Phase Ib Study of Enzalutamide with or Without Sorafenib in Patients with Advanced Hepatocellular Carcinoma |
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| Authors: | James J Harding Robin K Kelley Benjamin Tan Marinela Capanu Gian Kinh Do Jinru Shia Joanne F Chou Christine S Ferrer Chayma Boussayoud Kerri Muenkel Hooman Yarmohammadi Imane El Dika Danny N Khalil Carmen Ruiz Mariam Rodriguez-Lee Peter Kuhn John Wilton Renuka Iyer Ghassan K Abou-Alfa |
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| Affiliation: | 1. Department of Medicine, Memorial Sloan Kettering Cancer Center, Weill Cornell Medical College, New York, New York, USA;2. Department of Medicine, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, California, USA;3. Department of Medicine, Washington University, St. Louis, Missouri, USA;4. Department of Epidemiology-Biostatistics, Memorial Sloan Kettering Cancer Center, Weill Cornell Medical College, New York, New York, USA;5. Department of Radiology, Memorial Sloan Kettering Cancer Center, Weill Cornell Medical College, New York, New York, USA;6. Department of Pathology, Memorial Sloan Kettering Cancer Center, Weill Cornell Medical College, New York, New York, USA;7. University of Southern California USC Michelson Center, Los Angeles, California, USA;8. Department of Medicine, Roswell Park Cancer Institute, Buffalo, New York, USA |
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| 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.
BackgroundAndrogen receptor (AR) interference is deleterious to hepatocellular carcinoma (HCC) in preclinical models.MethodsThis 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.ResultsIn 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.ConclusionEnzalutamide is ineffective in HCC; further development is not supported by this study. |
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