Prostate cancer Management of metastatic castration sensitive cancer

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1 18 th Annual Advances in Oncology

2 Prostate cancer Management of metastatic castration sensitive cancer Urothelial carcinoma Non-muscle invasive urothelial carcinoma Updates in metastatic urothelial carcinoma management Renal cell carcinoma Evolution of front-line therapy in mrcc

3 Prior to 2017: Androgen deprivation therapy (ADT) [continuous or intermittent] STAMPEDE and CHAARTED trials established role of ADT + docetaxel Some suggestion of increased benefit with heavy disease burden CJ Sweeney et al, NEJM 2015

4 Cyp17 inhibition Approved for metastatic castration resistant prostate cancer (CRPC) based on results of Phase III studies in docetaxel-pretreated and docetaxel-naïve patients Studied in castration sensitive prostate cancer in two studies LATITUDE- aggressive metastatic disease STAMPEDE- high risk locally advanced to metastatic disease

5 Patients Treatment Metastatic castration sensitive prostate cancer Two or more: - Gleason > 8 - > 3 bony lesions - Visceral metastases Randomize 1:1 Arm A Androgen deprivation therapy + abiraterone + prednisone Arm B Androgen deprivation therapy alone Treatment until radiographic progression Primary endpoints: - Overall survival - Radiographic progressionfree survival K. Fizazi et al NEJM 2017

6 Median OS benefit: Not reached v 34.7 months HR = 0.62 (95% CI ); p=0.001 Radiographic PFS 33.0 v 14.8 months HR= 0.47 (95% CI: ); p=0.001 K Fizazi et al. NEJM 2017

7 Patients Treatment Metastatic OR node positive OR locally advanced high risk with > 2 of: - T3 or T4 - Gleason PSA > 40 Randomize 1:1 Arm A Androgen deprivation therapy + abiraterone + prednisolone Treatment until PSA, clinical or radiographic progression (or for 2 years if nonmetastatic) OR relapsed disease treated with ADT < 12 months and >12 months since treatment Arm B Androgen deprivation therapy alone Primary outcome: Overall Survival ND James et al NEJM 2017

8 Characteristic ADT alone (n=957) ADT alone + abi (n=960) Median age (range) 67 (62-72) 67 (63-72) Node-negative non-metastatic 256 (27%) 253 (26%) Node-positive non-metastatic 187 (20%) 182 (19%) Metastatic 476 (50%) 465 (48%) Previously treated nonmetastatic 12 (1%) 25 (3%) Previously treated metastatic 26 (3%) 35 (4%) No hypertension 571 (60%) 557 (58%) Hypertension but fit for trial 385 (40%) 401 (42%) ND James NEJM 2017

9 OS HR: 0.63 (95% CI: ); p<0.001 Treatment failure HR: 0.29 (95% CI: ); p <0.001 ND James NEJM 2017

10 ADT +/- docetaxel Newly diagnosed metastatic prostate cancer patients Randomize Node positive only allowed if: 1 extra pelvic LN > 2cm OR 1 pelvic LN > 2 cm + 1 extrapelvic LN > 1 cm ADT + abi/pred +/- docetaxel ADT +/- docetaxel + local RT ADT+ abi/pred +/- docetaxel + local RT Treatment until progression Target accrual n=916 Primary endpoint OS Started enrollment Expecting 5.5 years from first accrual NCT

11 For castration sensitive prostate cancer patients ADT ADT + docetaxel (for 6 cycles) ADT + abiraterone + prednisone Biomarkers to identify who most benefits given Cost considerations Toxicities associated with docetaxel, abiraterone + prednisone Potential for limiting treatments in castration resistant setting

12 Non-muscle invasive urothelial carcinoma treatment SWOG S0337 Metastatic urothelial carcinoma (muc) First-line treatment with ddmvac or gemcitabine + cisplatin Second-line treatment: atezolizumab accelerated approval in May 2016 for platinum-refractory muc Keynote 045

13 Patients Treatment Cystoscopy with new diagnosis, suspected low grade nonmuscle invasive bladder cancer Randomize 1:1 One instillation of intravesicular gemcitabine (2 g/100 ml saline) Instillation of saline alone Cystoscopy every 3 months for 2 years, then every 6 months for 2 years Primary endpoint: time to recurrence (TTR) E Messing et al AUA 2017

