Enzalutamide in Chemotherapy-Naïve Metastatic Castration-Resistant Prostate Cancer: An Asian Multiregional, Randomized Study

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Abstract

Introduction

Enzalutamide significantly improved clinical outcomes compared with placebo in patients with chemotherapy-naïve metastatic castration-resistant prostate cancer (mCRPC) with disease progression despite androgen deprivation therapy (ADT) in the PREVAIL study. However, few patients from Asia were enrolled. Our study (NCT02294461) aimed to evaluate the safety and efficacy of enzalutamide in this disease setting in patients in mainland China, Korea, Taiwan, and Hong Kong.

Methods

In this double-blind, phase III study, patients with asymptomatic/mildly symptomatic metastatic prostate cancer and disease progression despite ADT were randomized to enzalutamide (160 mg/day) or placebo. The primary endpoint was time to prostate-specific antigen (PSA) progression. Secondary endpoints included overall survival, radiographic progression-free survival, time to first skeletal-related event (SRE), time to initiation of cytotoxic chemotherapy, PSA response ≥ 50%, best overall soft-tissue response, and safety. Pre-planned interim analysis was scheduled following approximately 175 PSA-progression events (67% of targeted total of 261 events). An additional 5-year landmark analysis of overall survival, time to antineoplastic therapy, and safety was performed.

Results

The double-blind study period was stopped after interim analysis owing to the benefit of enzalutamide over placebo. Overall, 388 patients were randomized (enzalutamide, n = 198; placebo, n = 190). Baseline characteristics were balanced between treatment groups. Enzalutamide significantly reduced risk of PSA progression vs placebo (hazard ratio 0.38; 95% CI 0.27–0.52; P < 0.0001). Median time to PSA progression was 8.31 months with enzalutamide and 2.86 months with placebo. Secondary endpoints, including 5-year overall survival, were significantly improved with enzalutamide, except time to first SRE. Adverse-event incidence was similar between enzalutamide and placebo. Fatigue was the most common drug-related adverse event in both treatment groups.

Conclusion

Enzalutamide significantly reduced risk of PSA progression, improved secondary efficacy endpoints, and was well tolerated in chemotherapy-naïve Asian patients with mCRPC with disease progression despite ADT.

Trial Registration

www.clinicaltrials.gov NCT02294461.

Supplementary Information

The online version contains supplementary material available at 10.1007/s12325-022-02140-2.

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Most cited references 15

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Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries

Hyuna Sung, Jacques Ferlay, Rebecca Siegel … (2021)

This article provides an update on the global cancer burden using the GLOBOCAN 2020 estimates of cancer incidence and mortality produced by the International Agency for Research on Cancer. Worldwide, an estimated 19.3 million new cancer cases (18.1 million excluding nonmelanoma skin cancer) and almost 10.0 million cancer deaths (9.9 million excluding nonmelanoma skin cancer) occurred in 2020. Female breast cancer has surpassed lung cancer as the most commonly diagnosed cancer, with an estimated 2.3 million new cases (11.7%), followed by lung (11.4%), colorectal (10.0 %), prostate (7.3%), and stomach (5.6%) cancers. Lung cancer remained the leading cause of cancer death, with an estimated 1.8 million deaths (18%), followed by colorectal (9.4%), liver (8.3%), stomach (7.7%), and female breast (6.9%) cancers. Overall incidence was from 2-fold to 3-fold higher in transitioned versus transitioning countries for both sexes, whereas mortality varied <2-fold for men and little for women. Death rates for female breast and cervical cancers, however, were considerably higher in transitioning versus transitioned countries (15.0 vs 12.8 per 100,000 and 12.4 vs 5.2 per 100,000, respectively). The global cancer burden is expected to be 28.4 million cases in 2040, a 47% rise from 2020, with a larger increase in transitioning (64% to 95%) versus transitioned (32% to 56%) countries due to demographic changes, although this may be further exacerbated by increasing risk factors associated with globalization and a growing economy. Efforts to build a sustainable infrastructure for the dissemination of cancer prevention measures and provision of cancer care in transitioning countries is critical for global cancer control.

