ARACOG is a study that was performed in order to understand whether there may be differences in cognitive change associated with two different androgen receptor pathway inhibitor agents, enzalutamide and darolutamide, because they are incredibly commonly used in advanced prostate cancer. There was a thought that there may be differences in the way that they affected patients in terms of their fatigue levels or cognitive abilities.
The reason for this is that darolutamide has a very low penetration through the blood-brain barrier into the central nervous system, whereas enzalutamide has a higher penetration into the CNS. The thought was that with this greater penetration there may be greater effects on cognitive function for the patients who are receiving treatment.
Could you outline the methodology?
The study was a phase II randomised controlled trial in which patients with metastatic hormone-sensitive, metastatic castration resistant and non-metastatic castration resistant prostate cancer were prospectively enrolled and randomised to receive either darolutamide or enzalutamide. Importantly, darolutamide was provided through the study and enzalutamide was provided through standard of care with patients accepting whatever copay was assigned to them as part of the eligibility criteria to enrol.
Patients were followed and were assessed with CANTAB computer-based cognitive tests, as well as patient-reported outcome measures and functional assessments, as well as adverse event assessments at baseline, 12 weeks, 24 weeks and 48 weeks over basically a year of study follow-up, with the primary endpoint being change in cognitive function at 24 weeks, so at six months. If patients experienced a significant cognitive change on their objective computer-based cognitive tests or on their patient-reported perceived or subjective patient-reported outcome measure, or if they had a fall or were at higher risk of falls, or experienced a severe neurologic toxicity, they could crossover from one treatment arm to the other treatment arm and then continue on with their follow-up in the study.
At this meeting, ASCO 2026, we reported the primary endpoint of maximally changed cognitive domain or the domain on the computer-based cognitive test that had the greatest change within each treatment arm. These could be different domains, depending on the treatment. Basically, whichever cognitive domain looked like it did the worst on either treatment would be compared to each other so that we could understand the maximal effect of these treatments on cognitive function. This occurred at 24 weeks.
What we found in that comparison is that there was a greater decline in cognitive function among those patients treated with enzalutamide than among those patients treated with darolutamide and this was statistically significant. There was also a greater crossover from enzalutamide to darolutamide with all patients who did do crossover, actually crossing from enzalutamide to darolutamide within the study at the 24-week follow-up.
Importantly, I want to remind everyone, as I said, that patients did have darolutamide provided for free through the study and so financial toxicity or the burden of having to pay the copay for patients treated with enzalutamide may have contributed to them crossing over, but it’s also possible that the more substantial cognitive burden that they had from having that greater change on their computer-based cognitive tests may have played a role in them wanting to cross over as well.
What impact could these findings have?
The important thing to remember is that enzalutamide is used widely across the range of many different disease settings in advanced prostate cancer, including non-metastatic castrate sensitive or hormone sensitive disease or high-risk biochemical recurrence, as well as metastatic castration resistant prostate cancer and still, of course, will be used preferentially in those settings because that’s the approval that we have within the US and in many other areas of the world. But there are regions or stages of or states of prostate cancer where both drugs are easily accessible, including non-metastatic castration resistant prostate cancer and metastatic hormone sensitive prostate cancer. In those two settings clinicians and patients can consider this information about cognitive change as they’re making shared decisions and considering so many things about that decision, including the disease state, what’s accessible to them in terms of treatment, their other comorbidities and drug interactions, as they try to make that shared decision and choose the right treatment for them.
