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Clinical Trial
. 2020 Dec;25(12):e1825-e1836.
doi: 10.1634/theoncologist.2020-0521. Epub 2020 Jul 2.

Phase Ib Study of Enzalutamide with or Without Sorafenib in Patients with Advanced Hepatocellular Carcinoma

James J Harding  1 , Robin K Kelley  2 , Benjamin Tan  3 , Marinela Capanu  4 , Gian Kinh Do  5 , Jinru Shia  6 , Joanne F Chou  4 , Christine S Ferrer  1 , Chayma Boussayoud  1 , Kerri Muenkel  1 , Hooman Yarmohammadi  5 , Imane El Dika  1 , Danny N Khalil  1 , Carmen Ruiz  7 , Mariam Rodriguez-Lee  7 , Peter Kuhn  7 , John Wilton  8 , Renuka Iyer  8 , Ghassan K Abou-Alfa  1
Affiliations
Clinical Trial

Phase Ib Study of Enzalutamide with or Without Sorafenib in Patients with Advanced Hepatocellular Carcinoma

James J Harding et al. Oncologist. 2020 Dec.

Abstract

Lessons learned: Androgen receptor as assessed by immunohistochemistry is expressed in a high proportion of patients with hepatocellular carcinoma (HCC). Enzalutamide at 160 mg orally daily is safe and tolerable in patients with advanced HCC but has no single-agent antitumor activity. Enzalutamide, a CYP3A4 inducer, at a standard dose of 160 mg reduces the exposure of sorafenib, a CYP3A4 substrate. Enzalutamide and sorafenib is safe and tolerable in patients with advanced HCC, but the addition of enzalutamide to sorafenib did not enhance the antitumor activity of sorafenib.

Background: Androgen receptor (AR) interference is deleterious to hepatocellular carcinoma (HCC) in preclinical models.

Methods: This is a multicenter, phase Ib study of enzalutamide ± sorafenib in patients with advanced HCC. In part 1, a 3 + 3 dose de-escalation design with expansion established the recommended phase II dose (RP2D) of enzalutamide in patients in whom sorafenib treatment had failed. In part 2, a 3 + 3 dose escalation with expansion established the safety of enzalutamide with sorafenib in treatment-naive patients with HCC. Secondary objectives included objective response rate (ORR), progression-free survival (PFS), overall survival (OS), pharmacokinetics (PK), and determination of AR expression by immunohistochemistry. A 7-day run-in with sorafenib alone in part 2 allowed assessment of the impact of enzalutamide on sorafenib pharmacokinetics.

Results: In part 1, 16 patients received enzalutamide 160 mg daily. No dose-limiting toxicity (DLT) occurred; 1 patient required dose reduction. Responses were not observed; median PFS and OS were 1.8 (95% confidence interval [CI]: 1.6-3.6) and 7 (95% CI: 3.6 to not reached [NR]) months, respectively. In part 2, patients received sorafenib 400 mg daily (4) or twice a day (8) both with enzalutamide at the recommended phase II dose-no DLTs were observed. ORR was 10% (95% CI: 0.3-44.5), and median PFS and OS were 2.9 (95% CI: 1.6 to NR) and 6.7 (95% CI: 4.6 to NR) months, respectively. Enzalutamide reduced sorafenib exposure by 60%. Tumor AR expression did not associate with outcome.

Conclusion: Enzalutamide is ineffective in HCC; further development is not supported by this study.

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Figures

Figure 1
Figure 1
Efficacy and outcomes for advanced HCC patients treated with enzalutamide +/− sorafenib. Waterfall plot (A) and progression‐free survival (B) of enzalutamide. Waterfall plot (C) and progression‐free survival (D) of enzalutamide and sorafenib. Abbreviations: PD, progressive disease; PR, partial response; SD, stable disease.
See this image and copyright information in PMC

References

    1. Ma WL, Hsu CL, Wu MH et al. Androgen receptor is a new potential therapeutic target for the treatment of hepatocellular carcinoma. Gastroenterology 2008;135:947–955, 955 e1–5. - PMC - PubMed
    1. Ren H, Ren B, Zhang J et al. Androgen enhances the activity of ETS‐1 and promotes the proliferation of HCC cells. Oncotarget 2017;8:109271–109288. - PMC - PubMed
    1. Sun H, Yang W, Tian Y et al. An inflammatory‐CCRK circuitry drives mTORC1‐dependent metabolic and immunosuppressive reprogramming in obesity‐associated hepatocellular carcinoma. Nat Commun 2018;9:5214. - PMC - PubMed
    1. Zhang H, Li XX, Yang Y et al. Significance and mechanism of androgen receptor overexpression and androgen receptor/mechanistic target of rapamycin cross‐talk in hepatocellular carcinoma. Hepatology 2018;67:2271–2286. - PMC - PubMed
    1. Nicholson B, Gulding K, Conaway M et al. Combination antiangiogenic and androgen deprivation therapy for prostate cancer: A promising therapeutic approach. Clin Cancer Res 2004;10:8728–8734. - PubMed

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