Indirect Comparison of Darolutamide versus Apalutamide and Enzalutamide for Nonmetastatic Castration-Resistant Prostate Cancer

Open AccessJournal of UrologyAdult Urology1 Aug 2021Indirect Comparison Darolutamide versus Apalutamide and Enzalutamide for Nonmetastatic Castration-Resistant Prostate Cancer Susan Halabi, Shan Jiang, Emi Terasawa, Viviana Garcia-Horton, Rajeev Ayyagari, A. Reginald Waldeck, Neal Shore HalabiSusan Halabi http://orcid.org/0000-0003-4135-2777 Duke University, Durham, North Carolina Fellow the American Society Clinical Oncology (ASCO); has received consulting fees from Eisai, Ferring Bayer. More articles by this author , JiangShan Jiang Bayer, Whippany, New Jersey Employees holders stock/options TerasawaEmi Terasawa Analysis Group, Inc., York, York which Garcia-HortonViviana Garcia-Horton AyyagariRajeev Ayyagari http://orcid.org/0000-0003-0870-2309 Boston, Massachusetts WaldeckA. Waldeck ShoreNeal ‖Correspondence: 823 82nd Pkwy., Myrtle Beach, South 29572 telephone: 843-839-1679; E-mail Address: [email protected] http://orcid.org/0000-0001-5767-0548 Urologic Research Center, Has Janssen Scientific Affairs, Dendreon, Tolmar, Ferring, Medivation/Astellas, Amgen, Pfizer, AstraZeneca, Genentech/Roche, Myovant Sciences, Astellas Pharma Merck, as well speaker Janssen, Bayer Dendreon. View All Author Informationhttps://doi.org/10.1097/JU.0000000000001767AboutAbstractPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail Abstract Purpose: No published head-to-head randomized trials have compared safety efficacy darolutamide vs apalutamide or enzalutamide in nonmetastatic castration-resistant prostate cancer. This study compares prespecified adverse events metastasis-free survival associated with apalutamide, enzalutamide, via matching-adjusted indirect comparisons. Materials Methods: Individual patient data phase III ARAMIS trial (NPLACEBO=553; NDAROLUTAMIDE=943) were selected reweighted match inclusion criteria baseline characteristics SPARTAN (NPLACEBO=401; NAPALUTAMIDE=806) PROSPER (NPLACEBO=468; NENZALUTAMIDE=933) trials. Only factors consistently reported across included matching covariates. Both comparisons matched on age, specific antigen level doubling time, Eastern Cooperative Group performance status, Gleason score, bone-sparing agent use. also prior surgery region. Risk differences odds ratios calculated hazard survival. Results: found after either comparison. However, fall, fracture rash rates statistically significantly lower favor apalutamide. Fall, dizziness, mental impairment, fatigue severe enzalutamide. Conclusions: While did not differ drugs these cross-trial comparisons, showed a favorable tolerability profile Consideration is important clinical decision-making treatment selection Abbreviations Acronyms AE event APA BH Benjamini-Hochberg DARO ECOG ENZA ESS effective sample size MAIC comparison MFS nmCRPC cancer OS overall PBO placebo PSA RD risk difference SGARI second-generation androgen receptor inhibitor been an area unmet need advanced cancer, until recently options limited.1 In 2018, U.S. Food Drug Administration approved 2 inhibitors nmCRPC: enzalutamide.2,3 2019, was approved, distinguished its propensity crossing blood-brain barrier, reducing potential central nervous system side effects.4–6 The 3 (ARAMIS; NCT02200614), (SPARTAN; NCT01946204), (PROSPER; NCT02003924) demonstrated benefits patients treated placebo;6–8 however, no prospectively treatments. To address paucity comparative evidence evaluate benefit/risk treatments, conducted their using ARAMIS, PROSPER. Safety assessed all-grade events, priori well-recognized association SGARIs importance physicians, patients, caregivers; MFS.9–11 Outcomes accomplished