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Cancer statistics in China, 2015.

Wanqing Chen, Rongshou Zheng, Peter D Baade … (2016)

With increasing incidence and mortality, cancer is the leading cause of death in China and is a major public health problem. Because of China's massive population (1.37 billion), previous national incidence and mortality estimates have been limited to small samples of the population using data from the 1990s or based on a specific year. With high-quality data from an additional number of population-based registries now available through the National Central Cancer Registry of China, the authors analyzed data from 72 local, population-based cancer registries (2009-2011), representing 6.5% of the population, to estimate the number of new cases and cancer deaths for 2015. Data from 22 registries were used for trend analyses (2000-2011). The results indicated that an estimated 4292,000 new cancer cases and 2814,000 cancer deaths would occur in China in 2015, with lung cancer being the most common incident cancer and the leading cause of cancer death. Stomach, esophageal, and liver cancers were also commonly diagnosed and were identified as leading causes of cancer death. Residents of rural areas had significantly higher age-standardized (Segi population) incidence and mortality rates for all cancers combined than urban residents (213.6 per 100,000 vs 191.5 per 100,000 for incidence; 149.0 per 100,000 vs 109.5 per 100,000 for mortality, respectively). For all cancers combined, the incidence rates were stable during 2000 through 2011 for males (+0.2% per year; P = .1), whereas they increased significantly (+2.2% per year; P < .05) among females. In contrast, the mortality rates since 2006 have decreased significantly for both males (-1.4% per year; P < .05) and females (-1.1% per year; P < .05). Many of the estimated cancer cases and deaths can be prevented through reducing the prevalence of risk factors, while increasing the effectiveness of clinical care delivery, particularly for those living in rural areas and in disadvantaged populations.

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Increased survival with enzalutamide in prostate cancer after chemotherapy.

Howard I Scher, Karim Fizazi, Fred Saad … (2012)

Enzalutamide (formerly called MDV3100) targets multiple steps in the androgen-receptor-signaling pathway, the major driver of prostate-cancer growth. We aimed to evaluate whether enzalutamide prolongs survival in men with castration-resistant prostate cancer after chemotherapy. In our phase 3, double-blind, placebo-controlled trial, we stratified 1199 men with castration-resistant prostate cancer after chemotherapy according to the Eastern Cooperative Oncology Group performance-status score and pain intensity. We randomly assigned them, in a 2:1 ratio, to receive oral enzalutamide at a dose of 160 mg per day (800 patients) or placebo (399 patients). The primary end point was overall survival. The study was stopped after a planned interim analysis at the time of 520 deaths. The median overall survival was 18.4 months (95% confidence interval [CI], 17.3 to not yet reached) in the enzalutamide group versus 13.6 months (95% CI, 11.3 to 15.8) in the placebo group (hazard ratio for death in the enzalutamide group, 0.63; 95% CI, 0.53 to 0.75; P<0.001). The superiority of enzalutamide over placebo was shown with respect to all secondary end points: the proportion of patients with a reduction in the prostate-specific antigen (PSA) level by 50% or more (54% vs. 2%, P<0.001), the soft-tissue response rate (29% vs. 4%, P<0.001), the quality-of-life response rate (43% vs. 18%, P<0.001), the time to PSA progression (8.3 vs. 3.0 months; hazard ratio, 0.25; P<0.001), radiographic progression-free survival (8.3 vs. 2.9 months; hazard ratio, 0.40; P<0.001), and the time to the first skeletal-related event (16.7 vs. 13.3 months; hazard ratio, 0.69; P<0.001). Rates of fatigue, diarrhea, and hot flashes were higher in the enzalutamide group. Seizures were reported in five patients (0.6%) receiving enzalutamide. Enzalutamide significantly prolonged the survival of men with metastatic castration-resistant prostate cancer after chemotherapy. (Funded by Medivation and Astellas Pharma Global Development; AFFIRM ClinicalTrials.gov number, NCT00974311.).

