How I Think, How I Treat: Learning to Navigate the Modern Prostate Cancer Landscape.
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This document details various androgen receptor-targeted agents and their dosing regimens for treating prostate cancer, specifically metastatic and non-metastatic castration-resistant forms. It discusses adverse events, primary endpoints from clinical trials, and FDA approvals related to therapies like apalutamide, enzalutamide, darolutamide, and PARP inhibitors. Ongoing and planned studies assessing combinations of these therapies with immunotherapy and their outcomes are also summarized.
How I Think, How I Treat: Learning to Navigate the Modern Prostate Cancer Landscape.
- 1. AR-Targeted Agents in Prostate Cancer PRACTICE AID Access the activity, “How I Think, How I Treat: Learning to Navigate the Modern Prostate Cancer Landscape” at PeerView.com/JGU40 Indication • Patients with metastatic CSPC and nmCRPC Dosing • 240 mg orally once daily; swallow whole with or without food • Should also receive a GnRH analog concurrently or have had a bilateral orchiectomy AEs in ≥10% of Patients • Fatigue, arthralgia, rash, decreased appetite, falls, weight decrease, hypertension, hot flush, diarrhea, and fracture Indication • Patients with CRPC and metastatic CSPC AEs in ≥10% of Patients • Asthenia/fatigue, back pain, hot flush, constipation, arthralgia, decreased appetite, diarrhea, and hypertension Dosing • 160 mg orally once daily; swallow whole with or without food • Should also receive a GnRH analog concurrently or have had a bilateral orchiectomy Apalutamide1 Enzalutamide3 Darolutamide2 Indication • Patients with nmCRPC Dosing • Two 300-mg tablets administered orally twice daily; taken with food • Should also receive a GnRH analog concurrently or have had a bilateral orchiectomy AEs in ≥2% of Patients • Fatigue, pain in extremity, and rash Indication, Dosing, and AEs in AR-Targeted Agents for Prostate Cancer
- 2. AR-Targeted Agents in Prostate Cancer PRACTICE AID 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 • nmCRPC • Rising PSA despite castrate testosterone level (≤50 ng/dL) • PSADT ≤10 mo Apalutamide 40.5 mo Placebo 16.2 mo 1° endpoint: MFS Median OS, mo vs MFS Apalutamide 73.9 mo Placebo 59.9 mo mOS SPARTAN4,5,8 Apalutamide + ADT Placebo + ADT • nmCRPC • Rising PSA despite castrate testosterone level (≤50 ng/dL) • Baseline PSA ≥2 ng/mL; PSADT ≤10 mo Enzalutamide 36.6 mo Placebo 14.7 mo 1° endpoint: MFS Median OS, mo vs MFS Enzalutamide 67.0 mo Placebo 56.3 mo mOS PROSPER6,10,11 Enzalutamide + ADT Placebo + ADT • nmCRPC • Castrate level of serum testosterone (<50 ng/dL) • Baseline PSA ≥2 ng/mL; PSADT ≤10 mo 1° endpoint: MFS Median OS, moa vs Darolutamide 40.4 mo Placebo 18.4 mo Darolutamide NR Placebo NR MFS mOS ARAMIS7,9 Darolutamide + ADT Placebo + ADT AR-Targeted Agents in Nonmetastatic CRPC • mCSPC • Newly diagnosed or previously treated • ECOG PS 0 or 1 Apalutamide Not Reached Enzalutamide Not Reached Placebo 21.1 mo 1° endpoint: Median rPFS and OSb vs rPFS TITAN12,13 Apalutamide + ADT Placebo + ADT • mCSPC (confirmed by bone scan, CT, or MRI) • ECOG PS 0 or 1 Placebo 19.45 mo 1° endpoint: rPFS vs rPFS ARCHES15-17 Enzalutamide + ADT Placebo + ADT • mCSPC • Newly diagnosed • ECOG PS 0 or 1 1° endpoint: OS vs ARASENS14 Darolutamide + ADT + docetaxel Placebo + ADT + docetaxel AR-Targeted Agents in Metastatic CSPC Ongoing; primary completion date: August 2022
