NRGGU 009 Parallel Phase III Randomized Trials For

NRG-GU 009 Parallel Phase III Randomized Trials For High Risk Prostate Cancer Evaluating De-Intensification For Lower Genomic Risk and Intensification of Concurrent Therapy for Higher Genomic Risk with Radiation (Predict-RT*) *Prostate RNA Expression/Decipher To Individualize Concurrent Therapy with Radiation Paul Nguyen, MD & Oliver Sartor, MD NRG Semi-Annual Meeting July 17, 2020 @NRGOnc NRG Oncology

STUDY TEAM Paul Nguyen (Co-PI), Oliver Sartor (Co- PI), Felix Feng (NRG GU Chair) Radiation Oncology Co-Chairs: Karen Hoffman, Jason Efstathiou, Scott Morgan Medical Oncology Co-Chairs: Rana Mc. Kay, Tanya Dorff Quality of Life Co-Chair: James Yu Brachytherapy Co-Chair: Daniel Krauss Translational Co-Chairs: Robert Den, Phuoc Tran Urology Co-Chair: Todd Morgan Imaging Co-Chairs: Ashesh Jani, Thomas Hope Imaging TRP Co-Chairs: Daniel Spratt, William Hall NRG-GU 009

PREDICT-RT IS COMING SOON! PREDICT-RT TRIAL JULY 3 (Only on Disney+) FALL 2020 At Your Institution! NRG-GU 009

PREDICT-RT GOALS USE DECIPHER TO PERSONALIZE THERAPY FOR HIGH RISK OR NODE-POSITIVE PROSTATE CANCER SOC: RT+2 Years of ADT For Lower Genomic Risk, can we DEINTENSIFY to RT+ 1 year of ADT: Better QOL! For Higher Genomic Risk or N+, should we INTENSIFY to RT+2 years of ADT + Abi/Apa: More Cures!! NRG-GU 009

WE CAN USE DECIPHER TO STRATIFY BIOPSY SPECIMENS 5 -year metastasis by Biopsy Decipher Score for NCCN Int/High Risk Treated Mainly w/RT+ADT High – 23. 4% Intermediate- 9. 3% Low – 5. 0% Nguyen et al, Eur Urol 2018 NRG-GU 009

Genomics Can Enhance Risk Stratification Beyond Standard NCCN/D’Amico Groups Spratt JCO 2018 NRG-GU 009

Creation of Clinical-Genomic Risk Groups Spratt JCO 2018 NRG-GU 009

0. 9 0. 7 0. 8 0. 75 -0. 85 0. 62 -0. 68 20 - 40% improvement over NCCN 0. 5 C-Index for Metastasis Clinical-Genomic Risk Groups Improve C-Index over NCCN/D’Amico Groups Years Spratt JCO 2018 NRG-GU 009

Benefit of Longer Duration ADT on survival has been very modest, even in Genomically Unselected High Risk Patients 5 -yr 4 vs. 28 6 vs. 36 10 -yr 5% PCSM 3. 8% OS 6 vs. 18 3% PCSM 18 vs 36 0% OS Major opportunity to use genomics to safely halve ADT duration for men in lower 2/3 of genomic risk who are unlikely to be in the 3 -5% who benefit from standard long-term ADT. NRG-GU 009

SCHEMA Screening/Eligibility NCCN High Risk Decipher Score Bottom 2/3 N=1692 Decipher Score Upper 1/3 (or N 1) N=786 De-Intensification Study Stratify 1. Decipher Score 2. Boost type (EBRT vs. Brachy) 3. Pelvic Treatment (Y/N) Stratify 1. Boost type (EBRT vs. Brachy) 2. 2. Pelvic Treatment (Y/N) Randomize RT+ 12 Mos ADT RT+ 24 Mos ADT Randomize 24 Mos ADT + RT +24 Mos Abiraterone +24 Mos Apalutamide NRG-GU 009

PRIMARY HYPOTHESES • De-Intensification Trial: Reduction of ADT from 24 to 12 months will result in a non-inferior metastasis-free survival for men with lower genomic risk • Intensification Trial: Addition of Abiraterone and Apalutamide to 24 months of ADT will improve metastasis-free survival for men with higher genomic risk NRG-GU 009

CORRELATIVE STUDIES • QOL: • Improved Hormonal Bother & Sexual Function for 12 vs. 24 • Non-Inferior Fatigue for ADT/Abi/Apa vs. ADT • Also Tracking Depression, Neurocognition, Global QOL, EPIC • Translational: • Re-Analyses of Data from Decipher (Affymetrix) Platform • Cardiovascular Markers • Imaging: • 200 patients on Intensification Trial Will Get with Axumin Scans Before and After Therapy Paid by Blue Earth NRG-GU 009

NRG-GU 009

• 2600 is a Lot of Patients • But RTOG 09 -24 just successfully enrolled over 2500 patients • NRG sites have been very successful at accruing high risk patients NRG-GU 009

WHY ENROLL? NRG-GU 009

Increasing Use of Surgery, Decreased RT for High Risk We need to offer our high risk patients something innovative and personalized to counter this trend Mahal BM…. . Nguyen PL JAMA 2019 NRG-GU 009

WHY ENROLL? • Offer patients an innovative trial • All patients get free Decipher • Lower-risk patients get a chance at much less toxicity • Higher-risk patients get a chance to use novel drugs and a chance at more cures • We all get a chance to advance the field beyond a one size fits all to a precision approach to future care NRG-GU 009

POLL QUESTION Will you enroll patients on NRG-GU 009 PREDICT-RT? 1) Yes !!! 2) No NRG-GU 009