Darolutamide (NUBEQA), developed by Bayer, was evaluated against enzalutamide in the Phase II ARACOG (AFT-47) trial, a prospective randomized study designed to assess cognitive function and quality-of-life outcomes in patients with advanced prostate cancer, including metastatic hormone-sensitive prostate cancer (mHSPC), metastatic castration-resistant prostate cancer (mCRPC), and non-metastatic castration-resistant prostate cancer (nmCRPC). Given the differing central nervous system (CNS) penetration profiles of androgen receptor pathway inhibitors (ARPIs), the study aimed to determine whether darolutamide could offer cognitive advantages over enzalutamide.

At the 2026 ASCO Annual Meeting, Bayer presented primary results demonstrating that darolutamide was associated with significantly less cognitive decline than enzalutamide. The trial met its primary endpoint, with patients receiving darolutamide experiencing a median change of -15.8% in the maximally changed cognitive domain (MCCD) compared with -36.1% for enzalutamide-treated patients (p=0.009). Improvements were particularly notable in executive function and working memory, cognitive domains critical for daily activities such as remembering instructions, following conversations, and managing tasks.

The study enrolled 111 patients, randomized to receive either darolutamide (n=55) or enzalutamide (n=56). Cognitive performance was assessed using the validated CANTAB platform across multiple domains, including memory recall, spatial working memory, visual memory, attention, and executive function. Among the 95 evaluable patients, baseline cognitive scores were comparable between treatment arms. Notably, all treatment crossovers occurred from the enzalutamide arm to the darolutamide arm, primarily due to objective or patient-reported cognitive decline. By week 24, 23 patients had crossed over, further supporting the favorable cognitive profile of darolutamide. These findings suggest that darolutamide may offer an important quality-of-life advantage while maintaining its established efficacy in advanced prostate cancer.

KOL insights

“When choosing treatment for advanced prostate cancer, physicians and patients increasingly consider not only survival and disease control, but also how treatment may affect the patient’s daily life, including cognitive function. Data such as these offer evidence that can help inform treatment discussions and support a more patient-focused approach to care.” –Expert Opinion

“At Bayer, we are committed to supporting people living with prostate cancer by advancing innovative treatment options. Data have demonstrated that darolutamide does not have the same impact on the central nervous system as enzalutamide.”–Expert Opinion

Conclusion

According to global epidemiological estimates, prostate cancer remains one of the most commonly diagnosed cancers among men worldwide, with a significant proportion of patients eventually progressing to metastatic hormone-sensitive prostate cancer (mHSPC), metastatic castration-resistant prostate cancer (mCRPC), or non-metastatic castration-resistant prostate cancer (nmCRPC). As survival improves and treatment durations lengthen, preserving cognitive function and quality of life has become an increasingly important consideration alongside efficacy in the management of advanced prostate cancer.

In the competitive androgen receptor pathway inhibitor (ARPI) market, Bayer’s darolutamide (NUBEQA), Pfizer/Astellas’ enzalutamide (XTANDI), Janssen’s apalutamide (ERLEADA), and Johnson & Johnson’s abiraterone acetate (ZYTIGA) continue to compete across multiple prostate cancer settings. While these agents have demonstrated meaningful clinical benefits, differentiation based on tolerability, CNS-related adverse events, and patient-reported outcomes is becoming increasingly relevant as physicians seek therapies that can maintain long-term quality of life. Results from the Phase II ARACOG trial suggest that darolutamide may offer a meaningful cognitive advantage over enzalutamide, demonstrating significantly less decline in cognitive performance at 24 weeks and a more favorable CNS profile.