- 3. Novel Approaches in Advanced Prostate Cancer PRACTICE AID Access the activity, “How I Think, How I Treat: Learning to Navigate the Modern Prostate Cancer Landscape” at PeerView.com/JGU40 Galahad (NCT02854436); Phase 2 RESULTS • mCRPC previously treated with ≥1 line of taxane-based chemo; received ≥1 line of AR-targeted therapy • DDR anomalies • Planned N = 301 N = 81 (46 with BRCA1/2 and 35 with non-BRCA1/2) ORR 41% in BRCA1/2; 9% in non-BRCA1/2 Composite response rate 63% in BRCA1/2; 17% in BRCA1/2 PSA response rate 50% in BRCA1/2; 3% in non-BRCA1/2 Niraparib 1° endpoint: ORR Selected Ongoing Trials of PARP Inhibitors1-8 TOPARP-B (NCT01682772); Multi-stage phase 2 design RESULTS • mCRPC; ongoing ADT or prior bilateral orchiectomy • Previously treated with 1 or 2 lines of taxane-based chemo and/or AR-directed therapy • N = 98 RR; evaluable N = 98 Endpoints: ORR 54% in 400 mg, 37% in 300 mg olaparib cohort Median PFS: 5.4 mo Primary endpoint per gene subgroup: BRCA1/2: 80% PALB2: 57% Olaparib 1° endpoint: RR ATM: 37% CDK12: 25% Olaparib + abiraterone Placebo + abiraterone vs 1° endpoint: rPFS NCT01972217; Phase 2 RESULTS • mCRPC • ECOG PS 0 or 1 • ≤2 prior lines of chemo • Planned N = 158 rPFS; evaluable N = 142 Olaparib: 13.8 mo Placebo: 8.2 mo HR = 0.65; P = .034 PROfound (NCT02987543); Phase 3 • mCRPC; ongoing ADT or prior bilateral orchiectomy • Previously treated with AR-targeted therapy • N = 387 RESULTS Olaparib: median rPFS 7.39 mo Physician's choice: rPFS 3.55 mo HR = 0.34 (95% CI, 0.25-0.47); P < .0001 1° endpoint: rPFSvs Enzalutamide or abiraterone Olaparib FDA Approved May 20207,a TRITON2 (NCT02952534); Phase 2 • mCRPC; progression on AR-directed therapy and1 prior taxane; HRR gene aberration • No prior PARP inhibitor, mitoxantrone, cyclophosphamide, or platinum-based chemo • Planned N = 360 RESULTS ORR BRCA1/2 pts, n = 57; 43.9% PSA response BRCA1/2 pts, n = 57; 59.6% Rucaparib 1° endpoints: ORR, PSA response FDA Approved May 20208,b Recruiting
- 4. Novel Approaches in Advanced Prostate Cancer PRACTICE AID Access the activity, “How I Think, How I Treat: Learning to Navigate the Modern Prostate Cancer Landscape” at PeerView.com/JGU40 Talazoparib + enzalutamide vs 1° endpoints: dose, rPFS Placebo + enzalutamide Selected Ongoing Trials of PARP Inhibitors1 (Cont’d) PROpel (NCT03732820); Phase 3 • mCRPC; ongoing ADT or prior bilateral orchiectomy • ECOG PS 0 or 1 • Assessment of HRR gene aberrations • Planned N = 720 vs 1° endpoint: rPFS Placebo + abiraterone Olaparib + abiraterone vs 1° endpoint: rPFS Placebo + abiraterone Niraparib + abiraterone MAGNITUDE (NCT03748641); Phase 3 • mCRPC; ongoing ADT or prior bilateral orchiectomy • Planned N = 1,000 TRITON3 (NCT02975934); Phase 