Rezvilutamide-ADT trumps bicalutamide-ADT for high-volume mHSPC

In the interim analyses of the phase III CHART trial, a combination regimen of ADT* and the novel second-generation androgen-receptor (AR) inhibitor rezvilutamide trumped the bicalutamide-ADT combination in terms of survival outcomes in individuals with high-volume metastatic hormone-sensitive prostate cancer (mHSPC).

“The traditional standard of care (SoC) for mHSPC used to be ADT, with or without first-generation AR inhibitors,” said the researchers. The addition of first-generation AR inhibitors to ADT reportedly yields better clinical outcomes. [BJU Int 2004;93:1177-1182]

Second-generation AR inhibitors (eg, enzalutamide and apalutamide) were eventually incorporated into the treatment landscape of prostate cancer, which have led to significant clinical improvements when added to a background of ADT. [N Engl J Med 2019;381:121-131; J Clin Oncol 2019;37:2974-2986; N Engl J Med 2019;381:13-24] However, these were countered by increased CNS**-related toxicities that impaired quality of life (QoL). [Am Health Drug Benefits 2017;10:143-153; J Clin Oncol 2021;39:2294-2303; N Engl J Med 2018;378:1408-1418]

“Optimal treatment options that improve QoL and OS are therefore still greatly needed,” said the researchers.

The study randomized 654 participants 1:1 to receive ADT plus either rezvilutamide 240 mg or bicalutamide 50 mg orally QD in 28-day treatment cycles until disease progression, unacceptable toxicities, consent withdrawal, or investigator’s decision. [Lancet Oncol 2022;23:1249-1260]

At the preplanned interim analysis for radiographic progression-free survival (rPFS; median follow-up 21.2 months), significant improvement in rPFS was observed in the rezvilutamide vs the bicalutamide arm (median not reached [NR] vs 25.1 months; hazard ratio [HR], 0.44; p<0.0001). At 2 years, rPFS rate was higher in the rezvilutamide vs the bicalutamide arm (72 percent vs 50 percent).

“The treatment effects of rezvilutamide on rPFS were observed in all subgroups, except for patients with visceral metastases and patients not from China,” said the researchers. The lack of OS benefit in the subgroup of patients with visceral metastases may have been driven by the small number of events, they noted.

At the preplanned interim analysis for overall survival (OS; median follow-up 29.3 months), rezvilutamide also fared significantly better than bicalutamide in improving OS (median NR [both]; HR, 0.58; p=0.0001). The 2-year OS rate was also higher in the rezvilutamide vs the bicalutamide arm (82 percent vs 70 percent).

Bicalutamide-ADT has shown a longer OS than ADT alone in a previous study (HR, 0.78). [Cancer 2009;115:3437-3445] “Although comparisons between studies should be interpreted cautiously, [our] data suggest the superior clinical efficacy of early addition of rezvilutamide to ADT for high-volume mHSPC,” said the researchers.

The most frequently reported any-cause, grade ≥3 treatment-emergent adverse events (AEs) with rezvilutamide were hypertension, hypertriglyceridaemia, and increased weight (8, 7, and 6 percent, respectively). The corresponding incidences in the bicalutamide arm were 7, 2, and 4 percent, respectively. Almost 30 percent of participants in the rezvilutamide arm reported serious AEs, as opposed to 21 percent in the bicalutamide arm.

There were similar numbers of participants who discontinued treatment due to AEs (n=5 in each arm), as well as deaths owing to AEs (n=13 [rezvilutamide] vs 14 [bicalutamide]). While none of the deaths were deemed related to rezvilutamide, one was considered by the investigators as bicalutamide-related.

“Our findings further validate the clinical benefit of adding second-generation AR axis inhibitors to the ADT backbone in patients with mHSPC,” the researchers concluded. “The observed clinical benefit and desirable safety profile in the two interim analyses support the use of rezvilutamide in combination with ADT as SoC/frontline treatment for patients with high-volume mHSPC.”

Longer trials shall be conducted to validate the efficacy and safety of this combination regimen in this patient setting.