ARASENS trial: Darolutamide合併雄性素剝奪治療與Docetaxel對轉移性荷爾蒙敏感攝護腺癌病患治療結果: 疾病風險之次族群分析

吳錫金¹, Maha Hussain², Bertrand Tombal³, Fred Saad⁴, Karim Fizazi⁵, Cora N. Sternberg⁶, E. David Crawford⁷, Neal Shore⁸, Evgeny Kopyltsov⁹, Arash Rezazadeh Kalebasty¹⁰, Martin Bögemann¹¹, Dingwei Ye¹², Felipe Cruz¹³, Hiroyoshi Suzuki¹⁴, Frank Verholen¹⁵, Shankar Srinivasan¹⁶, Iris Kuss¹⁷, Heikki Joensuu¹⁸, Matthew R. Smith¹⁹

¹中國醫藥大學附設醫院, ²Northwestern University, Feinberg School of Medicine, Chicago, Illinois, USA; ³Division of Urology, IREC, Cliniques Universitaires Saint Luc, UCLouvain, Brussels, Belgium; 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, New York, USA; ⁷University of California San Diego School of Medicine, San Diego, California, USA; ⁸Carolina Urologic Research Center/Genesis Care, Myrtle Beach, South Carolina, USA; ⁹Clinical Oncological Dispensary of Omsk Region, Omsk, Russian Federation; ¹⁰University of California Irvine, Division of Hematology/Oncology, Orange, California, USA; ¹¹Department of Urology, Münster University Medical Center, Münster, Germany; ¹²Fudan University Shanghai Cancer Center, Xuhui District, Shanghai, China; ¹³Núcleo de Pesquisa e Ensino da Rede São Camilo, São Paulo, Brazil; ¹⁴Toho University Sakura Medical Center, Chiba, Japan; ¹⁵Bayer Consumer Care AG, Basel, Switzerland; ¹⁶Bayer HealthCare Pharmaceuticals Inc., Whippany, New Jersey, USA; ¹⁷Bayer AG, Berlin, Germany; ¹⁸Orion Corporation, Espoo, Finland; ¹⁹Massachusetts General Hospital Cancer Center, Boston, Massachusetts, USA.

Darolutamide in combination with androgen-deprivation therapy and docetaxel in patients with metastatic hormone-sensitive prostate cancer by disease volume and risk in the phase 3 ARASENS trial

Hsi-Chin Wu¹, Maha Hussain², Bertrand Tombal³, Fred Saad⁴, Karim Fizazi⁵, Cora N. Sternberg⁶, E. David Crawford⁷, Neal Shore⁸, Evgeny Kopyltsov⁹, Arash Rezazadeh Kalebasty¹⁰, Martin Bögemann¹¹, Dingwei Ye¹², Felipe Cruz¹³, Hiroyoshi Suzuki¹⁴, Frank Verholen¹⁵, Shankar Srinivasan¹⁶, Iris Kuss¹⁷, Heikki Joensuu¹⁸, Matthew R. Smith¹⁹

¹China Medical University Hospital, Taichung, ²Northwestern University, Feinberg School of Medicine, Chicago, Illinois, USA; ³Division of Urology, IREC, Cliniques Universitaires Saint Luc, UCLouvain, Brussels, Belgium; 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, New York, USA; ⁷University of California San Diego School of Medicine, San Diego, California, USA; ⁸Carolina Urologic Research Center/Genesis Care, Myrtle Beach, South Carolina, USA; ⁹Clinical Oncological Dispensary of Omsk Region, Omsk, Russian Federation; ¹⁰University of California Irvine, Division of Hematology/Oncology, Orange, California, USA; ¹¹Department of Urology, Münster University Medical Center, Münster, Germany; ¹²Fudan University Shanghai Cancer Center, Xuhui District, Shanghai, China; ¹³Núcleo de Pesquisa e Ensino da Rede São Camilo, São Paulo, Brazil; ¹⁴Toho University Sakura Medical Center, Chiba, Japan; ¹⁵Bayer Consumer Care AG, Basel, Switzerland; ¹⁶Bayer HealthCare Pharmaceuticals Inc., Whippany, New Jersey, USA; ¹⁷Bayer AG, Berlin, Germany; ¹⁸Orion Corporation, Espoo, Finland; ¹⁹Massachusetts General Hospital Cancer Center, Boston, Massachusetts, USA.

Purpose: In the ARASENS trial (NCT02799602), darolutamide plus androgen-deprivation therapy (ADT) and docetaxel significantly reduced the risk of death by 32.5% (hazard ratio [HR] 0.68; 95% confidence interval [CI]: 0.57–0.80; P<0.0001) compared with placebo plus ADT and docetaxel in patients with metastatic hormone-sensitive prostate cancer (mHSPC). The overall incidences of treatment-emergent adverse events (TEAEs) were similar between groups. The overall survival (OS) benefit was consistent across prespecified subgroups, including patients with de novo (HR 0.71; 95% CI: 0.59–0.85) and recurrent mHSPC (HR 0.61; 95% CI: 0.35–1.05). Metastatic burden affects outcomes in patients with mHSPC. We evaluated efficacy and safety from ARASENS by disease volume and risk.

Materials and Methods: Patients with mHSPC were randomized 1:1 to darolutamide 600 mg twice daily or placebo, with ADT and docetaxel. High-volume disease was defined per CHAARTED criteria as visceral metastases and/or ≥4 bone metastases with ≥1 beyond the vertebral column/pelvis. High-risk disease was defined per LATITUDE criteria as ≥2 risk factors: Gleason score ≥8, ≥3 bone lesions, and presence of measurable visceral metastasis. OS for these subgroups was assessed using an unstratified Cox regression model.

Results: Out of 1305 patients in ARASENS, 1005 (77%) had high-volume disease, 912 (70%) had high-risk disease, 300 (23%) had low-volume disease, and 393 (30%) had low-risk disease. Darolutamide plus ADT and docetaxel increased OS compared with placebo plus ADT and docetaxel in patients with high- or low-volume disease (HR [95% CI]: 0.69 [0.57–0.82] and 0.68 [0.41–1.13], respectively) and those with high- or low-risk disease (0.71 [0.58–0.86] and 0.62 [0.42–0.90]). Darolutamide improved clinically relevant secondary endpoints versus placebo in volume and risk subgroups, with HRs generally in the range of those observed in the overall population. Incidences of TEAEs were consistent with the overall ARASENS population across subgroups by high/low volume and risk.

Conclusion: In patients with mHSPC, treatment intensification with darolutamide plus ADT and docetaxel improved OS by approximately 30% across volume and risk subgroups. The favorable safety profile of darolutamide was confirmed in all subgroup populations. Darolutamide plus ADT and docetaxel should be considered as new standard of care for patients with mHSPC.