TY - JOUR
T1 - Phase Ib Study of Enzalutamide with or Without Sorafenib in Patients with Advanced Hepatocellular Carcinoma
AU - Harding, James J.
AU - Kelley, Robin K.
AU - Tan, Benjamin
AU - Capanu, Marinela
AU - Do, Gian Kinh
AU - Shia, Jinru
AU - Chou, Joanne F.
AU - Ferrer, Christine S.
AU - Boussayoud, Chayma
AU - Muenkel, Kerri
AU - Yarmohammadi, Hooman
AU - El Dika, Imane
AU - Khalil, Danny N.
AU - Ruiz, Carmen
AU - Rodriguez-Lee, Mariam
AU - Kuhn, Peter
AU - Wilton, John
AU - Iyer, Renuka
AU - Abou-Alfa, Ghassan K.
N1 - Publisher Copyright:
© AlphaMed Press; the data published online to support this summary are the property of the authors.
PY - 2020/12
Y1 - 2020/12
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85087297506&partnerID=8YFLogxK
U2 - 10.1634/theoncologist.2020-0521
DO - 10.1634/theoncologist.2020-0521
M3 - Article
C2 - 32548867
AN - SCOPUS:85087297506
SN - 1083-7159
VL - 25
SP - e1825-e1836
JO - Oncologist
JF - Oncologist
IS - 12
ER -