The addition of the PARP (poly [ADP-ribose] polymerase) inhibitor olaparib to standard-of-care abiraterone in the first-line setting of metastatic castration-resistant prostate cancer achieved longer progression-free survival vs abiraterone alone, as demonstrated in the final results of the phase III PROpel study, reported at the 2023 ASCO Genitourinary (GU) Cancers Symposium.1
A trend was also observed for improved median overall survival with the addition of olaparib. Although overall survival data were not mature, in the intention-to-treat population, median overall survival was 42.1 months with olaparib plus abiraterone vs 34.7 months with abiraterone plus placebo (P = .0544). Survival benefits were most pronounced in the BRCA-positive subgroup.
Noel Clarke, MBBS, FRCS, ChM
“The magnitude of improvement when olaparib was added [to abiraterone] is a significant improvement in outcome in a phase III trial in first-line metastatic castration-resistant prostate cancer,” said lead author Noel Clarke, MBBS, FRCS, ChM, Professor of Urological Oncology at The Christie and Salford Royal Hospitals in Manchester, UK. “The overall results support combination treatment with abiraterone plus olaparib as an important new first-line treatment in patients with metastatic castration-resistant prostate cancer.”
Dr. Clarke explained that even though there are many new drugs for first-line treatment of metastatic castration-resistant prostate cancer, median overall survival is still only about 3 years in clinical trials and less than 2 years in clinical practice. He pointed out that only half of patients receive one line of treatment, so the impact of first-line treatment is important.
The primary analysis of the PROpel trial, which was presented at the 2022 ASCO GU Cancers Symposium, showed a significant 34% reduction in the risk of disease progression or death with olaparib plus abiraterone vs placebo and abiraterone (P < .0001).2
The final analysis of the randomized, double-blind, placebo-controlled trial included 796 patients with prostate cancer and at least one metastatic lesion on imaging. Patients were randomly assigned 1:1 to receive abiraterone at 1,000 mg/d in combination with olaparib at 300 mg twice daily vs placebo and abiraterone at the same dose. Patients were unselected for homologous recombination repair (HRR) status; however, 28.4% of the intent-to-treat population had HRR-positive disease. The non-HRR population comprised 69.3% of patients.
Key Results and Toxicity
Subgroup analysis mirrored that of the intent-to-treat analysis. In the patients with HRR-positive disease, median overall survival was not reached in the experimental arm vs 28.5 months in the control arm. In the non-HRR population, median overall survival was 42.1 months compared with 38.9 months in the placebo-containing arm.
Mutational status is known to be important with PARP inhibitors: several trials have shown improvements mainly in patients with HRR mutations and particularly in those of BRCA type.
Dr. Clarke elaborated: “Patients with HRR mutations and those without are somewhat different populations. The control arm patients in the HRR-mutated group have a much more aggressive phenotype than those in the non-HRR–mutated group. Notwithstanding, there is improved survival [with the experimental regimen].”
KEY POINTS
The addition of the PARP inhibitor olaparib to standard-of-care abiraterone in the first-line setting of metastatic castration-resistant prostate cancer achieved longer progression-free survival vs abiraterone alone, according to the final results of the phase III PROpel study.
Overall survival data were not mature, but the investigators observed a trend toward improved median overall survival with the addition of olaparib. However, others believe longer-term follow-up is needed to confirm the overall survival results.
Survival benefits with the addition of olaparib were most pronounced in the BRCA-positive subgroup.
In patients with BRCA-positive disease, median overall survival was not reached in the olaparib-containing arm vs 23 months in the placebo/abiraterone arm. In the BRCA-negative group, median overall survival was 39.6 months and 38 months, respectively.
For the key secondary endpoints of time to first subsequent therapy and time to second disease progression, the combination led to a 24% improvement over placebo/abiraterone for both comparisons. Subsequent chemotherapy or hormonal therapy was required in 44.9% of the olaparib/abiraterone arm and 54.2% of the placebo/abiraterone arm.
No new safety signals emerged with longer follow-up. Adverse events occurring in 20% or more of patients in the experimental arm included anemia (49.7%), fatigue (38.7%), nausea (30.7%), back pain (21.6%), and diarrhea (20.6%). Two patients developed myelodysplastic syndrome. Both arms had a similar incidence of new primary cancers and pneumonitis. At the final data cutoff, no deterioration of quality of life was evident in the olaparib arm vs the placebo arm.
DISCLOSURE: The PROpel trial was sponsored by AstraZeneca and Merck Sharp & Dohme. Dr. Clarke has served as a consultant for Astellas, AstraZeneca, Bayer, Janssen, Pfizer, Novartis, and Merck and is CoPI of the Stampede and Radicals Trials.
REFERENCES
1. Clarke NW, Armstrong AJ, Thiery-Vuillemin A, et al: Final overall survival in PROpel: Abiraterone and olaparib versus abiraterone and placebo as first-line therapy for metastatic castration-resistant prostate cancer. 2023 ASCO GU Cancers Symposium. Abstract LBA16. Presented February 16, 2023.
2. Saad F. Armstrong AJ, Thiery-Vuillemin A, et al: PROpel: Phase III trial of olaparib and abiraterone versus placebo and abiraterone as first-line therapy for patients with metastatic castration-resistant prostate cancer. 2022 ASCO GU Cancers Symposium. Abstract 11. Presented February 16, 2022.
