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

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Highlights

Abstract

Introduction: Studies using apalutamide, enzalutamide, or darolutamide have shown improved metastasis free survival (MFS) rates, leaving clinicians with a dilemma of choosing one over the other, for nonmetastatic castration recurrent prostate cancer (nmCRPC). We performed a network meta-analysis to provide an indirect comparison of oncologic outcomes and adverse events (AEs) of these medications. Material and Methods: We searched PubMed, MEDLINE, and SCOPUS databases, for studies reporting apalutamide, enzalutamide, or darolutamide until January 25, 2020. Results were input into an EndNote library, and data were extracted into a predefined template. Progression free survival (PFS) was defined as radiologic progression or death. Network meta-analysis was done using R and meta-analysis was performed with RevMan v. 5. Surface under the cumulative ranking (SUCRA) value was used to provide rank probabilities. Results: We found 3 studies reporting results for apalutamide, enzalutamide, and darolutamide. MFS was significantly lower in patients receiving darolutamide compared to both apalutamide (hazard ratio [HR]: 0.73, 95% confidence interval [CI]: 0.55–0.97) and enzalutamide (HR: 0.71, 95% CI: 0.54–0.93). MFS was similar for enzalutamide and apalutamide (HR: 0.97, 95% CI: 0.73–1.28). In PFS, apalutamide showed a slightly higher rate compared to darolutamide (HR: 0.76, 95% CI: 0.59–0.99). There was no difference in overall survival (OS) between any of the medications. There was no statistically significant difference in AEs profile of the 3 medications. However, darolutamide had the highest SUCRA value and probability of being the most preferred medication based on AEs profile. Conclusion: Enzalutamide and apalutamide had similar and higher MFS rate in indirect comparison with darolutamide. In cases where AEs are concerning, darolutamide might be the preferred agent.

Introduction

Prostate cancer remains the most common non-cutaneous cancer among American men [1]. Although most men are diagnosed with localized prostate cancer, still around 20% of men are diagnosed with advanced disease [2] in the United States. Initially, most men will respond to androgen deprivation therapy (ADT), however, the majority of men will develop castration-resistant prostate cancer (CRPC) within 1 year of initiation of ADT [3,4]. The annual incidence of nonmetastatic CRPC (nmCRPC) is estimated between 50,000 and 60,000 cases in the United States [5], [6], [7]. About 34% to 60% of nmCRPC patients advance to mCRPC within 1 to 5 years, with a median survival of less than 3 years with metastatic disease. Currently, delaying the progression of nmCRPC to mCRPC remains a treatment challenge [6,8,9].

In recent years, several randomized controlled clinical trials have been conducted on novel hormonal agents which target the androgen axis in the treatment of CRPC to improve metastasis free survival (MFS) rates. To date, 3 trials using second-generation androgen receptor antagonists (SGARA), apalutamide, enzalutamide, and darolutamide have shown significant improvement in MFS rates and prolonged time to symptomatic progression in the treatment of nmCRPC [10], [11], [12]. Given the similar MFS improvements and lack of randomized controlled trials for head to head comparisons of these novel antiandrogen agents, the selection of most appropriate agent in the clinic for patients with nmCRPC remains unclear. Previously, Wallis et al., reported an indirect comparison of enzalutamide and apalutamide [13]. They did not find any significant difference in MFS and adverse events (AEs) profile between the 2 medications. The present study was designed to further differentiate and stratify the efficacy and adverse effect profiles of apalutamide, enzalutamide, and darolutamide using a network meta-analysis (NMA) framework.

Section snippets

Search strategy and study selection

A systematic search using PubMed, MEDLINE, and SCOPUS was conducted on August 25, 2019 and updated on January 25, 2020. Key search terms included castration resistance prostate cancer, androgen deprivation therapy, androgen receptor, enzalutamide, apalutamide, and darolutamide. Results were input into an EndNote library, and duplicates were removed automatically. Two independent researchers (SBJ, JK) screened the search results and studies with the following criteria were selected:(1)

Studies and patient characteristics

Overall, found 1987 articles of which after selection of title and abstract and reviewing of the full-texts, 3 studies fulfilling our criteria were included in the analysis (Fig. 1). The SGARA medications used were apalutamide, enzalutamide, and darolutamide in a total of 4117 patients. Characteristics of the studies included in the analyses are summarized in Table 1. All trials in the selected studies were randomized 2:1 for SGARA to placebo. Results of various endpoints included in the final

Discussion

Based on modeling studies, it is estimated that over 3 million Americans in the United States will be diagnosed with prostate cancer by 2020 [6]. An estimated 100,000 men are living with nmCRPC in the United States. It is also estimated that 42,790 men will develop new CRPC in 2020, and 86% of these men will progress from nmCRPC to metastatic CRPC [6]. Since the publication of the modeling study in 2015, three SGARAs have been approved for the treatment of men with nmCRPC. In this NMA, we could

Conclusions

All SGARA medications improved MFS. Apalutamide and enzalutamide demonstrated similar MFS rates, which was higher than darolutamide. We could not find a significant difference in the AE profile of the 3medications. In cases where AEs limit the usage of enzalutamide and apalutamide, darolutamide can be considered as an alternative option.

Conflicts of interests

Authors have no conflicts of interests to report.

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  • Cited by (0)

    The first two authors contributed equally to the preparation of this manuscript.

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