that adjusted observable heterogeneity characteristics. Methods Data Sources Patient-level aggregate used.6-8,12-15 These double-blind, placebo-controlled, among men aged ≥18 years nmCRPC. As analysis based data, institutional board review required. Eligibility Criteria excluded seizure history, while not. seminal publication does mention history exclusion criterion,7 clearly stated protocol.16 minimize bias, analyses (1 12 patients). outcomes AEs interest nmCRPC, experts working disease area, associations inhibitors, comprised falls, mental-impairment disorder, hypertension, seizure, rash, diarrhea, nausea, (with without asthenia), fracture, asthenia, headache. documented relevant decision clinicians, caregivers evidenced ‘preference’ studies.9–11 General any AE, serious leading discontinuation, death. list MAIC-specific statistical plan before conducting analyses. Efficacy outcome Definitions differed slightly SPARTAN, defined time randomization first occurrence metastasis death cause, whichever occurred first. PROSPER, definitions applied: 1) radiographic progression cause during period 112 days discontinuation regimen progression, (Definition 1), 2) (regardless timing) 2). Patients confirmed metastatic at censored but ARAMIS. ensure comparability between when computing MFS, who later prerandomization date (39 50 Statistical MAICs compare anchoring arm common comparator.17–19 made For each comparison, arms such average respective active comparator trials.18 Three separate performed match-adjust Supplementary table 1 (https://www.jurology.com) lists matched-on primary listed Chowdhury et al (2018 2020),20,21 due (ie modification) major differences. Two sensitivity performed. all available both SPARTAN. second subset 8 per (2019).22 clinically Baseline summarized populations demographics (age, race geographic region) (time initial diagnosis, serum level, classification local/regional nodal disease, testosterone use agents, previous surgical procedures, tumor stage diagnosis status). Comparisons chi-square tests categorical variables matching, Wald continuous matching. A p value 0.05 used determine significance. Effective sizes square summed weights divided sum squared weights. outcomes, measures calculated: comparing [Active–PBO]ARAMIS – [Active–PBO]Comparator), ratio [OddsDARO/OddsARAMIS PBO]/[OddsComparator/OddsComparator PBO]).23 Adjustments multiplicity interest, analyses, procedure.24 Other exploratory; point estimates 95% confidence intervals are presented. duration (eg median followup: 17.9 20.3 months) assessment schedules (every 4 months every month). assess impact relative additional adjustments (see supplementary figure, https://www.jurology.com). estimated unweighted weighted proportional hazards models respectively. HRs obtained values. HR HRDARO/HRComparator) calculated.23 Results (ARAMIS SPARTAN) total, 1,496 (NPBO=553, NDARO=943) considered weighting. 401 806 arms, Prior several (table 1). Table 1. Observed Characteristics Before Matching After (Primary Analysis) (Sensitivity % (806 pts) (401 (943 (553 (ESS 604 391 295 203 Age >SPARTAN 50.0 49.1 45.8 Race: White 65.0 68.8 79.5 78.3 79.9 77.3 81.3 75.0 Black 6.0 5.0 3.0 4.3 2.8 4.5 6.3 13.5 Asian 11.5 11.7 12.8 12.4 13.9 9.6 9.0 Other/missing 17.5 14.5 4.7 4.6 4.9 2.5 Region: Asia-Pacific 15.6 15.7 12.5 12.1 12.0 13.1 8.1 America 35.4 33.4 11.2 13.6 17.4 16.9 Europe 49.0 50.9 65.2 62.6 60.4 57.9 Other* 0.0 11.1 10.2 6.6 7.6 Time 44.2 43.2 47.7 45.7 Serum 54.8 57.7 Classification local regional disease: N0 83.5 83.8 51.7 58.0 54.5 52.0 52.7 N1 16.5 16.2 9.1 11.0 13.0 8.5 11.6 Nx 36.1 37.3 32.4 32.5 39.5 35.7 time: 49.6 51.5 ≤6 Mos 71.5 70.8 69.8 66.9 >6 28.5 29.2 30.2 33.1 16.4 16.6 14.1 status: 0 