Darolutamide合併ADT搭配docetaxel與安慰劑合併ADT搭配docetaxel在 III期ARASENS臨床試驗用於轉移性荷爾蒙敏感攝護腺癌的整體存活率結果

馮思中¹、Matthew R. Smith, MD, PhD²、Maha Hussain, MD³、Fred Saad, MD⁴、Karim Fizazi, MD, PhD⁵、Cora N. Sternberg, MD⁶、E. David Crawford, MD⁷、Evgeny Kopyltsov, MD⁸、Chandler H. Park, MD⁹、Boris Alekseev, MD¹⁰、Álvaro Montesa Pino, MD¹¹、Dingwei Ye, MD¹²、Francis Parnis, MB, BS¹³、Felipe Melo Cruz, MD¹⁴、Teuvo L.J. Tammela, MD, PhD¹⁵、Hiroyoshi Suzuki, MD, PhD¹⁶、Heikki Joensuu, MD¹⁷、Silke Thiele, MD¹⁸、Rui Li, MS¹⁹、Iris Kuss, MD¹⁸、Bertrand Tombal, MD, PhD²⁰

¹長庚醫院; ²Massachusetts General Hospital Cancer Center, Boston, MA; ³Northwestern University, Feinberg School of Medicine, Chicago, IL; ⁴University of Montreal Hospital Center, Montreal, Quebec, Canada; ⁵Institut Gustave Roussy, University of Paris-Saclay, Villejuif, France; ⁶Englander Institute for Precision Medicine, Weill Cornell Department of Medicine, Meyer Cancer Center, New York-Presbyterian Hospital, New York, NY; ⁷UC San Diego School of Medicine, San Diego, CA; ⁸Clinical Oncological Dispensary of Omsk Region, Omsk, Russian Federation; ⁹Norton Cancer Institute, Louisville, KY; ¹⁰P.Hertsen Moscow Oncology Research Institute, Moscow, Russian Federation; ¹¹UGC Intercentros de Oncología Médica, Hospitales Universitarios Regional y Virgen Victoria, IBIMA, Málaga, Spain; ¹²Fudan University Shanghai Cancer Center, Xuhui District, Shanghai, China; ¹³Ashford Cancer Centre Research, Kurralta Park, SA, Australia; ¹⁴Núcleo de Pesquisa e Ensino da Rede São Camilo, São Paulo, Brazil; ¹⁵Tampere University Hospital, Tampere, Finland; ¹⁶Toho University Sakura Medical Center, Chiba, Japan; ¹⁷Orion Corporation Orion Pharma, Espoo, Finland; ¹⁸Bayer AG, Berlin, Germany; ¹⁹Bayer HealthCare Pharmaceuticals Inc., Whippany, NJ, USA; ²⁰Division of Urology, IREC, Cliniques Universitaires Saint-Luc, UCLouvain, Brussels, Belgium

Overall Survival with Darolutamide versus Placebo in Combination with Androgen-Deprivation Therapy and Docetaxel for Metastatic Hormone-Sensitive Prostate Cancer in the Phase 3 ARASENS Trial

See-tong Pang, MD, PhD,¹ presenting on behalf of the authors、Matthew R. Smith, MD, PhD²、Maha Hussain, MD³、Fred Saad, MD⁴、Karim Fizazi, MD, PhD⁵、Cora N. Sternberg, MD⁶、E. David Crawford, MD⁷、Evgeny Kopyltsov, MD⁸、Chandler H. Park, MD⁹、Boris Alekseev, MD¹⁰、Álvaro Montesa Pino, MD¹¹、Dingwei Ye, MD¹²、Francis Parnis, MB, BS¹³、Felipe Melo Cruz, MD¹⁴、Teuvo L.J. Tammela, MD, PhD¹⁵、Hiroyoshi Suzuki, MD, PhD¹⁶、Heikki Joensuu, MD¹⁷、Silke Thiele, MD¹⁸、Rui Li, MS¹⁹、Iris Kuss, MD¹⁸、Bertrand Tombal, MD, PhD²⁰

