Rucaparib improves rPFS vs docetaxel or 2nd-generation ARPI in BRCA-mutated mCRPC

Rucaparib significantly improves radiographic progression-free survival (rPFS) vs physician’s choice of docetaxel, abiraterone acetate or enzalutamide in patients with metastatic castration-resistant prostate cancer (mCRPC) harbouring BRCA alterations whose disease has progressed after treatment with a second-generation androgen-receptor pathway inhibitor (ARPI), results of the phase III TRITON3 trial have shown.

The trial included 405 patients with mCRPC with a BRCA1/2 (n=302) or ATM (n=103) alteration, about 18 percent of whom had received no prior therapy for CRPC. All patients had disease progression after treatment with a second-generation ARPI (ie, abiraterone acetate, enzalutamide, apalutamide, or an investigational agent), but had not received chemotherapy for CRPC. The patients were randomized 2:1 to receive oral rucaparib 600 mg BID (n=270; median age, 70 years), or physician’s choice of a control medication (ie, docetaxel, abiraterone acetate or enzalutamide) (n=135; median age, 71 years). [Bryce AH, et al, ASCO GU 2023, abstract 18; N Engl J Med 2023;388:719-732]

In the control group, abiraterone acetate or enzalutamide could not be selected for patients who had received either ARPI before trial initiation. Docetaxel was the mostly commonly chosen control medication (56 percent), followed by enzalutamide (24 percent) and abiraterone acetate (21 percent).

At 62 months, median rPFS was significantly longer with rucaparib vs control in both the BRCA-altered population (11.2 months vs 6.4 months; hazard ratio [HR], 0.50; 95 percent confidence interval [CI], 0.36–0.69; p<0.001) and the intention-to-treat (ITT) population (10.2 months vs 6.4 months; HR, 0.61; 95 percent CI, 0.47–0.80; p<0.001). In patients with an ATM alteration, no rPFS benefit was observed with rucaparib vs control (median, 8.1 months vs 6.8 months; HR, 0.95; 95 percent CI, 0.59–1.52).

Exploratory efficacy analysis in the BRCA-altered population showed longer median rPFS with rucaparib compared with docetaxel (11.2 months vs 8.3 months; HR, 0.53; 95 percent CI, 0.37–0.77) and abiraterone acetate or enzalutamide (11.2 months vs 4.5 months; HR, 0.38; 95 percent CI, 0.25–0.58).

“Rucaparib is the first drug to show superiority over docetaxel in a randomized clinical trial of mCRPC,” said principal investigator, Dr Alan Bryce of Mayo Clinic, Phoenix, Arizona, US.

“The benefit was even greater compared with a second-generation ARPI,” said discussant Dr Elena Castro of Hospital Universitario 12 de Octubre, Madrid, Spain. “It helps us decide the best treatment sequence in the setting of a BRCA mutation: a PARP inhibitor before a taxane.”

Although overall survival (OS) data were only 54 percent mature in the BRCA-altered population and 59 percent mature in the ITT population, interim analysis at 62 months showed a trend in favour of rucaparib vs control (BRCA-altered population: median, 24.3 months vs 20.8 months; HR, 0.81; 95 percent CI, 0.58–1.12; p=0.21) (ITT population: median, 23.6 months vs 20.9 months; HR, 0.94; 95 percent CI, 0.72–1.23; p=0.67), despite a 75 percent rate of crossover from the control to the rucaparib group at the time of radiographic progression.

Grade ≥3 adverse events (AEs) were reported in 60 percent vs 53 percent of patients in the rucaparib vs control group. The most common grade ≥3 AEs in the rucaparib group were anaemia or decreased haemoglobin (24 percent), fatigue (7 percent), and neutropenia or decreased neutrophil count (7 percent). In the control group, the most common grade ≥3 AEs were fatigue (9 percent), neutropenia or decreased neutrophil count (8 percent), and febrile neutropenia (6 percent).

“Toxicities of rucaparib were in line with previous reports in patients with breast and ovarian cancer,” said Bryce. “No cases of myelodysplastic syndrome or acute myeloid leukaemia were reported.”