AR-Targeted Agents in Prostate Cancer

PRACTICE AID AR-Targeted Agents in Prostate Cancer

Indication, Dosing, and AEs in AR-Targeted Agents for Prostate Cancer

Apalutamide1 Darolutamide2 Enzalutamide3

Indication Indication Indication • Patients with metastatic CSPC and nmCRPC • Patients with nmCRPC • Patients with CRPC and metastatic CSPC

Dosing Dosing Dosing • 240 mg orally once daily; swallow whole with • Two 300-mg tablets administered orally twice • 160 mg orally once daily; swallow whole with or without food daily; taken with food or without food • Should also receive a GnRH analog concurrently • Should also receive a GnRH analog concurrently • Should also receive a GnRH analog concurrently or have had a bilateral orchiectomy or have had a bilateral orchiectomy or have had a bilateral orchiectomy

AEs in ≥10% of Patients AEs in ≥2% of Patients AEs in ≥10% of Patients • Fatigue, arthralgia, rash, decreased appetite, • Fatigue, pain in extremity, and rash • Asthenia/fatigue, back pain, hot ush, falls, weight decrease, hypertension, hot ush, constipation, arthralgia, decreased appetite, diarrhea, and fracture diarrhea, and hypertension

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AR-Targeted Agents in Nonmetastatic CRPC

SPARTAN4,5,8 ARAMIS7,9 PROSPER6,10,11 • nmCRPC • nmCRPC • nmCRPC • Rising PSA despite castrate testosterone • Castrate level of serum testosterone • Rising PSA despite castrate testosterone level (≤50 ng/dL) (<50 ng/dL) level (≤50 ng/dL) • PSADT ≤10 mo • Baseline PSA ≥2 ng/mL; PSADT ≤10 mo • Baseline PSA ≥2 ng/mL; PSADT ≤10 mo

Apalutamide Placebo 1° endpoint: Darolutamide Placebo 1° endpoint: Enzalutamide Placebo 1° endpoint: vs MFS vs MFS vs MFS + ADT + ADT Median OS, mo + ADT + ADT Median OS, moa + ADT + ADT Median OS, mo

Apalutamide Placebo Enzalutamide Placebo MFS MFS Darolutamide Placebo MFS 40.5 mo 16.2 mo 40.4 mo 18.4 mo 36.6 mo 14.7 mo Enzalutamide Placebo Apalutamide Placebo mOS Darolutamide Placebo mOS mOS 73.9 mo 59.9 mo NR NR 67.0 mo 56.3 mo

AR-Targeted Agents in Metastatic CSPC

TITAN12,13 ARASENS14 ARCHES15-17 • mCSPC • mCSPC • mCSPC (conrmed by bone scan, CT, or MRI) • Newly diagnosed or previously treated • Newly diagnosed • ECOG PS 0 or 1 • ECOG PS 0 or 1 • ECOG PS 0 or 1

1° endpoint: Darolutamide Placebo Apalutamide Placebo Enzalutamide Placebo vs Median rPFS + ADT vs + ADT 1° endpoint: vs 1° endpoint: + ADT + ADT + ADT + ADT and OSb + docetaxel + docetaxel OS rPFS

Ongoing; primary completion date: rPFS Apalutamide Placebo rPFS Enzalutamide Placebo Not Reached 21.1 mo August 2022 Not Reached 19.45 mo

a Final analysis after 254 deaths (15.5% darolutamide and 19.1% placebo). b OS not reached in apalutamide or placebo groups as of May 15, 2019. ADT: androgen deprivation therapy; AE: adverse event; AR: androgen receptor; CRPC: castration-resistant prostate cancer; CSPC: castration-sensitive prostate cancer; CT: computed tomography; ECOG PS: Eastern Cooperative Oncology Group Performance Status; GnRH: gonadotropin- releasing hormone; HSPC: hormone-sensitive prostate cancer; MFS: metastasis-free survival; mHSPC: metastatic hormone-sensitive prostate cancer; nmCRPC: nonmetastatic castration-resistant prostate cancer; PSA: prostate-specific antigen; PSADT: prostate-specific antigen doubling time; rPFS: radiographic progression-free survival. 1. http://www.janssenlabels.com/package-insert/product-monograph/prescribing-information/ERLEADA-pi.pdf. 2. http://labeling.bayerhealthcare.com/html/products/pi/Nubeqa_PI.pdf. 3. https://www.astellas.us/docs/12A005-ENZ-WPI.PDF. 4. Small EJ et al. Ann Oncol. 2019;30:1813- 1820. 5. Smith MR et al. N Engl J Med. 2018;378:1408-1418. 6. Hussain M et al. N Engl J Med. 2018;378:2465-2474. 7. Fizazi K et al. American Society of Clinical Oncology 2019 Genitourinary Cancers Symposium (ASCO GU 2019). Abstract 140. 8. Small EJ et al. 2020 ASCO Virtual Scientific Program (ASCO 2020). Abstract 5516. 9. Fizazi K et al. ASCO 2020. Abstract 5514. 10. Sternberg CN et al. ASCO 2020. Abstract 5515. 11. Sternberg CN et al. N Engl J Med. 2020;382:2197-2206. 12. Chi KN et al. N Engl J Med. 2019;381:13-24. 13. https://clinicaltrials.gov/ct2/show/NCT02489318. 14. https://clinicaltrials.gov/ct2/show/NCT02799602. 15. https://clinicaltrials.gov/ct2/show/NCT02677896. 16. Armstrong AJ et al. ASCO GU 2019. Abstract 687. 17. https://www.ascopost.com/issues/april-10-2019-supplement-conference-highlights-gugi-2019/interim-analysis-of-the- arches-trial. Access the activity, “How I Think, How I Treat: Learning to Navigate the Modern Prostate Cancer Landscape” at PeerView.com/JGU40 PRACTICE AID Novel Approaches in Advanced Prostate Cancer