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All references

Author and article information

Contributors

Yeong-Shiau Pu: yspu@ntu.edu.tw

Hanjong Ahn: hjahn@amc.seoul.kr

Weiqing Han: md70210@sina.com

Shu-Pin Huang: shpihu73@gmail.com

Hsi-Chin Wu: d4746@mail.bh.cmu.edu.tw

Lulin Ma: malulin@medmail.com.cn

Shunsuke Yamada: shunsuke.yamada@astellas.com

Kazutaka Suga: kazutaka.suga@astellas.com

Li-Ping Xie: xielp@zju.edu.cn

Journal

Journal ID (nlm-ta): Adv Ther

Journal ID (iso-abbrev): Adv Ther

Title: Advances in Therapy

Publisher: Springer Healthcare (Cheshire )

ISSN (Print): 0741-238X

ISSN (Electronic): 1865-8652

Publication date (Electronic): 10 April 2022

Publication date PMC-release: 10 April 2022

Publication date (Print): 2022

Volume: 39

Issue: 6

Pages: 2641-2656

Affiliations

[1 ]GRID grid.412094.a, ISNI 0000 0004 0572 7815, National Taiwan University Hospital, ; Taipei, Taiwan

[2 ]GRID grid.267370.7, ISNI 0000 0004 0533 4667, Asan Medical Center, , University of Ulsan, ; Seoul, South Korea

[3 ]GRID grid.410622.3, ISNI 0000 0004 1758 2377, Hunan Cancer Hospital, ; Hunan, China

[4 ]GRID grid.412027.2, ISNI 0000 0004 0620 9374, Kaohsiung Medical University Hospital, ; Kaohsiung, Taiwan

[5 ]GRID grid.411508.9, ISNI 0000 0004 0572 9415, China Medical University Hospital, ; Taichung, Taiwan

[6 ]GRID grid.411642.4, ISNI 0000 0004 0605 3760, Peking University Third Hospital, ; Beijing, China

[7 ]GRID grid.423286.9, ISNI 0000 0004 0507 1326, Astellas Pharma Inc, ; Northbrook, IL USA

[8 ]GRID grid.418042.b, ISNI 0000 0004 1758 8699, Astellas Pharma Inc, ; Tokyo, Japan

[9 ]GRID grid.452661.2, ISNI 0000 0004 1803 6319, The First Affiliated Hospital of Zhejiang University School of Medicine, ; Zhejiang, China

Article

Publisher ID: 2140

DOI: 10.1007/s12325-022-02140-2

PMC ID: 9123068

PubMed ID: 35397772

SO-VID: 0ef0cc32-81d9-49be-a91b-6251230aafc2

License:

Open AccessThis article is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License, which permits any non-commercial use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc/4.0/.

History

Date received : 14 January 2022

Date accepted : 17 March 2022

Funding

Funded by: Astellas Pharma Inc.

Funded by: Pfizer Inc.

Custom metadata

Keywords: enzalutamide,metastasis,castration-resistant prostate cancer,treatment efficacy,asia

Data availability:

Keywords: enzalutamide, metastasis, castration-resistant prostate cancer, treatment efficacy, asia

Enzalutamide in Chemotherapy-Naïve Metastatic Castration-Resistant Prostate Cancer: An Asian Multiregional, Randomized Study

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Abstract

Introduction

Methods

Results

Conclusion

Trial Registration

Supplementary Information

Related collections

Karger: Oncology

Most cited references 15

Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries

Cancer statistics in China, 2015.

Increased survival with enzalutamide in prostate cancer after chemotherapy.

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Contributors

Journal

Affiliations

Article

History

Funding

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