Correlation of BRCA and HRD status with clinical and survival outcomes in patients with advanced-stage ovarian cancer in the age of PARPi maintenance therapy (187)

Abstract

Objectives: Fifty percent of patients with high-grade ovarian cancer (HGOC) have a germline or somatic (tumor) mutation in BRCA1/BRCA2 or are women who have tumors that do not have a somatic mutation but are classified as homologous recombination deficient (HRD). Current studies suggest that patients with HGOC who are germline BRCA+ (gBRCA) or somatic BRCA (sBRCA)/HRD+ will have a favorable response to poly (ADP-ribose) polymerase inhibitors (PARPi). We aimed to compare clinical and survival outcomes of women with HGOC stratified by germline BRCA or somatic BRCA/HRD status and evaluate the impact of PARPi maintenance therapy. Methods: We performed a retrospective analysis of all patients with advanced HGOC from April 2013 to March 2021. Patients were included if germline BRCA and HRD status were known. Clinical outcomes were analyzed and stratified by (1) gBRCA+ (2) gBRCA - and sBRCA/HRD+, or (3) BRCA-/HRD-. Progression-free survival (PFS) was estimated using Kaplan-Meier methods stratified by HRD status and modeled via Cox proportional hazards regression. Results: A total of 1,124 patients were reviewed, and 352 met our inclusion criteria. The Median follow-up was 27.3 months. One hundred and thirty-nine patients had gBRCA+ mutation, 69 sBRCA+/ HRD+, and 143 BRCA-/HRD-. Patients with BRCA-/HRD- tumors had older median age (64 vs 54 and 62 years, p<0.001) and lower median CA-125 at diagnosis (423 vs 832 and 857 U/ml, p=0.002), were more likely of White race (87% vs 76% and 66%, p=0.008), required more median NACT cycles (4 vs 3 and 3 cycles, p=0.03), were more likely to have surgically unresectable disease at diagnosis (52% vs 35% and 46%, p=0.02), and were less likely to get PARPi frontline maintenance therapy (7% vs 17% and 25%, p=0.001). Twenty-nine patients (8%) received PARPi frontline, and 51 patients (14%) received PARPi maintenance therapy at recurrence. Patients with BRCA-/HRD- disease had worse PFS (16.9 months vs 25 and 25.2 months, p<0.001) than those with gBRCA+ and sBRCA+/HRD+ disease. Multivariate analysis for PFS revealed that age (HR: 1.02, 95% CI: 1.00-1.03, p=0.04), stage III, IV (HR: 5.02, 95% CI: 1.21-20.94, p=0.03), complete gross resection at tumor reductive surgery (HR: 0.40, 95% CI: 0.23-0.69, p=0.004), and BRCA-/HRD- status (HR: 1.74, 95% CI: 1.20-2.51, p=0.004) were significant factors for PFS. The 6-month and 12-month survival probabilities of patients on frontline PARPi maintenance therapy were 1.00 (95% CI: NE) and 0.82 (0.59-0.93), respectively, regardless of gBRCA+ or sBRCA+/HRD+ status. Objectives: Fifty percent of patients with high-grade ovarian cancer (HGOC) have a germline or somatic (tumor) mutation in BRCA1/BRCA2 or are women who have tumors that do not have a somatic mutation but are classified as homologous recombination deficient (HRD). Current studies suggest that patients with HGOC who are germline BRCA+ (gBRCA) or somatic BRCA (sBRCA)/HRD+ will have a favorable response to poly (ADP-ribose) polymerase inhibitors (PARPi). We aimed to compare clinical and survival outcomes of women with HGOC stratified by germline BRCA or somatic BRCA/HRD status and evaluate the impact of PARPi maintenance therapy. Methods: We performed a retrospective analysis of all patients with advanced HGOC from April 2013 to March 2021. Patients were included if germline BRCA and HRD status were known. Clinical outcomes were analyzed and stratified by (1) gBRCA+ (2) gBRCA - and sBRCA/HRD+, or (3) BRCA-/HRD-. Progression-free survival (PFS) was estimated using Kaplan-Meier methods stratified by HRD status and modeled via Cox proportional hazards regression. Results: A total of 1,124 patients were reviewed, and 352 met our inclusion criteria. The Median follow-up was 27.3 months. One hundred and thirty-nine patients had gBRCA+ mutation, 69 sBRCA+/ HRD+, and 143 BRCA-/HRD-. Patients with BRCA-/HRD- tumors had older median age (64 vs 54 and 62 years, p<0.001) and lower median CA-125 at diagnosis (423 vs 832 and 857 U/ml, p=0.002), were more likely of White race (87% vs 76% and 66%, p=0.008), required more median NACT cycles (4 vs 3 and 3 cycles, p=0.03), were more likely to have surgically unresectable disease at diagnosis (52% vs 35% and 46%, p=0.02), and were less likely to get PARPi frontline maintenance therapy (7% vs 17% and 25%, p=0.001). Twenty-nine patients (8%) received PARPi frontline, and 51 patients (14%) received PARPi maintenance therapy at recurrence. Patients with BRCA-/HRD- disease had worse PFS (16.9 months vs 25 and 25.2 months, p<0.001) than those with gBRCA+ and sBRCA+/HRD+ disease. Multivariate analysis for PFS revealed that age (HR: 1.02, 95% CI: 1.00-1.03, p=0.04), stage III, IV (HR: 5.02, 95% CI: 1.21-20.94, p=0.03), complete gross resection at tumor reductive surgery (HR: 0.40, 95% CI: 0.23-0.69, p=0.004), and BRCA-/HRD- status (HR: 1.74, 95% CI: 1.20-2.51, p=0.004) were significant factors for PFS. The 6-month and 12-month survival probabilities of patients on frontline PARPi maintenance therapy were 1.00 (95% CI: NE) and 0.82 (0.59-0.93), respectively, regardless of gBRCA+ or sBRCA+/HRD+ status.