Comparative efficacy of apalutamide darolutamide and enzalutamide for treatment of non-metastatic castrate-resistant prostate cancer: A systematic review and network meta-analysis

Kumar, J.; Jazayeri, Seyed Behzad; Gautam, Shiva; Norez, Daniel; Alam, Muhammad Umar; Tanneru, Karthik; Bazargani, Soroush; Costa, Joseph; Bandyk, Mark; Ganapathi, Hariharan Palayapalayam; Koochekpour, Shahriar; Balaji, K.C.

doi:10.1016/j.urolonc.2020.03.022

Cited by 32 publications

(33 citation statements)

References 22 publications

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“…At this primary analysis, although OS data consistently favored nHT over placebo in all the mentioned trials, the results with respect to OS did not meet the criteria for significance. Recent meta-analyses showed that nHT prolonged OS in a statistically significant manner, yet at that time median OS -still not reached in all experimental arm-and the short follow-up precluded from definitive conclusions (18)(19)(20). Results from the prespecified OS final analyses of the 3 trials were presented at the 2020 ASCO Annual Meeting, and then recently published (13)(14)(15).…”

Section: Discussionmentioning

confidence: 99%

A Systematic Review and Meta-Analysis of Randomized Controlled Trials With Novel Hormonal Therapies for Non-Metastatic Castration-Resistant Prostate Cancer: An Update From Mature Overall Survival Data

et al. 2021

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IntroductionTo get better insight into the management of non-metastatic castration-resistant prostate cancer (M0 CRPC), in this meta-analysis and review we aimed to present an updated evaluation of the efficacy and safety of novel hormonal therapies (nHT) for M0 CRPC according to final analyses with mature overall survival (OS) and safety data.MethodsWe analyzed metastasis-free survival (MFS), OS, time to prostate-specific antigen (PSA) progression, second-line therapies data, adverse events (AEs), including all AEs, serious AEs (SAEs), AEs leading to discontinuation of trial regimen, AEs leading to death, fatigue, dizziness, cardiovascular events, and fractures; moreover, we evaluated the impact of PSA doubling time (PSA-DT), Eastern Cooperative Oncology Group (ECOG) score, use of bone-targeted therapy, lymph lodes (LN) status, and prior HT on final OS data. A comparison among the placebo arms of the included trials in terms of survival and safety profiles was assessed.ResultsAccording to the pooled analysis with updated and mature OS data, OS was significantly improved with nHT compared to placebo (hazard ratio (HR)= 0.74, 95% confidence interval (CI)= 0.66–0.84). nHT significantly improved OS over placebo across all pre-specified subgroups. Subgroup analysis revealed a greater OS benefit in patients with PSA-DT >6 months than ≤6 months (HR= 0.69 versus HR= 0.75), ECOG 0 than 1 (HR= 0.70 versus HR= 0.80), N1 disease than N0 (HR= 0.61 versus HR= 0.78), and in those receiving bone-targeted therapy (HR= 0.65 versus HR= 0.74), and a comparable OS by number of prior HT (HR= 0.75 versus HR= 0.76, for HT= 1 and ≥2); yet, differences between pre-specified subgroups were not significant (all p> 0.05). Overall, the nHT arm was significantly associated with higher rates of AEs, when compared with the placebo arm. The long-term analysis showed a worse safety profile with nHT than the interim analysis.ConclusionsAccording to final analyses, nHT have shown to improve OS over placebo in the setting of high-risk M0 CRPC. The long-term analysis showed a worse safety profile with nHT than the interim analysis, whit distinct profiles among different nHT. The lack of survival data regarding second-line therapies remains a major issue.

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Section: Discussionmentioning

confidence: 99%

A Systematic Review and Meta-Analysis of Randomized Controlled Trials With Novel Hormonal Therapies for Non-Metastatic Castration-Resistant Prostate Cancer: An Update From Mature Overall Survival Data

et al. 2021

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“…These developments are of particular interest, as previous network meta-analyses did not include recently reported data [ 25 ] [ 26 ]. Therefore, we included recently published data, such as updated results from the PROSPER and SPARTAN trials [ 16 , 24 ].…”

Section: Discussionmentioning

confidence: 99%

“…In addition, this network meta-analysis included detailed AE outcomes. This is of greater relevance to clinical practice than the recent network meta-analyses [ 25 , 26 ]. On these points, current paper may more readily facilitate individualized treatment selection.…”