77.8 68.2 70.7 77.7 22.7 22.3 31.8 29.3 score: <7 18.9 18.0 22.8 25.7 21.0 ≥7 78.4 78.6 74.4 71.2 76.0 Missing 2.7 3.5 3.1 3.4 1.9 Previous procedures 57.1 55.4 32.7 34.6 Use 9.7 3.2 5.8 Tumor diagnosis: T1 15.4 T2 32.9 30.7 31.2 35.3 31.0 35.8 34.8 T3 36.7 40.6 43.3 38.9 39.3 40.7 38.2 T4 4.0 4.2 3.8 2.6 Tx 7.4 7.2 6.5 5.7 4.8 1.5 1.7 3.7 Geographic region categories Asia-Pacific, America, only. Europe, rest world (nonEuropean countries). analysis, 7 (supplementary 1, https://www.jurology.com) balanced SPARTAN; 391, respectively Differences remained post-matching race, region, and, treatment-arm diagnosis. resulted very low (≤80) arm; therefore, 2, score Figures show analyses’ post-match RDs ORs, respectively, outcomes. Among exhibited absolute risks falls (RD −6.3%, Benjamini-Hochberg-adjusted [pBH] <0.05), (−16.0%, pBH<0.0001), (−6.2%, pBH<0.05) than (fig. results largely preserved where significant risk/odds (both pBH <0.05) (pBH <0.0001; numerically impairment (OR 0.4, fig. Figure matching: Analysis). a, including asthenia. *, significance 5%. highlighted yellow. 2. Ratios ORs because OR least arm. b, observed treatments general −3.4%) (−0.7%); (1.4%). −6.6%, 0.5). pre-match 1.29 (95% CI 0.95–1.74) 1.14 (0.83–1.58), Similarly, (HR 1.11, 0.72–1.70). Adjustment Differing Followup Duration Assessment Schedule Compared shows MAIC-adjusted under different followup scenarios mirror adjust SPARTAN’s more frequent schedule. arm, increased added, increases substantial. tables (RDs) 5 (ORs; summarize extending patients’ time. persisted even differences: had fractures, measured 4, fractures OR, persist 5, PROSPER) MAIC, 943 553 468 933 populations; 395 580, (933 (468 580 >PROSPER 51.2 15.1 36.9 23.6 23.8 43.6 48.1 60.1 66.0 76.7 77.1 23.3 22.9 80.2 81.8 19.8 18.2 Low (2–4) 2.3 Medium (5–7) 52.6 54.3 52.3 High (8–10) 40.8 40.1 Unknown 4.1 11.3 10.3 Disease Metastatic 5.3 7.1 97.5 97.0 94.7 92.9 pBH<0.01), dizziness (−4.9%, pBH<0.05), disorder (−3.5%, asthenia (−12.8%, pBH<0.0001) (−2.2%, 3). Lower 0.4), (0.3), (0.6, pBH=0.160) 4) significant. 3. 4. although −0.1%), (−1.6%), (−1.8%). Under PROSPER’s Definition 1.23 0.93–1.64) 1.20 (0.87–1.65), 1.22 0.92–1.62) 1.18 (0.86–1.62), Discussion utilized established methodology17–19 indicate adjusting advantages over profile, particularly individual AEs. example, differences, set variables, Moreover, frequency, RDs. disorders, (not asthenia) multiplicity-adjusted suggest superior respect Importantly, related possibly supported darolutamide’s blood brain-barrier penetration, thus system-related risk. shown be caregivers, preference studies.9,11 extend further clarify similarities efficacy, meaningful safety, SGARIs. Few studies darolutamide, (2019) patient-level summary OS, progression-free survival, outcomes.22 consistent findings present study, similar cohort our (2019). Finally, there some covariates study. addition, authors access whereas we Altavilla evaluated network meta-analysis ARAMIS.25 Notably, meta-analyses do contrast MAICs. meta-analysis, apalutamide; marginally (all grades), fatigue, hypertension approach strengths contribute results’ enhanced reliability robustness. First, PROSPER; additionally, ARAMIS’s enabled high granularity handling removal excluding metastases outcome) studies. Second, MAICs’ anchored leveraged trials’ placebo-arm comparators, mitigating confounding prognostic Third, two scenarios, sets (primary analyses). most pronounced effects conserved lending credence results. Fourth, adjustment according applied inference drawn responsible manner, conservative conclusions; investigating times frequency Even adjustment, sustained. current subject limitations inherent only known nonrandomized groups, bias