14 N=406 Intention to treat analysis Intravesicular gemcitabine with decreased risk of recurrence compared to saline: HR = 0.66; 95% CI , p=0.010 In low-grade non-muscle invasive urothelial cancer patients enrolled HR = 050; 95% CI , p=0.001 E Messing AUA 2017

15 Patients Treatment Advanced urothelial carcinoma with predominantly transitional cell histology - Progressed after 1-2 platinumbased CT - ECOG 0-2 Randomize 1:1 Pembrolizumab 200 mg IV q3weekly Paclitaxel 175 mg/m2 IV q3weekly OR docetaxel 75 mg/m2 IV q3weekly OR vinflunine 320 mg/m2 IV q3weekly Treatment for 2 years or until progression, toxicity or withdrawal of consent Primary outcome: Overall Survival Progression- Free Survival DF Bajorin et al ASCO 2017

16 HR: 0.70 (95% CI ) P= OS (%) Median OS, mos (95% CI) 44.4% 30.2% Pembro (n = 270) 10.3 ( ) 36.1% 20.5% CT (n = 272) 7.4 ( ) 20 Pembro CT Mos DF Bajorin et al. ASCO 2017

17 Drug Target Efficacy Phase Type & Date of approval atezolizumab Anti-PD- L1 ORR: 14.8% (95% CI: ) nivolumab Anti-PD-1 ORR: 19.6% (95% CI: ) avelumab durvalumab Anti-PD- L1 Anti-PD- L1 ORR: 13.3% (95% CI: ) ORR: 17.0% (95% CI: ) pembrolizumab Anti-PD-1 HR: 0.70 (95% CI ); p= I/II I/II I/II I/II III Accelerated May 2016 Accelerated Feb 2017 Accelerated May 2017 Accelerated May 2017 Full May 2017

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19 CheckMate 214: Study design Patients Treatment Treatment-naïve advanced or metastatic clearcell RCC Measurable disease KPS 70% Tumor tissue available for PD- L1 testing Randomize 1:1 Stratified by IMDC prognostic score (0 vs 1 2 vs 3 6) Region (US vs Canada/Europe vs Rest of World) Arm A 3 mg/kg nivolumab IV + 1 mg/kg ipilimumab IV Q3W for four doses, then 3 mg/kg nivolumab IV Q2W Arm B 50 mg sunitinib orally once daily for 4 weeks (6-week cycles) Treatment until progression or unacceptable toxicity Escudier et al ESMO 2017

20 Median duration of response, months (95% CI) Patients with ongoing response, % Outcome NIVO + IPI N = 425 N = 847 SUN N = 422 Confirmed ORR, % (95% CI) 42 (37 47) 27 (22 31) Confirmed BOR, a % Complete response Partial response Stable disease Progressive disease Unable to determine/not reported P < Duration of Response (Probability) NIVO + IPI NR (21.8 NE) 72 SUN 18.2 (14.8 NE) No. at Risk NIVO + IPI SUN Months Escudier et al ESMO 2017

21 Median OS, months (95% CI) NIVO + IPI NR (28.2 NE) Overall Survival (Probability) No. at Risk NIVO + IPI SUN SUN 26.0 (22.1 NE) Hazard ratio (99.8% CI), 0.63 ( ) P < Months Escudier et al ESMO 2017

22 Trial/ drugs Comparator N Results Phase JAVELIN Avelumab + axitinib IMmotion 150 Atezolizumab + bevacizumab Study 111 Lenvatinib + pembrolizumab Echo- 202/Keynote- 037 Epocadostat + pembrolizumab None 55 ORR: 58.2% ( ) Atezolizum ab OR Sunitinib 305 PFS HR: 0.64; p=0.095 None 30 ORR: 63% (44-80) None 19 ORR: 47% I Ib II II

23 Combination Comparators planned n Bevacizumab + atezolizumab Axitinib + avelumab Axitinib + pembrolizumab Lenvatinib + pembrolizumab Nivolumab + ipilimumab + cabozantinib Endpoint Expected to finish Sunitinib 900 PFS 2020 Sunitinib 583 PFS 2020 Sunitinib 840 PFS 2020 Lenvatinib + everolimus OR Sunitinib Nivolumab + ipilimumab OR Sunitinib 735 PFS 2020?? PFS 2021

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