¹Chang-Gung Memorial Hospital, Taiwan; ²Massachusetts General Hospital Cancer Center, Boston, MA; ³Northwestern University, Feinberg School of Medicine, Chicago, IL; ⁴University of Montreal Hospital Center, Montreal, Quebec, Canada; ⁵Institut Gustave Roussy, University of Paris-Saclay, Villejuif, France; ⁶Englander Institute for Precision Medicine, Weill Cornell Department of Medicine, Meyer Cancer Center, New York-Presbyterian Hospital, New York, NY; ⁷UC San Diego School of Medicine, San Diego, CA; ⁸Clinical Oncological Dispensary of Omsk Region, Omsk, Russian Federation; ⁹Norton Cancer Institute, Louisville, KY; ¹⁰P.Hertsen Moscow Oncology Research Institute, Moscow, Russian Federation; ¹¹UGC Intercentros de Oncología Médica, Hospitales Universitarios Regional y Virgen Victoria, IBIMA, Málaga, Spain; ¹²Fudan University Shanghai Cancer Center, Xuhui District, Shanghai, China; ¹³Ashford Cancer Centre Research, Kurralta Park, SA, Australia; ¹⁴Núcleo de Pesquisa e Ensino da Rede São Camilo, São Paulo, Brazil; ¹⁵Tampere University Hospital, Tampere, Finland; ¹⁶Toho University Sakura Medical Center, Chiba, Japan; ¹⁷Orion Corporation Orion Pharma, Espoo, Finland; ¹⁸Bayer AG, Berlin, Germany; ¹⁹Bayer HealthCare Pharmaceuticals Inc., Whippany, NJ, USA; ²⁰Division of Urology, IREC, Cliniques Universitaires Saint-Luc, UCLouvain, Brussels, Belgium

Purpose: Darolutamide (DARO) is a structurally distinct and highly potent androgen receptor inhibitor that improved overall survival (OS) and metastasis-free survival vs placebo (PBO), with a low incidence of treatment-emergent adverse events (TEAEs) in patients (pts) with nonmetastatic castration-resistant prostate cancer (CRPC). We investigated whether DARO in combination with standard androgen-deprivation therapy (ADT) + docetaxel would increase OS in pts with metastatic hormone-sensitive prostate cancer (mHSPC).

Methods: This international, double-blind, phase 3 study (NCT02799602), randomized pts with mHSPC 1:1 to DARO 600 mg twice daily or PBO in addition to ADT + docetaxel. Randomization was stratified by extent of disease according to TNM (M1a vs M1b vs M1c) and alkaline phosphatase levels (< vs ≥ upper limit of normal). The primary endpoint was OS. Secondary endpoints included times to CRPC, pain progression, first symptomatic skeletal event (SSE), and initiation of subsequent systemic antineoplastic therapies, and safety.

Results: From Nov 2016 to June 2018, 1306 pts (median age 67 years) were randomized, 651 to DARO and 655 to PBO, in combination with ADT + docetaxel. At the primary data cutoff (Oct 25, 2021), DARO significantly decreased the risk of death by 32.5% vs PBO (HR 0.68, 95% CI 0.57–0.80; P<0.001). The significant improvement in OS was observed even though substantially more pts received subsequent life-prolonging systemic antineoplastic therapy in the PBO arm (75.6%) vs the DARO arm (56.8%). The significant OS benefit was consistent across prespecified subgroups. DARO significantly delayed time to CRPC vs PBO (HR 0.36, 95% CI 0.30–0.42; P<0.001). Time to pain progression was also significantly longer with DARO vs PBO (HR 0.79, 95% CI 0.66–0.95; P=0.01), as were times to first SSE and start of subsequent systemic antineoplastic therapy. TEAEs were similar between study arms. In both arms, the incidences of the most common TEAEs (≥10%) were highest during the overlapping docetaxel treatment period, with grade 3/4 TEAEs of 66.1% for DARO and 63.5% for PBO, mainly due to neutropenia (33.7% vs 34.2%, respectively). TEAEs led to discontinuation of DARO and PBO in 13.5% and 10.6% of pts, respectively.

Conclusions: In pts with mHSPC, early treatment combining DARO with ADT + docetaxel significantly increased OS and improved key secondary endpoints vs ADT + docetaxel alone. The incidence of TEAEs was similar in the two treatment arms.