Selected Ongoing Trials of PARP Inhibitors1-8

PROfound (NCT02987543); Phase 3 TRITON2 (NCT02952534); Phase 2 • mCRPC; ongoing ADT or prior bilateral orchiectomy • mCRPC; progression on AR-directed therapy and1 prior taxane; ORR • Previously treated with AR-targeted therapy HRR gene aberration BRCA1/2 pts, n = 57; 43.9% • N = 387 • No prior PARP inhibitor, mitoxantrone, cyclophosphamide, PSA response

or platinum-based chemo RESULTS BRCA1/2 pts, n = 57; 59.6% • Planned N = 360 Olaparib: median rPFS 7.39 mo Physician's choice: rPFS 3.55 mo FDA Approved FDA Approved 7,a 8,b HR = 0.34 (95% CI, 0.25-0.47); May 2020 May 2020

RESULTS P < .0001

Enzalutamide 1° endpoint: Rucaparib 1° endpoints: ORR, PSA response Olaparib vs or abiraterone rPFS

Recruiting TOPARP-B (NCT01682772); NCT01972217; Phase 2 Galahad (NCT02854436); Phase 2 Multi-stage phase 2 design • mCRPC; ongoing ADT or prior bilateral • mCRPC • mCRPC previously treated N = 81 (46 with BRCA1/2 orchiectomy • ECOG PS 0 or 1 with ≥1 line of taxane-based and 35 with non-BRCA1/2) • Previously treated with 1 or 2 lines of • ≤2 prior lines of chemo chemo; received ≥1 line of ORR taxane-based chemo and/or AR-directed • Planned N = 158 AR-targeted therapy 41% in BRCA1/2; 9% in non-BRCA1/2 therapy rPFS; evaluable N = 142 • DDR anomalies Composite response rate • N = 98 Olaparib: 13.8 mo • Planned N = 301 RESULTS 63% in BRCA1/2; 17% in BRCA1/2 RR; evaluable N = 98 Placebo: 8.2 mo PSA response rate 50% in BRCA1/2; 3% in non-BRCA1/2

Endpoints: RESULTS HR = 0.65; P = .034 ORR 54% in 400 mg, 37% in 300 mg olaparib cohort Olaparib Placebo 1° endpoint: vs Niraparib 1° endpoint: ORR Median PFS: 5.4 mo + abiraterone + abiraterone rPFS

RESULTS Primary endpoint per gene subgroup: BRCA1/2: 80% ATM: 37% PALB2: 57% CDK12: 25%

Olaparib 1° endpoint: RR

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Selected Ongoing Trials of PARP Inhibitors1 (Cont’d)

Recruiting Recruiting Recruiting PROpel (NCT03732820); Phase 3 TRITON3 (NCT02975934); Phase 3 MAGNITUDE (NCT03748641); Phase 3

• mCRPC; ongoing ADT or prior bilateral orchiectomy • mCRPC previously treated with 1 next-generation • mCRPC; ongoing ADT or prior bilateral orchiectomy • ECOG PS 0 or 1 AR-targeted therapy • Planned N = 1,000 • Assessment of HRR gene aberrations • Deleterious mutation in BRCA1/2 or ATM • Planned N = 720 • Planned N = 400

Olaparib Placebo Abiraterone 1° endpoint: Niraparib Placebo vs 1° endpoint: Rucaparib vs or enzalutamide vs 1° endpoint: + abiraterone + abiraterone rPFS + abiraterone + abiraterone rPFS or docetaxel rPFS

Recruiting Recruiting LODESTAR (NCT04171700); Phase 2, open-label Avelumab + bempegaldesleukin (NKTR-214) + talazoparib or enzalutamide (NCT04052204); Phase 2, open-label • Unresectable, locally advanced, or metastatic solid tumor and relapsed/progressive disease • mCRPC • Planned N = 160 • At least 1 prior line of therapy extending OS or SOC therapy for advanced disease • ECOG PS 0 or 1 • mCRPC with BRCA1/2 mutations • ECOG PS 0 or 1 • Planned N = 220 (with solid tumors) Avelumab + Avelumab + 1° endpoints: bempegaldesleukin vs bempegaldesleukin + con rmed OR, Rucaparib • Cohort A: deleterious mutations in BRACA1/2 1° endpoint: talazoparib or PSA response, DLTs • Cohort B: non-BRACA1/2 mutations ORR enzalutamide