unobserved unmeasurable confounders may occur. generalizable beyond sample. Despite limitations, robust, concurrence substitute prospective they best can provide given lack Conclusions testing, reaching select inhibition. Specifically, (neither higher generally cancer-related symptoms drug-induced negatively daily activities, especially long-term treatment. Therefore, consideration within shared making clinicians Acknowledgments Editorial assistance provided Shelley Batts, PhD, employee Inc. Assistance David Steffen, Akanksha Dua, Andi Chin, employees Support References : landscape non-metastatic Clin Med Insights Oncol 2019; 13: Google Scholar United States (FDA): FDA approves Available https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-apalutamide-non-metastatic-castration-resistant-prostate-cancer. Accessed March 26, 2020. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-enzalutamide-castration-resistant-prostate-cancer. Darolutamide: novel androgen-signaling J Androl 2020; 22: 76. 5. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-darolutamide-non-metastatic-castration-resistant-prostate-cancer. 6. nonmetastatic, N Engl 380: 1235. 7. 2018; 378: 1408. 8. 2465. 9. Physician preferences BMC Urol 20: 73. 10. Evaluation drug-drug interactions population pharmacokinetics cancer: pre-specified post hoc trial. Target 14: 527. 11. Patient caregiver benefit-risk 37: 196. 12. Effect health-related quality life randomised, Lancet 19: 1404. 13. (FDA) Center Research: NDA/BLA Multi-disciplinary evaluation NDA 210951 (apalutamide). https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/210951Orig1s000OtherR.pdf. 14. Patient-reported following non-metastatic, (PROSPER): multicentre, 556. 15. National Institute Health Care Excellence (NICE): Single Technology Appraisal: treating hormone-relapsed [ID1359]. https://www.nice.org.uk/guidance/ta580/evidence/appraisal-consultation-committee-papers-pdf-6781040029. 16. ClinicalTrials.gov: (ARN-509) (SPARTAN). Identifier: NCT01946204. https://clinicaltrials.gov/ct2/show/NCT01946204. February 19, 2021. 17. Comparative effectiveness trials: method psoriasis adalimumab etanercept. Pharmacoeconomics 2010; 28: 935. 18. Matching-adjusted comparisons: new tool timely research. Value 2012; 15: 940. 19. NICE DSU Technical Document 18: population-adjusted submissions NICE. http://www.nicedsu.org.uk/wp-content/uploads/2017/05/Population-adjustment-TSD-FINAL.pdf. 20. ADT Adv Ther 501. 21. PCN37 - 21: S20. 22. CL4 Health, suppl., S407. 23. estimating external control data. Ann Appl Stat 1806. 24. Controlling false discovery rate: practical powerful multiple testing. R Soc Ser B Methodol 1995; 57: 289. 25. (ARi) (nmCRPC): controlled (RCT). 30: v339. work funded sponsor involved design conduct study; collection, management, interpretation data; preparation, review, approval manuscript. full take responsibility integrity accuracy analysis. Portions research presented meetings: AMCP Annual Meeting April 21–24, 2020 (virtual); ASCO May 29–June Nexus October 20–23, (virtual). other researchers collected proprietary database; publicly available. open article distributed terms Creative Commons Attribution-NonCommercial-NoDerivatives License (CC BY-NC-ND), permits downloading sharing it properly cited. cannot changed way commercially permission journal.© 2021 Author(s). Published behalf Urological Association, Education Research, Inc.FiguresReferencesRelatedDetails Volume 206Issue 2August 2021Page: 298-307Supplementary Advertisement Copyright & Permissions© Inc.Keywordsnetwork meta-analysisapalutamidedarolutamideprostatic neoplasmsMDV 3100castration-resistantAcknowledgmentsEditorial Bayer.MetricsAuthor Information Expand Loading ...