Phase Ib study of enzalutamide with or without sorafenib in patients with advanced hepatocellular carcinoma Journal Article
| Authors: | Harding, J. J.; Kelley, R. K.; Tan, B.; Capanu, M.; Do, G. K.; Shia, J.; Chou, J. F.; Ferrer, C. S.; Boussayoud, C.; Muenkel, K.; Yarmohammadi, H.; El Dika, I.; Khalil, D. N.; Ruiz, C.; Rodriguez-Lee, M.; Kuhn, P.; Wilton, J.; Iyer, R.; Abou-Alfa, G. K. |
| Article Title: | Phase Ib study of enzalutamide with or without sorafenib in patients with advanced hepatocellular carcinoma |
| 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. © AlphaMed Press; the data published online to support this summary are the property of the authors. |
| Journal Title: | The Oncologist |
| Volume: | 25 |
| Issue: | 12 |
| ISSN: | 1083-7159 |
| Publisher: | Oxford University Press |
| Date Published: | 2020-12-01 |
| Start Page: | e1825 |
| End Page: | e1836 |
| Language: | English |
| DOI: | 10.1634/theoncologist.2020-0521 |
| PUBMED: | 32548867 |
| PROVIDER: | scopus |
| PMCID: | PMC8186405 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 4 January 2021 -- Source: Scopus |
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