3 • mCRPC previously treated with 1 next-generation AR-targeted therapy • Deleterious mutation in BRCA1/2 or ATM • Planned N = 400 vs 1° endpoint: rPFS Abiraterone or enzalutamide or docetaxel vs Avelumab + bempegaldesleukin + talazoparib or enzalutamide Rucaparib Avelumab + bempegaldesleukin Recruiting Recruiting Recruiting Recruiting Recruiting Rucaparib 1° endpoint: ORR 1° endpoints: confirmed OR, PSA response, DLTs LODESTAR (NCT04171700); Phase 2, open-label • Unresectable, locally advanced, or metastatic solid tumor and relapsed/progressive disease • At least 1 prior line of therapy extending OS or SOC therapy for advanced disease • mCRPC with BRCA1/2 mutations • ECOG PS 0 or 1 • Planned N = 220 (with solid tumors) Avelumab + bempegaldesleukin (NKTR-214) + talazoparib or enzalutamide (NCT04052204); Phase 2, open-label • mCRPC • ECOG PS 0 or 1 • Planned N = 160 • Cohort A: deleterious mutations in BRACA1/2 • Cohort B: non-BRACA1/2 mutations Recruiting Talazoparib 1° endpoint: ORR TALAPRO-1 (NCT03148795); Phase 2, open-label • mCRPC; metastatic disease in bone • Assessment of DDR mutation status • ECOG PS 0 to 2 • Planned N = 100 TALAPRO-2 (NCT03395197); Phase 3 • mCRPC; metastatic disease in bone • Assessment of DDR mutation status • ECOG PS 0 or 1 • Planned N = 1,037 RESULTS Confirmed ORR:9,c 28.0% Composite response:9 51.2%
- 5. Novel Approaches in Advanced Prostate Cancer PRACTICE AID Access the activity, “How I Think, How I Treat: Learning to Navigate the Modern Prostate Cancer Landscape” at PeerView.com/JGU40 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). Selected Ongoing Trials of PARP Inhibitors Combined With PD-1/PD-L1 Inhibitors1,7-10 JAVELIN PARP MEDLEY (NCT03330405); Phase 2 • Locally advanced or mCRPC • Primary or metastatic tumor biopsy • ECOG PS 0 or 1 • Planned N = 242 CheckMate -9KD (NCT03338790); Phase 2 • mCRPC; ongoing ADT • Plasma and fresh or archival tumor tissue • ECOG PS 0-1 Recruiting 1° endpoints: DLTs, OR 1° endpoints: safety, ORR, composite RR • HRD status (must be available before tx arm assignment) • Planned N = 330 1° endpoints: ORR, PSA response Avelumab + talazoparib Nivolumab + rucaparib or docetaxel or enzalutamide KEYNOTE-365 (NCT02861573); Phase 1b/211-13 • mCRPC; ongoing ADT • Tissue biopsy from site not previously irradiated • Planned N = 400 QUEST (NCT03431350); Phase 1/2 • mCRPC • DDR gene anomalies • Prior novel AR-targeted therapy • Planned N = 80 NCT02484404; Phase 2 (prostate cohort) • mCRPC; ongoing ADT or prior bilateral orchiectomy • ECOG PS 0 or 1; previously treated with enzalutamide and/or abiraterone • Planned N = 384 RecruitingRecruiting Recruiting Niraparib + cetrelimab RESULTS PSA response Pembro + olaparib, n = 84; 9% Pembro + docetaxel, n = 104; 28% Pembro + enzalutamide, n = 102; 22% 1° endpoint: PSA response Pembrolizumab + olaparib or docetaxel/prednisone or enzalutamide or abiraterone 1° endpoints: dose, safety Durvalumab + olaparib RESULTS rPFS; evaluable N = 17 Durvalumab + olaparib: 16.1 mo 12-month rPFS: 51.5% 9/17 (53%) patients had a radiographic and/or PSA response