Recruiting TALAPRO-1 (NCT03148795); Phase 2, open-label TALAPRO-2 (NCT03395197); Phase 3

• mCRPC; metastatic disease • ECOG PS 0 or 1 • mCRPC; metastatic disease in bone • ECOG PS 0 to 2 in bone • Planned N = 1,037 • Assessment of DDR mutation status • Planned N = 100 • Assessment of DDR mutation status

1° endpoint: RESULTS Talazoparib Placebo 1° endpoints: Talazoparib 9,c vs ORR Confirmed ORR: 28.0% + enzalutamide + enzalutamide dose, rPFS Composite response:9 51.2%

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Selected Ongoing Trials of PARP Inhibitors Combined With PD-1/PD-L1 Inhibitors1,7-10

Recruiting JAVELIN PARP MEDLEY CheckMate -9KD (NCT03338790); (NCT03330405); Phase 2 Phase 2 • Locally advanced or mCRPC • mCRPC; ongoing ADT • HRD status (must be • Primary or metastatic tumor biopsy • Plasma and fresh or available before tx • ECOG PS 0 or 1 archival tumor tissue arm assignment) • Planned N = 242 • ECOG PS 0-1 • Planned N = 330

Avelumab + 1° endpoints: Nivolumab + rucaparib or 1° endpoints: talazoparib DLTs, OR docetaxel or enzalutamide ORR, PSA response

Recruiting Recruiting Recruiting KEYNOTE-365 (NCT02861573); NCT02484404; QUEST (NCT03431350); Phase 1b/211-13 Phase 2 (prostate cohort) Phase 1/2 • mCRPC; ongoing ADT • mCRPC; ongoing ADT or prior bilateral orchiectomy • mCRPC • Tissue biopsy from site not previously irradiated • ECOG PS 0 or 1; previously treated with enzalutamide • DDR gene anomalies • Planned N = 400 and/or abiraterone • Prior novel AR-targeted therapy • Planned N = 384 • Planned N = 80

PSA response rPFS; evaluable N = 17 Pembro + olaparib, n = 84; 9% Durvalumab + olaparib: 16.1 mo Niraparib 1° endpoints: 12-month rPFS: 51.5% Pembro + docetaxel, n = 104; 28% + cetrelimab safety, ORR,

RESULTS Pembro + enzalutamide, n = 102; 22% 9/17 (53%) patients had a radiographic and/or RESULTS PSA response composite RR

Pembrolizumab + olaparib 1° endpoint: Durvalumab 1° endpoints: or docetaxel/prednisone or + olaparib dose, safety enzalutamide or abiraterone PSA response

a In May 2020, the FDA approved olaparib for adult patients with deleterious/suspected deleterious germline/somatic HRR gene-mutated mCRPC following progression on enzalutamide of abiraterone. b In May 2020, the FDA approved rucaparib for patients with deleterious germline/ somatic BRCA mutation-associated mCRPC previously treated with AR-directed therapy and a taxane-based chemotherapy. c In patients who received talazoparib for ≥16 weeks. ADT: androgen deprivation therapy; AR: androgen receptor; DDR: DNA damage repair; DLT: dose-limiting toxicity; ECOG PS: Eastern Cooperative Oncology Group Performance Status; HRD: homologous recombination deficiency; HRR: homologous recombination repair; mCRPC: metastatic castration-resistant prostate cancer; OR: overall response; ORR: objective response rate; PARP: poly (ADP-ribose) polymerase; PD-1: programmed cell death protein 1; PD-L1: programmed death ligand 1; PSA: prostate-specific antigen; rPFS: radiographic progression-free survival ; RR: response rate. 1. https://clinicaltrials.gov. 2. Mateo J et al. 2019 American Society of Clinical Oncology Annual Meeting (ASCO 2019). Abstract 5005. 3. Clarke N et al. Lancet Oncol. 2018;19:975-986. 4. de Bono J et al. N Engl J Med. 2020;382:2091-2102. 5. Abida W et al. ESMO 2019. Abstract 846PD. 6. Smith MR et al. American Society of Clinical Oncology 2019 Genitourinary Cancers Symposium (ASCO GU 2019). Abstract 202. 7. https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-olaparib-hrr-gene-mutated-metastatic-castration-resistant-prostate-cancer. 8. https://www.fda.gov/drugs/fda-grants-accelerated-approval-rucaparib-brca-mutated-metastatic-castration-resistant-prostate. 9. De Bono JS et al.2020 ASCO Virtual Scientific Program (ASCO 2020). Abstract 5566. 10. Karzai F et al. J Immunother Cancer. 2018;6:141. 11. Yu EY et al. J Clin Oncol. 2020;38 (suppl; abstr 5544). 12. Sridhar SS et al. J Clin Oncol. 2020;38 (suppl; abstr 5550). 13. Conter HJ et al. J Clin Oncol. 2020;38 (suppl; abstr 5545). Access the activity, “How I Think, How I Treat: Learning to Navigate the Modern Prostate Cancer Landscape” at PeerView.com/JGU40