222P - Tolerability and treatment response to darolutamide (DARO) in patients with non-metastatic castration-resistant prostate cancer (nmCRPC) in the phase III ARAMIS trial

Background

Androgen receptor inhibitors (ARIs) approved for treating nmCRPC are associated in varying degrees with certain adverse events (AEs), e.g., fatigue, risk of falls or rash. In phase III studies, dose modification and discontinuation due to AEs was higher with ARIs vs placebo. Reduced dose, compliance patterns and treatment adherence may impact drug efficacy. Tolerability of DARO and association of prostate-specific antigen (PSA) decline in response to DARO treatment with metastasis-free survival (MFS) in the ARAMIS trial are reviewed.

Methods

1509 patients with nmCRPC and PSA doubling time (PSADT) ≤10 months were randomised 2:1 to DARO 600 mg twice daily (n=955) or placebo (PBO; n=554) while continuing androgen deprivation therapy. AEs and dose modifications were assessed every 16 weeks. The association between PSA decline from baseline in response to DARO treatment and MFS was evaluated using the Cox proportional hazards model. An association with overall survival will be investigated.

Results

DARO was well tolerated; 97.2% of patients on DARO received the full planned dose. Permanent treatment discontinuation due to AEs was similar for patients treated with DARO as compared with PBO (8.9% vs 8.7%). Few patients had dose modifications for AEs or any other reason (15.2% vs 9.7% for DARO vs PBO). Almost all of the patients on DARO who had dose interruptions or modifications were able to resume and re-establish the indicated dose (91.7% vs 88.9% for DARO vs PBO). In the ARAMIS trial, 50.9% of patients on DARO had a maximal PSA response (≥90% decrease from baseline) vs 1.8% of patients on PBO. Pharmacodynamic modelling showed that longer MFS was positively associated with maximum decrease in PSA from baseline. Prostate cancer-related quality of life was maintained with DARO treatment.

Conclusions

Favourable tolerability of DARO at the recommended dose of 600 mg twice daily was associated with low rates of dose reduction and treatment discontinuation, which in turn may lead to extended survival with longer duration of treatment with DARO. It is important to further assess the real-world tolerance of different ARIs in men with nmCRPC.

Clinical trial identification

NCT02200614.

Editorial acknowledgement

Editorial assistance was provided by Lucy Smithers, PhD, and Annabel Ola, MSc, both of Scion, London, and supported by Bayer.

Legal entity responsible for the study

Bayer AG and Orion Pharma.

Funding

Bayer AG and Orion Pharma.

Disclosure

M.R. Smith: Honoraria (self), Advisory/Consultancy, Research grant/Funding (self): Bayer; Honoraria (self), Advisory/Consultancy, Research grant/Funding (self): Amgen; Honoraria (self), Advisory/Consultancy: Astellas; Honoraria (self), Advisory/Consultancy, Research grant/Funding (self): Janssen; Honoraria (self), Advisory/Consultancy, Research grant/Funding (self): Lilly; Honoraria (self), Advisory/Consultancy: Novartis; Honoraria (self), Advisory/Consultancy: Pfizer. N.D. Shore: Advisory/Consultancy, Speaker Bureau/Expert testimony: Bayer; Advisory/Consultancy, Speaker Bureau/Expert testimony: Janssen; Advisory/Consultancy: Tolmar; Advisory/Consultancy: Ferring; Advisory/Consultancy: Medivation; Advisory/Consultancy: Amgen; Advisory/Consultancy: Pfizer; Advisory/Consultancy: AstraZeneca; Advisory/Consultancy: Genentech/Roche; Advisory/Consultancy: Myovant Sciences; Advisory/Consultancy: Astellas Pharma; Advisory/Consultancy: Merck; Advisory/Consultancy, Speaker Bureau/Expert testimony: Dendreon. T.L.J. Tammela: Research grant/Funding (institution): Bayer; Advisory/Consultancy: Janssen; Research grant/Funding (institution): Lidds AB; Research grant/Funding (institution): Astellas Pharma. M-A. Le Berre: Full/Part-time employment: Bayer. O. Petrenciuc: Full/Part-time employment: Bayer. C. Zurth: Full/Part-time employment: Bayer. I. Kuss: Shareholder/Stockholder/Stock options, Full/Part-time employment: Bayer. K. Fizazi: Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Janssen; Honoraria (self), Advisory/Consultancy: Bayer; Honoraria (self), Advisory/Consultancy: Astellas Pharma; Honoraria (self), Advisory/Consultancy: Sanofi; Advisory/Consultancy: Orion Pharma GmbH; Advisory/Consultancy: Curevac; Honoraria (institution): AstraZeneca; Advisory/Consultancy: ESSA; Advisory/Consultancy, Travel/Accommodation/Expenses: Amgen; Advisory/Consultancy: Roche.