Darolutamide Shows Favorable Safety Profile in Patients With Nonmetastatic Prostate Cancer


Men with nonmetastatic castration-resistant prostate cancer tolerated treatment with darolutamide well, according to findings from the phase 3 ARAMIS trial.

Karim Fizazi, MD

Karim Fizazi, MD

Results from the phase 3 ARAMIS trial revealed that darolutamide (Nubeqa) remained well-tolerated with a highly favorable safety profile compared with placebo and androgen deprivation therapy in patients with nonmetastatic castration-resistant prostate cancer (nmCRPC), according to data presented at the 2021 ASCO Annual Meeting.

“Almost all patients treated with darolutamide were able to receive the full planned dose with no change between double-blind and open-label periods,” said Karim Fizazi, MD, medical oncologist at Gustave Roussy, while presenting the findings. “And the majority of patients who required dose modifications subsequently reescalated to the full dose.”

ARAMIS was a double-blind and randomized phase 3 trial (NCT02200614) of darolutamide (Nubeqa) in men with nmCRPC to examine the potential of second-generation androgen receptor inhibitors (ARI), which could prolong metastasis-free survival with minimal adverse events (AE). The trial was unblinded at primary analysis, after which all patients could receive open label darolutamide.

Patients were randomized 2:1 to receive either darolutamide (n = 955) or a placebo (n = 554) with androgen deprivation therapy, with assessments of tolerability every 16 weeks. Median time on treatment was 18.5 months in the darolutamide double-blind (DB) group, 11.6 months in the placebo DB group, 25.8 months in the darolutamide DB and open label (OL) group and 11 in the placebo crossover to darolutamide OL group. Pharmacodynamic modeling was used to examine the association between maximum prostate-specific antigen (PSA) decline and overall survival (OS) at 2 years.

Darolutamide was well-tolerated over the DB and OL periods (98.9% of patients received full-planned dose) and majority of patients with dose modifications were able to resume the planned dose (darolutamide 89.6%, placebo 89.7%). The discontinuation rate due to disease progression was lower in the darolutamide group compared to the placebo group during the DB period (12.5% vs 35.3%). It remained a similar number with extended treatment during the DB and OL period (12.6%). Discontinuation due to AE increased slightly from the DB period (9%) to the DB and OL period (10.5%).

Pharmacodynamic modeling showed a positive association between OS and maximum PSA decline (defined as a ≥90% decline from baseline), indicating that long-term treatment with darolutamide delays disease progression and extends survival.

“Landmark sensitivity analysis of patients with PSA data at week 16 confirmed a positive association between PSA declines at week 16 and subsequent outcomes including overall survival,” said Fizazi. “Adjusting the landmark analyses for baseline covariates had little impact on best effect on overall survival.”

Treatment-emergent adverse events (TEAE) led to permanent discontinuation in 85 DB darolutamide-treated patients (8.9%), 48 DB placebo-treated patients (8.7%), 100 DB and OL darolutamide-treated patients (10.5%) and 8 in the DB-darolutamide OL crossover group (4.7%). The most common TEAE included transaminase increases, blood creatinine increase or neutropenia; deep vein thrombosis, hypertension, hypotension, peripheral ischemia or vasculitis; and abdominal discomfort/distension/pain, diarrhea, gastritis, nausea or small-intestine perforation.


Fizazi K, Shore ND, Raymond Smith M, et al. Darolutamide (DARO) tolerability from extended follow up and treatment response in the phase 3 ARAMIS trial. J Clin Oncol. 2021;39(suppl 15):Abstract 5079.

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