Safety of darolutamide (DARO) for non-metastatic castration-resistant prostate cancer (nmCRPC) from extended follow-up in the phase III ARAMIS trial

See-tong Pang¹ presenting on behalf of the authors、 Matthew Smith²、Karim Fizazi³、Teuvo Tammela⁴、Felipe Melo Cruz⁵、Luke Nordquist⁶、Diana Sofia Aleman Polanco⁷、Urban Emmenegger⁸、Glauco Silveira⁹、Raoul Concepcion¹⁰、Adriano Paula¹¹、Carlos Augusto de Mendonca Beato¹²、Neil Fleshner¹³、Martin Richardet¹⁴、Iris Kuss¹⁵、Marie-Aude Le Berre¹⁶、Gustavo Borghesi¹⁵、Toni Sarapohja¹⁷、Neal Shore¹⁸

¹Chang-Gung Memorial Hospital, Taiwan; ²Massachusetts General Hospital Cancer Center, Boston, MA, USA; ³Institut Gustave Roussy, University of Paris Sud, Villejuif, France; ⁴Tampere University Hospital and Tampere University, Tampere, Finland; ⁵Instituto Brasileiro de Controle do Câncer, São Paulo, Brazil;⁶GU Research Network, Omaha, NE, USA; ⁷Centro Médico Monte Carmelo, Arequipa, Peru; ⁸Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Canada; ⁹Centro Oncológico do Triângulo, Uberlândia, Brazil; ¹⁰Urology Associates PC, Nashville, TN, USA; ¹¹Hospital Araujo Jorge, Goiânia, Brazil; ¹²Hospital Amaral Carvalho, São Paulo, Brazil; ¹³Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada; ¹⁴Sanatorio Aconcagua, Córdoba, Argentina; ¹⁵Bayer AG, Berlin, Germany; ¹⁶Bayer Healthcare SAS, Loos, France; ¹⁷Orion Corporation Orion Pharma, Espoo, Finland; ¹⁸Carolina Urologic Research Center, Myrtle Beach, SC, USA                                                     

Purpose:

n ARAMIS, DARO significantly prolonged median metastasis-free survival and overall survival. Adverse events (AEs) of interest commonly associated with androgen receptor inhibitor (ARI) therapy, such as fatigue, falls, fractures, rash, mental impairment, and hypertensioncan impact patient daily life. In the final analysis of the double-blind (DB) period, DARO had a favorable safety profile, showing ≤2% difference vs placebo (PBO) for most AEs of interest. Fatigue was the only AE with >10% incidence. Permanent discontinuation due to AEs was also similar between DARO and PBO (8.9% vs 8.7%). Here we present safety data for prolonged treatment with DARO from the final analysis of the DB + open-label (OL) period.

Methods:

Patients (pts) with nmCRPC (N=1509) were randomized 2:1 to DARO or PBO while continuing androgen deprivation therapy. The data cut-off for the primary analysis of the DB period was September 3, 2018. Study unblinding occurred on November 30, 2018, after which DARO pts still receiving study treatment continued with OL DARO. The data cut-off for final analysis of the DB+OL period was November 15, 2019.

Results:

At the final analysis, the median treatment duration for DARO was 18.5 months for the DB period and 25.8 months for the DB+OL period. At the final cut-off date, 48.8% of patients in the DARO DB+OL group were still receiving DARO treatment. The increase in the incidence of any-grade AEs (85.7% vs 89.8%) and serious AEs (26.1% vs 32.1%) between the DB and DB+OL period was small. Between the DB and DB+OL periods, only minor numerical changes for ARI-associated AEs were observed. When the incidences were corrected for exposure, there were minimal differences between the DB and DB+OL period. Fatigue was the only ARI-associated AE of interest with >10% incidence in the DARO arm during the DB+OL period. The incidence of permanent discontinuation of DARO due to AEs increased slightly from 8.9% during the DB period to 10.5% during the DB+OL period; the incidence of discontinuation of PBO due to AEs during the DB period was 8.7%.  

Conclusions:

With longer treatment exposure, DARO remained well-tolerated. In the DB+OL period, no new safety signals were observed. The expected increases in incidence of AEs between the DB and DB+OL periods largely disappeared when adjusted for the longer exposure, confirming the favorable safety profile of DARO with prolonged treatment.