Updated Results From the Phase 3 PROpel Trial

The prostate-focused session at the European Society for Medical Oncology Congress (ESMO) 2022 meeting in September offered presentations on several interesting trial results and analyses. Below, we highlight findings from the biomarker analysis, as well as updated results of the PROpel trial (NCT03732820)¹ investigating the role of olaparib in addition to abiraterone acetate plus prednisolone (AAP) in first-line treatment of patients with metastatic castration-resistant prostate cancer (mCRPC). The presentation was delivered by Fred Saad, MD, FRCS, the Raymond Garneau Chair in Prostate Cancer, and professor and chair of urology and director of genitourinary oncology at University of Montreal Hospital Center in Canada.

Poly (ADP-ribose) polymerase, or PARP, is a family of proteins involved in DNA repair pathways.² Annually, an estimated 270,0003 new cases of prostate cancer are diagnosed in the United States alone, and nearly 35,000³ men will experience prostate-cancer related mortality. Many of these individuals have metastatic castration-resistant prostate cancer (mCRPC) at the time of death. The concept of PARP inhibition as a therapeutic modality in this setting stems from the fact that an estimated 1 of 4 patients with mCRPC has a germline mutation in BRCA2, BRCA1, ATM, or CHEK2, with BRCA2 mutation being the most common.⁴ The good news is that the treatment armamentarium for mCRPC has expanded significantly in the past decade. Median overall survival (OS) has also significantly increased over prior historical averages of 18 to 24 months.⁵ However, there is a growing number of patients presenting with de novo metastatic disease at diagnosis,⁶ emphasizing the importance of continuing to expand treatment modalities.

Olaparib and AAP for mCRPC

PROpel is a phase 3 clinical trial investigating the role of olaparib in addition to AAP (olaparib+AAP) versus AAP alone as primary therapy for patients with mCRPC who have received no prior cytotoxic chemotherapy or hormonal therapy. Dr Saad began his presentation by explaining the impetus for the PROpel. Patients with mCRPC, even in the clinical trial setting, have a median OS of only ~36 months. Therefore, further investigation and trials of new therapies are needed to improve patient outcomes. Additionally, prior trials involving olaparib have demonstrated improvements in radiographic progression-free survival (rPFS) and OS in mCRPC patients with germline mutations who had disease progression despite treatment with next-generation hormonal agents.⁷ In a report published earlier this year in The New England Journal of Medicine, the results of the PROpel trial demonstrated significant improvement in rPFS in patients in the olaparib+AAP arm compared with the placebo+AAP arm regardless of their HRR (homologous recombination repair gene) mutational status.⁸

It is important to remember that PARP inhibition works via the concept of synthetic lethality. That is, the PARP protein complex is involved in single-stranded DNA repair; therefore inhibiting the PARP complex renders prostate cancer cells unable to repair single-stranded DNA damage.⁹ Cells with persistent single-stranded DNA damage will undergo replication, which results in double-stranded DNA damage that requires repair via double-strand repair mechanisms, such as homologous recombination repair and nonhomologous end joining.⁹ Both of these repair mechanisms rely on peptide products encoded in the ATM, CHK2, BRCA1, PALB2, and BRCA2 genes to correctly repair double-stranded DNA damage. However, in patients with germline mutations, 1 or more of these genes may be damaged.⁹ Consequently, we can understand that PARP inhibition via synthetic lethality will result in cell death, as both single-stranded and double-stranded DNA repair mechanisms are unable to function.

Dr Saad briefly reviewed the PROpel trial design. He explained that patients were enrolled for primary treatment with olaparib+AAP (n=399) compared with placebo+AAP (n=397). Patients with prior AAP exposure were excluded, but patients with exposure to other hormonal agents were included if exposure occurred >12 months before enrollment. The baseline characteristics of patients in the 2 arms were well balanced. In both the olaparib+AAP and placebo+AAP arms, most patients had an Eastern Cooperative Oncology Group performance status score of 0 (71.7% and 68.5%. respectively), and median ages were 69 and 70 years, respectively. Dr Saad remarked that, like prior trials of olaparib in patients with mCRPC, about 30% of patients had detectable HRR mutations (27.8% and 29%, respectively).

PROpel Trial Results

The primary endpoint for the trial was rPFS. Dr Saad explained that the olaparib+AAP arm saw an 8.2-month improvement in rPFS compared with the control arm (24.8 vs 16.6 months; hazard ratio [HR], 0.66; P<0.001), correlating to a 34% reduction. Based on updated results, Dr Saad explained that rPFS had improved to 8.6 months at the time of the ESMO presentation (25.0 vs 16.4 months; HR, 0.67; P<0.0001). When patients were stratified by HRR mutation status, subgroup analysis demonstrated benefit regardless of HRR mutation status (HR 0.50 for the HRRm and HR 0.76 for non-HRRm). The investigators also stratified patients by BRCA mutation status and found patients had benefit regardless of their status (HR for cohorts with vs without the mutation: 0.23 and 0.76). Dr Saad further remarked that in all subgroup analyses, including stratification by age at randomization and site of distant metastasis, patients in the olaparib+AAP arm experienced an rPFS benefit.

Dr Saad also discussed some other key secondary endpoints of interest, including time to first secondary therapy (TFST) and time to second progression (PFS2). TFST improved substantially in the combination arm compared with the placebo arm (25.4 vs 19.5 months; HR, 0.76; P=0.0032). Regarding PFS2, Dr Saad mentioned that the endpoints were not reached in either group, but preliminary data appear to favor the combination arm (HR, 0.71; P=0.019). Finally, although the final OS endpoint was not reached, the data continue to show high promise with significant improvement in OS, noted specifically after ~22 months of combination therapy. Safety endpoints were also explored in both arms. Dr Saad explained that there was no significant increase in toxicity noted in the combination arm despite a longer duration of therapy at the second analysis. An overall difference of ~12% in grade ≥3 adverse events was noted between the 2 therapeutic arms. Dr Saad remarked that this was primarily driven by the higher rate of anemia in the combination arm compared with the placebo arm (15.8% vs 3.3%).

In concluding remarks, Dr Saad explained that, compared to placebo +AAP, the combination of olaparib+AAP as primary therapy for mCRPC yielded a substantial improvement in rPFS (8.6 months; HR, 0.66; P<0.0001). Moreover, at the time of this analysis, data continued to demonstrate developing improvement in OS. Dr Saad also emphasized that the safety profile of combination therapy remained consistent with the original publication data. Thus, the data presented in this trial provide substantial support for the use of olaparib+AAP in the mCRPC setting. We look forward to the final results for OS and other secondary endpoints.

Akhil Abraham Saji, MD is a urology resident at New York Medical College / Westchester Medical Center. His interests include urology education and machine learning applications in urologic care. He is a founding and current member of the EMPIRE Urology New York AUA section team.

References

1. A Randomised, Double-blind, Placebo-controlled, Multicentre Phase III Study of Olaparib Plus Abiraterone Relative to Placebo Plus Abiraterone as First-line Therapy in Men With Metastatic Castration-resistant Prostate Cancer (PROpel Study). ClinicaTrials.gov identifier: NCT03732820. Accessed September 20, 2022. https://clinicaltrials.gov/ct2/show/NCT03732820
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