <0.0001 39% 30% 23% 15% Local Failure P 10 yr 5 yr 10 yr 5 yr RT+HT at Relapse (n=468) RT+ Adj LHRH (n=477)

4. Absolute Survival Central Gleason 7 Years from Randomization Percent (%) 0 3 6 9 12 RT+Immediate Hormones RT+Hormones at Relapse P =0.042 Pilepich et al. Proc Am Soc Clin Oncol . 2003;22:381(Abs1530). 0 25 50 75 100

5. Absolute Survival Central Gleason 8-10 P =0.0061 Pilepich et al. Proc Am Soc Clin Oncol . 2003;22:381(Abs1530). Years from Randomization Percent (%) 0 3 6 9 12 RT+Immediate Hormones RT+Hormones at Relapse 0 25 50 75 100

12. Randomized Trials Using NHT Progression-free survival advantage with short follow-up 23 ng/mL 28% NR NR 33% NR NR 646 / 0 0 1291 / 645 Roach (2003) RTOG 9413 Disease-specific survival and Overall for GS = 8-10. 20 ng/mL 40% 35% 26% 0 45% 55% 0 / 753 0 1514 / [761 vs 753 (+adjuvant)] Hanks (2003) RTOG 9202 Survival advantage for GS <7, Included N+ patients 26 ng/mL - - 28% 0% 30% 70% 0 / 0 230 456 / 226 Pilepich (2001) RTOG 8610 Comments: PreTx PSA (Med)^ GS# 2-6 7 8-10 T-Stages T1-2b T2c T3-4 Short / Long Term Adjuvant HT (no.) No HT Total / No. patients with NHT +/- concurrent HT First Author (Year)

13. Phase III RTOG Trial 8610 of Androgen Deprivation Adjuvant to Definitive Radiotherapy in Locally Advanced Carcinoma of the Prostate 0 10 20 30 40 50 60 70 80 90 100 0 1 2 3 4 5 6 7 8 RT + NHT RT alone Survival (%) Gleason 2-6 Years P =0.015 Pilepich MV et al. Int J Radiat Oncol Biol Phys 2001; 50(5): 1243-52.

14. RTOG 92-02 Arm 1: goserelin and flutamide 2 months before and during standard RT (STAD) Arm 2: goserelin and flutamide 2 months before and during standard RT, followed by goserelin alone for 24 months (LTAD) T2c-T4 PreRx PSA <150 ng/mL R A N D O M I Z E

15. Overall Survival All Patients RTOG 9202 Years since randomization Survival rate STAD+RT LTAD+RT 0 . 0 0 . 2 0 . 4 0 . 6 0 . 8 1 . 0 0 1 2 3 4 5 6 7 8 159 22 169 28 P =0.73

16. 9202 Prostate Cancer Survival 0 . 0 0 . 2 0 . 4 0 . 6 0 . 8 1 . 0 0 1 2 3 4 5 6 7 8 Failed/Total STAD+RT 87/762 LTAD+RT 55/755 Years Since Randomization Survival Rate P =0.006

17. RTOG 9413 Scheme: Timing First Month HT T HT HT HT none none EBRT EBRT none none HT HT HT HT EBRT EBRT Arms 1 & 2 Arms 3 & 4 2 months different Rx duration Second Month Third Month Fourth Month Fifth Month Sixth Month

18. Progression-Free Survival Arm 2 vs Arm 4 (RTOG 9413) Years since randomization Approximately two months N&CHT+PO RT 0 . 0 0 . 2 0 . 4 0 . 6 0 . 8 1 . 0 0 1 2 3 4 5 Non-failure rate PO RT+AHT

19. Progression-Free Survival Arm 1 vs Arm 2 (RTOG 9413) Years since randomization 0 . 0 0 . 2 0 . 4 0 . 6 0 . 8 1 . 0 0 1 2 3 4 5 Non-failure rate N&CHT+WP RT N&CHT+PO RT

20. Randomized Trials Using NHT Overall no difference in PSA failure rates ~10 ng/mL 50% 38% 11% ~52% ~35% 13% 0 0 378 / 378 (3 vs 8 months) Crook (2004) Princess Margaret Overall & disease specific survival advantage 11 ng/mL 35% 59% 15% 100%, 0% 0 / 0 102 206 / 104 D’Amico (2004) Harvard Study PSA failure rates higher with EBRT alone, otherwise no difference s 10 ng/mL 12 ng/mL (7-10) = 26%^ (7-10) = 28% NA NA 30% NA NA 13.5% 55 / 0 148 / 0 43 0 161 / 63 296 / 148 (3 months) Laverdeire (2004) Quebec Trials Comments: PreTx PSA (Med) GS# 2-6 7 8-10 T-Stages T1-2b T2c T3-4 Short / Long Term Adjuvant HT (no.) No HT Total / No. patients with NHT +/- concurrent HT First Author (Year)

21. Laverdiere Scheme: Timing of Hormonal Therapy (HT) Arm (no.) Group 1 Study 1 EBRT EBRT none none none none Group 2 Study 1 HT HT H T EBRT EBRT none Group 3 Study 1 HT HT HT HT EBRT HT EBRT HT* Maximum field size 10 x 10 cm to 64 Gy. *HT = Combined Androgen Blockade with a LHRH & Flutamide *10 months. Laverdiere J et al. J Urol 2004; 171(3): 1137-40. First Month Second Month Third Month Fourth Month Fifth Month Sixth- Tenth

22. The Efficacy and Sequencing of Short Course of Androgen Suppression on Freedom from Biochemical Failure When Administered with Radiation Therapy for T2-T3 Prostate Cancer 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 0 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0 5.5 6.0 6.5 7.0 7.5 8.0 Months bNED Survival (%) 3 month NHT N&CHT+Adj (10 months) EBRT Alone Laverdiere J et al. J Urol 2004; 171(3): 1137-40.

23. Laverdiere Scheme: Timing of Hormonal Therapy (HT) Group 1 Study 2 HT HT HT HT EBRT HT EBRT none Group 2 Study 2 HT HT HT HT EBRT HT EBRT HT* *HT = Combined Androgen Blockade with a LHRH & Flutamide Maximum field size 10 x 10 cm to 64 Gy. *10 months. Laverdiere J et al. J Urol 2004; 171(3): 1137-40. Arm (no.) First Month Second Month Third Month Fourth Month Fifth Month Sixth- Tenth

24. 6-Month Androgen Suppression Plus Radiation Therapy vs Radiation Therapy Alone for Patients with Clinically Localized Prostate Cancer 0 10 20 30 40 50 60 70 80 90 100 0.0 1.0 2.0 3.0 4.0 5.0 6.0 3D-CRT + Hormones 3D-RT alone Survival (%) Years P =0.04 D’Amico et al. JAMA. 2004;292:821-827.

27. Model and Literature on the Impact of Short-Term NHT and EBRT on Outcome in Treatment of Clinically Localized from Prostate Cancer RTOG 9413 RTOG 9202 RTOG 8610 Princess Margaret Quebec Studies Harvard Study Relative Extent of Disease -50 -40 -30 -20 -10 0 10 20 30 40 Low Risk Intermediate High Risk Very High Risk Dz Impact of Short Term NHT on Survival Impact of Disease on survival Net Impact of Dz & HT