Lynparza Latest News: Post hoc analysis confirms consistent clinical benefit of olaparib plus abiraterone in HRR-mutant mCRPC

Statistically and clinically meaningful improvements in radiographic progression-free survival (rPFS) and overall survival (OS) in patients with metastatic castration-resistant prostate cancer compared with first-line treatment with placebo plus abiraterone acetate (Zytiga), according to Presented at the 2024 Genitourinary Cancers Symposium The Phase 3 PROpel trial (NCT03732820) Post hoc analysis, metastatic castration-resistant prostate cancer (mCRPC) contains common homologous recombination repair (HRR) mutations.

Clinical benefit of olaparib plus abiraterone was observed in patients harboring BRCA2, ATM, and CDK12 mutations, which are the most common single-gene HRR mutations among all patients treated. For patients with BRCA2, ATM, and CDK12 mutations, rPFS rates were 27% (HR, 0.20; 95% CI, 0.08-0.44), 29% (HR, 0.55; 95% CI, 0.20-1.38), and 42% (HR, 0.51, 95% CI, 0.20-1.18) with the olaparib combination, respectively. The corresponding OS rates were 20% (HR, 020; 95% CI, 0.07-0.48), 43% (HR, 0.79; 95% CI, 0.33-1.77), and 47% (HR, 0.57; 95% CI, 0.24-1.27).

In the placebo group, rPFS was 71%, 50%, and 67% in patients with BRCA2, ATM, and CDK12 mutations, respectively. The corresponding OS rates were 64%, 54%, and 71%. Of note, due to the reduced incidence of other single-gene mutations, the analysis of olaparib combination therapy was limited to patients expressing other single-gene mutations.

Overall, the results were broadly consistent with the main results of the PROpel trial.

The results from PROpel collectively support olaparib plus abiraterone as an important new first-line treatment option to consider for patients with mCRPC and provide additional information on clinical outcomes in patients with various HRR mutations.

The PROpel trial previously met its primary endpoint of improved rPFS with olaparib compared with abiraterone and placebo in the intention-to-treat population. Previous data showed that the median rPFS for olaparib plus abiraterone was 24.8 months, compared with 16.6 months for abiraterone alone (HR, 0.66; 95% CI, 0.54-0.81; P < .0001). At the time of the final prespecified analysis, the median OS for the olaparib combination was 42.1 months compared with 34.7 months for the placebo regimen. This difference is numerically significant but not statistically significant.

A post hoc exploratory analysis examining the aggregated subgroups of HRR-mutated, non-HRR-mutated, BRCA-mutated, and non-BRCA-mutated disease further demonstrated favorable rPFS outcomes for olaparib plus abiraterone compared with abiraterone alone. The median HR for rPFS was 0.50 (95% CI, 0.34-0.73) in patients with HRR mutations and 0.76 (95% CI, 0.60-0.97) in patients without HRR mutations. Similarly, the HR for rPFS was 0.23 (95% CI, 0.12-0.43) in individuals with BRCA-positive disease, compared with 0.76 (95% CI, 0.61-0.94) in individuals without BRCA mutations.

PROpel's findings support the U.S. FDA's May 2023 approval of olaparib plus abiraterone and prednisone or prednisolone for the treatment of harmful or suspected harmful patients with BRCA-mutated mCRPC.

The researchers conducted the current post hoc analysis to build on previous data and determine the efficacy of olaparib plus abiraterone based on the presence of single gene mutations in the PROpel trial.

This double-blind, placebo-controlled trial enrolled patients at least 18 years of age with histologically or cytologically confirmed mCRPC and at least 1 documented metastatic lesion. The patient had an ECOG performance status of 0 or 1, ranging from asymptomatic to symptomatic, and had not received prior abiraterone treatment. The use of other next-generation hormonal drugs was allowed if the patient discontinued them at least 1 year before study enrollment. Of note, patients were included in the study regardless of HRR gene mutation and were tested after randomization.

HRR mutations are defined as mutations in one of the following genes: ATM, BRCA1/2, BARD1, BRIP1, CDK12, CHEK1/2, FANCL, PALB2, RAD51B/C/D, and RAD54L. In the current analysis, HRs and confidence intervals were not reported for gene subgroups with fewer than 5 rPFS or OS events in either group.

Patient with Patients were randomized in a 1:1 ratio to receive twice daily doses of olaparib (300 mg) and daily doses of abiraterone (1000 mg) (n = 399) or placebo plus abiraterone alone (n = 397). All patients received prednisone or prednisolone twice daily at a dose of 5 mg per label requirement. Treatment continued until disease progression, intolerable toxicity, or withdrawal of consent. The choice of subsequent treatment after progression is at the discretion of the investigator.

Patients were stratified according to the site of distant metastases (bone metastases only, visceral metastases, or other metastases) and whether they had previously received a taxane for metastatic hormone-sensitive prostate cancer (mHSPC).

The primary endpoint of the study was investigator-assessed rPFS rPFS. OS was a key secondary endpoint, and demonstration of a 50% reduction in prostate-specific antigen (PSA50) from baseline was an exploratory endpoint.

Baseline characteristics were generally balanced between groups. The median age in the olaparib group was 69 years (range, 43-91) and the median age in the placebo group was 70 years (range, 46-88). Most patients had an ECOG performance status of 0 (71.7% in the experimental group vs. 68.5% in the control group) and had distant bone metastases (87.5% vs. 85.4%). A total of 22.6% of patients in the olaparib group and 22.4% in the placebo group received docetaxel during the mHSPC phase. Symptoms were present in 25.8% and 20.2% of patients, respectively. Median PSA in each group was 17.90 (6.09-67.00) and 16.81 (6.26-53.30).

Of the 796 patients in the study 226 expressed HRR mutations. Furthermore, although patients were not stratified by HRR status, the proportion of patients with HRR mutations and the distribution of single-gene mutations were comparable between groups. In the olaparib group, 27.8% of patients had HRR mutations, 69.9% did not, and 2.3% had unknown status; the corresponding rates in the placebo group were 29.0%, 68.8%, and 2.3%, respectively. Single-gene mutations in BRCA2, ATM, and CDK12 were observed in 7%, 6%, and 40 patients, respectively. Other low-prevalence genes account for 6% of the population with HRR mutations.

In the olaparib combination group,5 patients had CHECK2 mutations (n = 7), 0 patients had BRCA1 mutations (n = 6), 1 patient had PALB2 mutations (n = 3), and 2 patients had RAD54L mutations (n = 6). 3), 3 patients with FANCL mutations (n u200bu200b= 3), and 0 patients with BARD1 mutations (n u200bu200b= 0) experienced OS events; the corresponding OS event rates in the placebo group were 8, 3, 3, 1, 0, and 1, respectively.

In the olaparib combined group,Four patients with CHECK2 mutations, 1 patient with BRCA1 mutations, 2 patients with PALB2 mutations, 2 patients with RAD54L, 2 patients with FANCL mutations, and 0 patients with BARD1 mutations experienced OS events; the corresponding OS event rates in the placebo group were 6, 3, 3, 0, 0, and 1, respectively.

Evaluation of PSA50 based on single-gene mutations Significant PSA50 responses to olaparib and abiraterone were achieved in 93%, 76%, and 83% of patients with BRCA2, ATM, and CDK12 mutations who had PSA measurements at baseline, respectively. In contrast, 41%, 75%, and 62% of patients achieved confirmed PSA50 responses with abiraterone plus placebo.

In patients with mutations in the HRR gene, results showed that olaparib plus abiraterone could slow disease progression and help patients live longer.