Olaparib-abiraterone combo improves PFS in mCRPC

The combination of olaparib and abiraterone in the first-line setting improved radiographic progression-free survival (rPFS) in patients with metastatic castration-resistant prostate cancer (mCRPC), results of the phase III PROpel trial showed.

The population comprised 796 patients (median age 69–70 years) with mCRPC and ECOG performance status 0–1, receiving androgen deprivation therapy, and with no prior abiraterone exposure. They were randomized 1:1 to receive abiraterone (1,000 mg QD) with either placebo or olaparib (300 mg BID). About 22 percent of patients had received docetaxel for metastatic hormone-sensitive prostate cancer and use of other next-generation hormonal agents was allowed if stopped ≥12 months pre-enrolment. About 28–29 percent had homologous recombination repair (HRR) gene mutations.

Investigator-assessed rPFS was significantly improved in patients who received olaparib-abiraterone compared with placebo-abiraterone (median 24.8 vs 16.6 months; hazard ratio [HR], 0.66, 95 percent confidence interval [CI], 0.54–0.81; p<0.0001). [ASCO GU 2022, abstract 11]

The rPFS rate at 12 months was 71.8 percent vs 63.4 percent with olaparib-abiraterone vs placebo-abiraterone, and 51.4 percent vs 33.6 percent at 24 months.

The results were echoed in the blinded independent central review analysis (median rPFS 27.6 vs 16.4 months; HR, 0.61, 95 percent CI, 0.49–0.74; p<0.0001), with 12- and 24-month rPFS rates of 73.8 percent vs 60.6 percent and 53.7 percent vs 34.1 percent, respectively.

This benefit was observed across all subgroups analysed including age, distant metastases site, baseline prostate specific antigen level, prior docetaxel receipt, and presence of HRR mutation.

Overall survival, though immature, showed a trend toward improved outcomes with olaparib-abiraterone vs placebo-abiraterone (median not reached in either group; HR, 0.86; p=0.29).

Time to first subsequent therapy or death was significantly extended in the olaparib-abiraterone vs placebo-abiraterone group (median 25.0 vs 19.9 months; HR, 0.74, 95 percent CI, 0.61–0.90; p=0.004), as was time to second progression or death (median not reached in either group; HR, 0.69, 95 percent CI, 0.51–0.94; p=0.0184).

Of the 321 patients with measurable disease at baseline, overall response rate improved by 10 percent with olaparib-abiraterone vs placebo-abiraterone (58.4 percent vs 48.1 percent; odds ratio, 1.60, 95 percent CI, 1.02–2.53; p=0.0409), with 4.3 percent vs 6.3 percent achieving complete response, and 54.0 percent vs 41.9 percent achieving partial response.

Grade ≥3 adverse events (AEs) occurred in 47.2 and 38.4 percent of olaparib-abiraterone and placebo-abiraterone recipients, respectively. AE-related deaths were comparable between groups (4.0 percent vs 4.3 percent), as was discontinuation of abiraterone (8.5 percent vs 8.8 percent). Olaparib was more commonly discontinued than placebo (13.8 percent vs 7.8 percent), and dose interruptions and reductions more common with olaparib than placebo (44.7 percent vs 25.3 percent [interruption] and 20.1 percent vs 5.6 percent [reduction]).

The most common grade ≥3 AEs in the olaparib-abiraterone and placebo-abiraterone groups were anaemia (15.1 and 3.3 percent, respectively) and hypertension (3.5 and 3.3 percent, respectively). There were no incidents of myelodysplastic syndrome or acute myeloid leukaemia and incidence of new primary malignancies and pneumonitis was comparable between groups. The incidence of cardiac failure was similar between groups (n=6 vs 5), as was arterial thromboembolic events (n=8 vs 10), while venous thromboembolic events were more frequent with olaparib-abiraterone (7.3 percent vs 3.3 percent).

“[T]here was no detriment to quality of life allowing most patients to stay on therapy,” presented study author Professor Fred Saad from the University of Montreal Hospital Center, Montreal, Canada, at ASCO GU 2022.

“Patients treated in the first-line mCRPC setting have a median survival of approximately 3 years in clinical trial settings. Unfortunately, in the real world and in clinical practice, many patients only receive one line of active therapy, and their median survival is … <2 years,” he said. “There’s clearly an unmet need to improve patient outcomes in the first-line mCRPC setting.”

“Olaparib-abiraterone led to a significant and clinically meaningful improvement in rPFS over placebo-abiraterone in first-line mCRPC,” Saad concluded.