Analyzing Benefits and Safety of Darolutamide in mHSPC

Metastatic hormone-sensitive prostate cancer (mHSPC) treatment continues to evolve with new therapies improving outcomes for this population. In a live Community Case Forum event in New Jersey with Regional Cancer Care Associates, Jahan Aghalar, MD, a medical oncologist/hematologist at New York Cancer and Blood Specialists, discussed the ARANOTE trial (NCT04736199) of darolutamide (Nubeqa). Aghalar delved into results of subgroup analyses and the toxicity profile relevant for those treating patients with mHSPC at their clinic.

This article is part 2 of a 2-part series from a Case-Based Roundtable event.

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Targeted Oncology: How was darolutamide evaluated in patients with mHSPC?

Jahan Aghalar, MD: The phase 3 ARANOTE study included patients who had confirmed metastatic prostate cancer. They needed to be on primary androgen deprivation therapy [ADT], but for no longer than 3 months prior to randomization. Patients were not allowed to have had any prior second-generation androgen receptor inhibitors. They had to have an adequate performance status and adequate organ function. Patients were randomly assigned in a 2:1 fashion to receive darolutamide at a dosage of 600 mg twice daily with ADT in comparison to the control group where they received placebo.

The primary end point was radiographic progression-free survival [rPFS]. The secondary end point was overall survival [OS], along with a lot of other secondary end points of interest. Looking at the baseline characteristics and demographics, patients were well balanced between both groups. There was a good representation of minorities within this trial, within the Asian and Black population.

What was the efficacy for the primary end point and in the subgroups of ARANOTE?

The Kaplan-Meier curve for the primary end point of rPFS favored the darolutamide plus ADT arm; 70% were progression free at 24 months compared with 52% in the control group. This was a statistically significant HR of 0.54 [95% CI, 0.41-0.71; P < .0001]. I want to point out also that the median follow-up was a little bit over 2 years, so we don't have extended follow-up yet for this study.

Looking at the subset analyses, the rPFS was consistent, regardless of whether you break down the patients based on age group, baseline prostate-specific antigen [PSA] values, disease volume, patients seem to benefit from the rPFS standpoint. Gleason scores didn't impact whether there's going to be a benefit, and this benefit was seen regardless of race and geographic region in which they were treated. In patients who had visceral organ metastases, it seemed like [the HR] did cross 1.0, but that was a small proportion of patients. Whether or not they had prior local therapy, be it a prostatectomy or a radiation treatment, both groups had an rPFS benefit.

Looking at the secondary efficacy end points, there was a strong signal favoring OS, but not statistically significant. This is at a 24-month follow-up, so it's possible that the OS signal is not yet seen as the data are still immature, but certainly a strong, statistically significant improvement in time to metastatic castration-resistant prostate cancer, time to PSA progression, time to initiation of subsequent systemic therapy, and time to pain progression favoring darolutamide.

Can you discuss the toxicities seen in this patient population?

In terms of any-grade toxicities between the control group vs the treatment group and of worst grade toxicities of grade 3 or grade 4, it was even. There were some grade 5 events, but I believe a lot of these grade 5 events were COVID related, so it's unclear whether or not it was related to the drug. It was also even between both groups in terms of serious adverse events, at 23% in both groups. Patients who permanently discontinued the study drug were more common in the placebo group.

Incidents of fatigue, interestingly enough, were less seen in the patients who received darolutamide, at 5.6% vs 8.1%. Mental impairment disorder was slightly more with darolutamide, at 1.6% vs 0.5%. There were otherwise no differences in hypertension, cardiac arrythmias, slight increased risk of coronary artery disorders, and no increased incidence of heart failure. Falls were observed in 1.3% vs 0.9%, fractures in 4% vs 2.3%, flushing in 9.2% vs 7.2%, no differences in glucose intolerance, and rash incidences were pretty much even.

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DISCLOSURES: There were no known relevant disclosures.

REFERENCE:

Saad F, Vjaters E, Shore N, et al. Darolutamide in combination with androgen-deprivation therapy in patients with metastatic hormone-sensitive prostate cancer from the phase III ARANOTE trial. J Clin Oncol. 2024;42(36):4271-4281. doi:10.1200/JCO-24-01798