Section: Discussionmentioning

confidence: 99%

Apalutamide, enzalutamide, and darolutamide for non-metastatic castration-resistant prostate cancer: a systematic review and network meta-analysis

et al. 2020

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Management of non-metastatic castration-resistant prostate cancer (nmCRPC) has undergone a paradigm shift with next-generation androgen receptor inhibitors. However, direct comparative data are not available to inform treatment decisions and/or guideline recommendations. Therefore, we performed network meta-analysis to indirectly compare the efficacy and safety of currently available treatments. Multiple databases were searched for articles published before June 2020. Studies that compared overall and/or metastasis-free and/or prostate-specific antigen (PSA) progression-free survival (OS/MFS/PSA-PFS) and/or adverse events (AEs) in nmCRPC patients were considered eligible. Three studies (n = 4117) met our eligibility criteria. Formal network meta-analyses were conducted. For MFS, apalutamide, darolutamide, and enzalutamide were significantly more effective than placebo, and apalutamide emerged as the best option (P score: 0.8809). Apalutamide [hazard ratio (HR): 0.85, 95% credible interval (CrI): 0.77–0.94] and enzalutamide (HR: 0.86, 95% CrI: 0.78–0.95) were both significantly more effective than darolutamide. For PSA-PFS, all three agents were statistically superior to placebo, and apalutamide emerged as the likely preferred option (P score: 1.000). Apalutamide (HR: 0.71, 95% CrI: 0.69–0.74) and enzalutamide (HR: 0.76, 95% CrI: 0.74–0.79) were both significantly more effective than darolutamide. For AEs (including all AEs, grade 3 or grade 4 AEs, grade 5 AEs, and discontinuation rates), darolutamide was the likely best option. Apalutamide and enzalutamide appear to be more efficacious agents for therapy of nmCRPC, while darolutamide appears to have the most favorable tolerability profile. These findings may facilitate individualized treatment strategies and inform future direct comparative trials.

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“…In this regard, one could question the responses regarding whether a drug that has been approved for both nmCRPC and M1-CRPC such as enzalutamide would not be the most obvious choice in a perfect scenario. On the other hand, in an indirect comparison made by 2 independent groups (3,4), apalutamide and enzalutamide were significantly more effective than darolutamide concerning metastasis-free survival and PSA progression-free survival; darolutamide, however, showed potential for a better-tolerated drug.…”

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confidence: 90%

National Consensus on Non-metastatic Castration-Resistant Prostate Cancer: more than just a snapshot

2021

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The landscape of castration-resistant prostate cancer (CRPC) has dramatically improved in the last few years. Still, it remains a very heterogeneous clinical setting. It ranges from patients with good performance status having an asymptomatic PSA elevation after hormone blockage failure with previous hormone-sensitive prostate cancer to those with a rapidly progressing disease and a dismal prognosis. Non-metastatic castration-resistant prostate cancer (nmCRPC-M0) is a transient stage that affects almost 10% of prostate cancer patients, with up to 60% progressing to the metastatic disease within 5 years (1). Recently 3 new androgen receptor blockers have been approved in Brazil by ANVISA for nmCRPC based on their level 1 pivotal studies-Spartan (apalutamide); Prosper (enzalutamide) and Aramis (darolutamide). These studies showed a remarkably similar result albeit targeting patients with slightly different characteristics (Table-1). Overall, the pooled analysis of the data revealed a significantly increased overall survival and improved progression-free survival due to these new agents compared with placebo. In the current edition of the IBJU, Maluf et al. describe a national consensus of experts on nmCRPC, aiming to provide data on diverse topics such as diagnosis, patient selection, management of comorbidities, treatment efficacy, side effects due to the "inexistence of a national guideline for this clinical scenario" (2). It was not stated on the paper which criteria was used for selecting the Specialists nor which Medical Societies (if any) promoted the consensus; and, there was no disclaimer of how the consensus was supported. The article brings a good review of the literature to hold up the expert's opinions. While every effort is expected from groups of experts to provide the best knowledge to diagnostic and treatments according to the most up-to-date data and international recommendations, one must not lose sight of the significant gaps and controversies that might coexist regarding clinically meaningful endpoints, financial toxicity, overtreatment, pharmacoeconomic and polypharmacy for this type of cancer patients, especially in a country as large and heterogeneous as Brazil, which may provide all available resources in one area but may lack significant basic means in several others. Thus, several important points deserve consideration. The consensus is somehow outdated; although the authors do mention data from the Aramis study, darolutamide was not included in the experts' questions and responses because it was only approved in Brazil by December 2019. The panel agreed to answer questions on the assumption of the existence of an ideal clinical scenario based on the best evidence available. Yet it was unable to reach consensus in any of the questions EDITORIAL COMMENT

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Comparative efficacy of apalutamide darolutamide and enzalutamide for treatment of non-metastatic castrate-resistant prostate cancer: A systematic review and network meta-analysis

Cited by 32 publications

References 22 publications

A Systematic Review and Meta-Analysis of Randomized Controlled Trials With Novel Hormonal Therapies for Non-Metastatic Castration-Resistant Prostate Cancer: An Update From Mature Overall Survival Data

A Systematic Review and Meta-Analysis of Randomized Controlled Trials With Novel Hormonal Therapies for Non-Metastatic Castration-Resistant Prostate Cancer: An Update From Mature Overall Survival Data

Apalutamide, enzalutamide, and darolutamide for non-metastatic castration-resistant prostate cancer: a systematic review and network meta-analysis

National Consensus on Non-metastatic Castration-Resistant Prostate Cancer: more than just a snapshot

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