First-line treatment with olaparib significantly improves PFS in mCRPC

The primary analysis of the PROpel trial showed that the addition of olaparib to abiraterone in first-line treatment of patients with metastatic castration-resistant prostate cancer (mCRPC) significantly improved radiographic progression-free survival (rPFS).

Patients with mCRPC treated in the first-line setting have a median survival of approximately 3 years in clinical trials. However, in clinical practice, approximately half of these patients receive only 1 line of active therapy, achieving a median survival of less than 2 years [1]. Recently, olaparib monotherapy has demonstrated to improve survival in patients with mCRPC with homologous recombination repair (HRR) gene alterations, post-next-generation hormonal agents [2,3]. In addition, the combination of olaparib plus abiraterone following docetaxel has shown to prolong rPFS irrespective of HRR mutational status [4].

The phase 3 PROpel study (NCT03732820) evaluates the efficacy and safety of PARP inhibitor olaparib plus abiraterone in the first-line mCRPC setting. The trial enrolled 796 mCRPC patients who failed primary androgen deprivation therapy, independent of HRR status. Participants were 1:1 randomised to receive olaparib plus abiraterone or placebo plus abiraterone. The primary endpoint was investigator-assessed rPFS. Dr Fred Saad (Centre Hospitalier de l’Université de Montréal, Canada) presented the first results [5].

Baseline patient characteristics were well-balanced between treatment arms (see Table). This planned interim analysis showed first-line treatment with olaparib plus abiraterone to significantly prolong rPFS versus placebo plus abiraterone (24.8 vs 16.6 months; HR 0.66; P<0.0001). Predefined subgroup analyses showed rPFS improvement across all subgroups, including participants with and without HRR mutations. A sensitivity analysis of rPFS by blinded independent central review showed similar results as the primary analysis (HR 0.61; P=0.004). The overall survival (OS) data is currently immature with 228 deaths (28.6%). A trend was observed in OS, favouring olaparib plus abiraterone (HR 0.86; P=0.29). The secondary endpoints of time to first subsequent treatment (HR 0.74; P=0.004) and time to second PFS or death (HR 0.69; P=0.0184) suggested long-term benefits of olaparib plus abiraterone. The overall response rate was 48.1% in the placebo arm versus 58.4% in the olaparib arm.

Table: Baseline patient characteristics in PROpel [5]



The most common grade ≥3 adverse event reported was anaemia (15.1 vs 3.3% for olaparib plus abiraterone versus placebo plus abiraterone). Quality of life was comparable between treatment arms over time.

“This interim analysis shows PROpel met its primary objective, demonstrating significant improvement in rPFS for olaparib plus abiraterone versus placebo plus abiraterone in patients with newly detected mCRPC who had not received prior first-line, irrespective of HRR status,” commented Dr Saad. “These results demonstrate the benefit of olaparib plus abiraterone without the need for HRR stratification in first-line treatment of mCRPC.”

Commenting on the results of PROpel and MAGNITUDE, discussant Dr Celestia Higano (University of British Columbia, Canada) cautioned to be aware of the differences in design between the 2 studies. In MAGNITUDE, HRR status was used to allocate patients to a cohort, while in PROpel patients were randomised regardless of their HRR status (which appeared to be well balanced in the end). In addition, due to the pre-specified futility analysis planned in the HRR-negative population in MAGNITUDE, the enrolment in this cohort was stopped after 200 patients (of the planned 600 patients). As a result, patient populations are not comparable in MAGNITUDE and PROpel, which could explain the differences in the results.

1. Shore ND, et al. Adv Ther 2021;38:4520–4540.
2. de Bono JS, et al. N Engl J Med 2020;382:2091–2102.
3. Hussain M, et al. N Engl J Med 2020;383:2345–2357.
4. Clarke N, et al. Lancet Oncol. 2018;19:975–986.
5. Saad F, et al. PROpel: Phase III trial of olaparib (ola) and abiraterone (abi) versus placebo (pbo) and abi as first-line (1L) therapy for patients (pts) with metastatic castration-resistant prostate cancer (mCRPC). Abstract 11, ASCO GU 2022, 17–19 February.

 

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Posted on 8 April, 202215 February, 2024