Darolutamide-containing triplet regimen ups survival in mHSPC regardless of disease volume, risk

In a post hoc analysis of the phase III ARASENS study, the triplet regimen comprising darolutamide, androgen deprivation therapy (ADT), and docetaxel continued to show overall survival (OS) benefit for metastatic hormone-sensitive prostate cancer (mHSPC) irrespective of disease volume and risk.

“In patients with mHSPC, metastatic disease burden is a prognostic factor,” said Dr Maha Hussain from Northwestern University, Feinberg School of Medicine, Chicago, Illinois, US, during her presentation at ASCO GU 2023.

“[Looking at OS] by disease volume, the hazard ratios (HRs) for both high-volume* and low-volume mHSPC favoured triplet therapy,” said Hussain. The respective HRs were 0.69 and 0.68. [ASCO GU 2023, abstract 15]

Hussain noted that the median OS for both subgroups in the triplet arm were not reached. “Both subgroups are generally favourable groups of patients … and there is some separation in the curves later on. It will be interesting to see if there are different signals as we do more follow ups.”

When stratifying by risk, triplet therapy was also associated with better HRs as opposed to the control arm, both in the high-risk** and low-risk subgroups (HRs, 0.71 and 0.62, respectively). Again, medians were not reached in both subgroups in the treatment arm.

Other secondary endpoints, safety

Time to castration-resistant PC (CRPC) strongly favoured the triplet vs the control regimen, regardless of disease volume (HRs, 0.41 and 0.21 for high- and low-volume disease, respectively) and risk (HRs, 0.38 and 0.32 for high- and low-risk, respectively). “These HRs were much better, and the separation of curves are quite impressive,” Hussain expressed.

The advantage of the triplet over the control regimen was consistently seen across all subgroups in terms of other key secondary endpoints, including time to pain progression (HRs ranging between 0.75 and 0.94), time to first symptomatic skeletal-related event (HRs ranging between 0.46 and 0.89), and initiation of next therapy (HRs ranging between 0.34 and 0.40).

“All of these are important secondary endpoints. Irrespective of risk criteria or volume of disease, overall, the triplet had a better outcome [than the control regimen], with HRs favouring triplet therapy,” said Hussain. The HRs were generally in the range of those seen in the overall cohort. [N Engl J Med 2022;386:1132-1142]

There were similar incidences of serious adverse events (AEs) in the high- and low-volume (45 percent vs 43 percent) and high- and low-risk subgroups (45 percent vs 44 percent). The rates of AEs leading to darolutamide discontinuation were also similar regardless of disease volume (13 percent vs 14 percent) and risk (13 percent vs 15 percent).

High-risk patient population

Hussain and colleagues sought to evaluate the benefits of early treatment intensification with darolutamide, ADT, and docetaxel for mHSPC. A total of 1,305 participants (median age 67 years) were randomized 1:1 to darolutamide 600 mg BID or placebo on top of ADT and docetaxel. Seventy-seven percent of participants had high-volume disease, while 70 percent had high-risk disease.

“ARASENS was quite a large study [with] a very high-risk patient population,” Hussain pointed out. “Essentially, most patients (>80 percent) have had de novo metastatic disease, [which is] another feature of poor risk disease.”

“[The current findings show that] the combination of darolutamide, ADT, and docetaxel improved OS, with the risk of death [dropping] by about 30 percent across volume and risk groups [in patients with mHSPC],” said Hussain.

The triplet regimen also improved clinically relevant secondary efficacy endpoints, with a favourable safety profile, across all subgroups. These findings align with published data looking at the overall population.

“Therefore, we conclude that darolutamide with ADT and docetaxel should be considered a new standard of care for patients with mHSPC,” said Hussain.