Darolutamide in Combination With Androgen-Deprivation Therapy in Patients With Metastatic Hormone-Sensitive Prostate Cancer From the Phase III ARANOTE Trial
Authors: Saad Fred , Vjaters Egils , Shore Neal , Olmos David , Xing Nianzeng , Pereira de Santana Gomes Andrea Juliana , Cesar de Andrade Mota Augusto , Salman Pamela , Jievaltas Mindaugas , Ulys Albertas , Jakubovskis Maris , Kopyltsov Evgeny , Han Weiqing , Nevalaita Liina , Testa Isabella , Le Berre Marie-Aude , Kuss Iris , Haresh Kunhi Parambath , Ganju Vinod , Gurney Howard , Krieger Laurence , Kwatra Vineet , Sewak Sanjeev , Stevanovic Amanda , Weickhardt Andrew , Azambuja Alan , Carcano Flavio Mavignier , Costa Marcio Valerio , Cruz Felipe , de Menezes Juliana , Joseph de Padua Charles Andree , Augusto de Paula Adriano , Santiago Escovar Carlos Eugenio , Couto Fernandez Fabio Leite , Gampel Otavio , de Santana Gomes Andrea Juliana P. , Luz Murilo , Marinho dos Santos Gisele , Cesar de Andrade Mota Augusto , Nogueira Lucas , D'Almeida Preto Daniel , Sant'Anna Alexandre , Tiscoski Katsuki Aruma , Giddens Jonathan , Jansz Godfrey , Kim Julian , Quellette Paul , Saad Fred , Vrabec George , Gaete Alejandro Acevedo , Medina Christian Caglevic , Cruzat Javier Dominguez , Salvo Marcelo Garrido , Pastor Arroyo Pedro Octavio , Huerta Anibal Salazar , Boghikian Pamela Salman , Valenzuela Velasquez Yasna Daniela , Zwenger Ariel , Fu Cheng , Guo Hongqian , Han Weiqing , Jiang Haowen , Jiang Junhui , Jiang Shusuan , Li Lei , Liu Tongzu , Liu Zhenhua , Ma Lulin , Qi Jun , Qiu Mingxing , Shi Guowei , Tian Ye , Wan Ben , Wang Chun-Xi , Wang Dongwen , Wang Shaogang , Wang Xiaolin , Wei Shaozhong , Wu Jitao , Xiao Jun , Xie Keji , Xie Liping , Xing Nianzeng , Xue Boxin , Yan Zejun , Yang Yong , Yu Zhixian , Zhang Dahong , Zheng Song , Zhou Fangjian , Advani Suresh , Agarwal Pawan , Bhatt Niraj , Biswajit Dubashi , Biswas Ghanashyam , Bondarde Shailesh A. , Das Chandan , Majumdar SarojKumar Das , Gupta Sujoy , Haresh Kunhi Parambath , James Francis , Jeyaraj Pamela , Joshi Amit , Kalyan Suman , Kashyapi Bhalchandra , Kaushal Ashish , Krishnappa Raghunath , Mavuduru Ravimohan , Nagarkar Rajanish , Panchal Harsha , Parkash Gourav , Philips Ashwin , Pooleri Ginil Kumar , Prabha Vikram , Rathnam Krishna Kumar , Ravel Naveen , Rawal Sudhir , Reddy Boya Rakesh , Shah Manasi , Voonna Praveena , Aleksandrovs Andrejs , Jakubovskis Maris , Laukmanis Alvis , Lietuvietis Vilnis , Vejins Mareks , Vjaters Egils , Jievaltas Mindaugas , Ulys Albertas , Venckus Raimundas , Zelvys Arunas , Bax Kevin , Gilling Peter , Holmes Michael , Tan Alvin , Deza Carlos Manuel Morante , Pazos Franco Alberto Juan , Salas Sanchez Jorge Fernando , Torrejon Alejandro Figueroa , Andabekov Timur , Atduev Vagif , Chapko Yana , Fadeeva Natalya , Filippov Alexander , Gafanov Rustem , Gladkov Oleg , Kasparov Boris , Kholtobin Denis , Kopyltsov Evgeny , Lykov Alexander , Nechaeva Marina , Plekhanov Alexey , Safina Sufia , Semenov Andrey , Shkolnik Mikhail , Skopin Pavel , Smirnov Roman , Solovyeva Ekaterina , Sultanbaev Alexander , Zavyalov Mikhail , Zyryanov Alexandr , Chabane Khabane , Coetzee Corlia , Jacobs Conrad , Madlala Thamsanqa , Malan Jorn , Mathijs Sophie , Abarca Carlos Llorente , Castellano Gauna Daniel Ernesto , Alvarez-Ossorio Fernandez Jose Luis , Diaz Enrique Gallardo , Garcia Pablo Borrega , Imbroda Bernardo Herrera , Medina Lopez Rafael Antonio , Gaya Sopena Josep Maria , Chung Hsiao-Jen , Huang Shu-Pin , Tsai Yuh-Shya , Wang Pai-Fu , Wang Shian-Shiang , Bondarenko Igor , Golovko Yurii , Ivashchenko Petro , Paramonov Viktor 
Published: September 2024

PURPOSE
For patients with metastatic hormone-sensitive prostate cancer (mHSPC), delaying progression to castration-resistant disease is important not only for overall survival (OS) but also for patients' quality of life. Darolutamide plus androgen-deprivation therapy (ADT) with docetaxel improved OS versus ADT and docetaxel in patients with mHSPC. The ARANOTE trial evaluated darolutamide and ADT without chemotherapy in patients with mHSPC.

METHODS
In this global phase III trial, patients were randomly assigned 2:1 to receive darolutamide 600 mg twice daily or placebo, with concomitant ADT. The primary end point was radiological progression-free survival (rPFS).

RESULTS

From March 2021 to August 2022, 669 patients were randomly assigned (darolutamide n = 446; placebo n = 223). At the primary cutoff date (June 7, 2024), darolutamide plus ADT significantly improved rPFS, reducing the risk of radiological progression or death by 46% versus placebo plus ADT (hazard ratio [HR], 0.54 [95% CI, 0.41 to 0.71];
P
< .0001), with consistent benefits across subgroups, including high- and low-volume disease. OS results were suggestive of benefit with darolutamide versus placebo (HR, 0.81 [95% CI, 0.59 to 1.12]), and clinical benefits were seen across all other secondary end points, including delayed time to metastatic castration-resistant prostate cancer (HR, 0.40 [95% CI, 0.32 to 0.51]) and time to pain progression (HR, 0.72 [95% CI, 0.54 to 0.96]). Adverse events were similar in the two groups. Notably, the incidence of fatigue was lower in patients receiving darolutamide (5.6%) versus those receiving placebo (8.1%), and fewer patients receiving darolutamide (6.1%) versus placebo (9.0%) discontinued treatment because of adverse events.

CONCLUSION
These results confirm the efficacy and tolerability of darolutamide plus ADT in patients with mHSPC, demonstrating clinically and statistically significant improvement in rPFS and a favorable safety profile consistent with prior phase III darolutamide trials.