PROfound Trial Subgroup Analysis Finds Consistent Olaparib Benefit for mCRPC With BRCA Alterations

PROfound Trial Subgroup Analysis Finds Consistent Olaparib Benefit for mCRPC With BRCA Alterations

Olaparib (Lynparza) improved survival outcomes in all assessed subgroups of patients with metastatic castration-resistant prostate cancer (mCRPC) and BRCA alterations, according to findings from the phase 3 PROfound trial (NCT02987543) published in the Journal of Clinical Oncology.

“In this post-hoc exploratory analysis of patients with an underlying BRCA alteration in PROfound, treatment with olaparib compared with abiraterone or enzalutamide [Xtandi] led to a radiological progression-free survival [rPFS] and overall survival benefit for patients with mCRPC and a BRCA alteration whose disease had progressed on previous next-generation hormonal agent,” study authors wrote.

Subgroup Analysis

The rPFS benefit was consistent across all zygosity subgroups. The authors conceded that certain analyses were limited by small patient numbers. However, they were able to perform germline DNA testing for 112 (70%) patients, concluding that the risk of disease progression was similar among those with germline (HR, 0.08; 95% CI, 0.03-0.18) and somatic (HR, 0.16; 95% CI, 0.07-0.37) BRCA alterations.

Of the 160 patients with a BRCA alteration, 64.4% were evaluable for zygosity based on targeted next-generation sequencing. Among them, 85% (n = 88) were predicted to associated with biallelic inactivation of a BRCA gene. There was only a small number of patients (n = 15) suspected to have heterozygous alterations.

Among those with BRCA1 alterations, 1 patient had biallelic inactivation and 5 had a heterozygous alteration. Among those with BRCA2 (n = 97), 87 patients had a biallelic inactivation and 10 had a heterozygous alteration.

Within the biallelic subgroup, the confirmed overall response rate (ORR) was 60.7% (n = 17) with olaparib vs 0% in the control arm. The benefit of olaparib was not limited to the biallelic subgroup—the ORR in the heterozygous subgroup was 44.4%.

Further, patients with the BRCA2 homozygous deletions achieved prolonged responses with olaparib.

Similarly, within the biallelic subgroup, patients with BRCA2 homozygous deletion experienced a prolonged median rPFS of 16.6 months (95% CI, 9.3-not reached) with a 79% 12-month PFS rate.

Additional Findings

In the olaparib arm, the median treatment was 9.6 months (range, <0.1-28.9) at the final analysis and 3.8 months (range, 0.7-14.7) in the control arm.

Among those who crossed over to receive olaparib, the median duration of subsequent olaparib was 8.9 months (range, 0.2-28.9).

Olaparib induced longer PFS (HR, 0.22; 95% CI, 0.15-0.32) and overall survival (OS; HR, 0.63; 95% CI, 0.42-0.95) than abiraterone or enzalutamide among those with BRCA alterations.

The median rPFS was 9.8 months with olaparib vs 3.0 months in the control arm among all those with BRCA alterations. Among those with BRCA2 alterations, specifically (n = 128), the median rPFS was 10.8 vs 3.5 months, and among those with BRCA1 alterations (n = 13), the median rPFS was 2.1 vs 1.8 months.

Of note, an rPFS benefit was observed both in patients who had received previous taxane therapy (9.0 vs 1.9 months; HR, 0.20, 95% CI, 0.12-0.34) and those who had not received precious taxane therapy (14.6 vs 3.7 months; HR, 0.13, 95% CI, 0.05-0.31).

In the population of patients with BRCA alterations who had been randomly assigned to control therapy, 40 (69%) crossed over to olaparib after it was confirmed that their disease had progressed. Investigators used RPSTMS, which is a method used to adjust for crossover, to conduct a sensitivity analysis. The analysis showed that the hazard ratio for olaparib vs control was 0.27 (95% CI, 0.19-0.75) and 0.40 (95% CI, 0.27-0.90), depending on the selected model (Appendix Fig A3A without recensoring or FIG A3B with recensoring).

PROfound trial

The PROfound trial was a randomized, open-label trial that included patients with mCRPC with alterations in BRCA1, BRCA2 (BRCA), and/or ATM (cohort A) whose disease had progressed on prior next-generation hormonal agent (NHA). Previous findings from the study have already been reported; the study met its primary and secondary end points by demonstrating longer rPFS and OS with the PARP inhibitor.

All patients underwent tumor tissue testing to confirm that they had an alteration in a homologous recombination repair gene.

Participants were randomly assigned 2:1 to receive either monotherapy with olaparib, with a twice daily dose of 300 mg, or physicians’ choice of enzalutamide or abiraterone, at a 160 mg and 1000 mg daily dose, respectively, along with 5 mg of prednisone twice daily.

Ultimately, among 387 patients randomly assigned, 160 had a BRCA alteration.

Key Takeaways

Zygosity refers to the genetic make-up of a pregnancy, and prostate cancer is thought to be the most heritable cancer.

Alterations associated with homologous recombination are common in mCRPC; approximately 20% to 25% of patients will have an alteration, such as BRCA1 and BRCA2. These alterations typically signify more aggressive prostate cancer phenotype, but they also are more likely to be sensitive to poly(ADP-ribose) polymerase (PARP) inhibitors.

“These findings are important, as approximately 10% of patients with mCRPC have alterations in BRCA1 and BRCA2 genes, which are associated with more aggressive disease and poorer outcomes,” study authors concluded.

Reference

Mateo J, de Bono JS, Fizazi K, et al. Olaparib for the treatment of patients with metastatic castration-resistant prostate cancer and alterations in BRCA1 and/or BRCA2 in the PROfound Trial. J Clin Oncol. Published online November 14, 2023. doi:10.1200/JCO.23.00339