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.

Abstract

13 Background: Darolutamide (DARO) is a structurally distinct and highly potent androgen receptor inhibitor that demonstrated improved overall survival (OS) and metastasis-free survival vs placebo (PBO) and 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) in the ARASENS study (NCT02799602). Methods: This international, double-blind, phase 3 study enrolled pts with mHSPC and ECOG PS 0/1 who were randomized 1:1 to DARO 600 mg twice daily or matching 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 efficacy endpoints included time to CRPC, time to pain progression, time to first symptomatic skeletal event (SSE), and time to initiation of subsequent systemic antineoplastic therapies. Safety was also assessed. Results: From Nov 2016 to June 2018, 1306 pts were randomized, 651 to DARO and 655 to PBO, in combination with ADT + docetaxel. Median age was 67 y in both arms. At the primary data cutoff (Oct 25, 2021), DARO significantly decreased the risk of death by 32.5% vs PBO (HR 0.675, 95% CI 0.568–0.801; P < 0.0001). 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. In addition, DARO significantly delayed time to CRPC versus PBO (HR 0.357, 95% CI 0.302–0.421; P < 0.0001). Time to pain progression was also significantly longer with DARO vs PBO (HR, 0.792, 95% CI 0.660–0.950; P= 0.0058), as were time to first SSE and time to initiation of subsequent systemic antineoplastic therapy. TEAEs were similar between treatment arms, and the incidences of the most common TEAEs (≥10%) were highest during the overlapping docetaxel treatment period for both arms, 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 treatment discontinuation in 13.5% of pts in the DARO arm and 10.6% of pts in the PBO arm. 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. Clinical trial information: NCT02799602.

Addition of Docetaxel to Androgen Receptor Axis–targeted Therapy and Androgen Deprivation Therapy in Metastatic Hormone-sensitive Prostate Cancer: A Network Meta-analysis

“…abstracts and a yet to be indexed article [12,[24][25][26], and three abstracts with updated analyses [11,27,28] of included RCTs. During the peer review process for this article in April 2022, full-text publications of two RCTs [29,30] and an update to a third RCT [31] appeared.…”

“…[1,2,5,6,[8][9][10][11][12][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31]. Overall, across these 11 RCTs, 11 546 patients were treated in one of the four treatment regimens: ADT alone (n = 4548), ADT plus ARAT (n = 3211), ADT plus docetaxel (n = 2366), and the triplet of ADT, ARAT, and docetaxel (n = 1421).…”

Clinical research regarding the treatment of prostate cancer

“…Sobre la base del beneficio de docetaxel y los ISRA en el escenario del CPHSm, con el objetivo de posponer lo máximo posible el inicio de la fase de resistencia a la castración, se han evaluado nuevas hipótesis sobre el papel de la combinación de docetaxel + ISRA + TPA (tratamiento conocido como "triplete") en dos EECC aleatorizados de fase III. El estudio ARASENS investigó la combinación de darolutamida + docetaxel + TPA en comparación con docetaxel + TPA en la primera línea del tratamiento del CPHSm, tanto sincrónico (86 %) como metacrónico (14 %), y demostró aumento de SG con una reducción del riesgo de muerte del 32,5 % con diferencias estadísticamente significativas para todos sus objetivos secundarios a favor del triplete y con un perfil de seguridad similar al del doblete (11). En un análisis post-hoc de dicho estudio, se estratificó a la población en función del volumen de la enfermedad según los criterios CHAARTED y se demostró un beneficio en SG en el subgrupo de alto volumen, pero sin demostrarse dicho beneficio en el subgrupo de bajo volumen, a expensas de un pequeño tamaño muestral.…”

Optimal combination therapy for metastatic hormone-sensitive prostate cancer: new evidence, challenges and unanswered questions

“…The SOC plus abiraterone group also experienced improved OS compared to the group without abiraterone, both in the overall population and in the population of patients receiving ADT and DOC [ 18 , 19 ]. The ARASENS trial [ 5 , 7 ], tested the triplet combination of ADT + DOC + DARO versus the DOC doublet in newly diagnosed mHSPC patients with mostly de novo mHSPCA and high-volume disease. DARO demonstrated a significant 32.5% reduction in the risk of death compared to the control regimen.…”