Lynparza is indicated in combination with bevacizumab for the maintenance treatment of adult patients with advanced epithelial ovarian, fallopian tube or primary peritoneal cancer who are in complete or partial response to first-line platinum-based chemotherapy and whose cancer is associated with homologous recombination deficiency (HRD)-positive status defined by either: a deleterious or suspected deleterious BRCA mutation, and/or genomic instability.

Newly Diagnosed Ovarian Cancer...The addition of olaparib to bevacizumab maintenance may be offered to patients who have stage III-IV HGS or endometrioid ovarian cancer and germline or somatic pathogenic or likely pathogenic variants in BRCA1 or BRCA2 genes and/or genomic instability, as determined by Myriad myChoice CDx, and who have had a partial or complete response to chemotherapy plus bevacizumab combination...

Olaparib has been added as an option for patients with a CR/PR and germline or somatic BRCA1/2 mutation, if bevacizumab was used as primary part of primary therapy.

The phase III PAOLA-1/ENGOT-ov25 study (NCT02477644) showed that addition of olaparib to bevacizumab maintenance improved progression-free survival (PFS) in patients with newly diagnosed advanced ovarian cancer....After median follow-up of 22.1 months, median PFS was 21.6 months with olaparib versus 16.6 months with placebo in the older population (hazard ratio [HR] 0.55, 95% confidence interval [CI] 0.41-0.75), comparable with the younger population (median 22.9 versus 16.9 months; HR 0.61, 95% CI 0.49-0.77). PFS benefits were observed in patients with a BRCA mutation or homologous recombination deficiency-positive tumours.

The benefit was particularly high for those with BRCA1m located in the DBD, with 24-month PFS estimated to be 89% and 15% [olaparib + bevacizumab versus placebo + bevacizumab hazard ratio = 0.08 (95% confidence interval 0.02-0.28); interaction P = 0.03]. In BRCA2m patients, 24-month PFS rates for those with mutations located in the DBD were 90% and 100% (olaparib + bevacizumab versus placebo + bevacizumab), respectively....Advanced-stage BRCA-mutated HGOC patients reported PFS benefit from maintenance olaparib and bevacizumab regardless of mutation location. The benefit is particularly high for patients with mutations located in the DBD of BRCA1. Mutations located in the DBD of BRCA2 are also associated with excellent outcome.

Among the 806 randomized pts, 235 (29.2%) harbored a BRCAm: 160 (19.9%) with a BRCA1 mutand 76 (9.4%) with a BRCA2 mut. BRCA1 mut in FDs of RING, DNA-BD and BRCT were detected in 19 (11.8%), 41 (25.6%) and 34 (21.2%) pts, respectively. BRCA2 mut were detected in FDs of RAD51-BD and DNA-BD in 37 (48.7%) and 14 (18.4%) pts, respectively...In this exploratory analysis, pts with newly diagnosed advanced HGOC and a BRCAm had a PFS benefit from maintenance ola + bev...

Of 806 randomized pts, 292 (36%) were ≥65 y (Table). Median age: older pts, 69 y (range 65–87 y); younger pts, 56 y (range 26–64 y). A lower proportion of older vs younger pts had an ECOG performance status of 0 (62% vs 75%), upfront surgery (39% vs 57%) and, of pts who had upfront surgery, a lower proportion had complete macroscopic resection (54% vs 62%). Older pts were less likely to have a BRCA1/2 mutation (BRCAm) (17% vs 36% of younger pts) or a homologous recombination deficiency (HRD)-positive status (36% vs 55%) and were more likely to be HRD-negative (46% vs 28%). Data cut off was 22 March 2019. After a median follow-up (in censored pts) of 22.1 months (mo) in older pts and 24.0 mo in younger pts, similar PFS was observed in the older and younger pt subgroups (Table). In older pts, greater PFS benefits with olaparib were seen in those with a BRCAm or who were HRD-positive...Despite a lower rate of complete surgical debulking, older pts achieved a similar PFS benefit vs younger pts (including in the BRCAm and both HRD positive cohorts) when olaparib was added to first-line maintenance bev, with a comparable safety profile.

...Among HRD+ stage III pts, 36-mo PFS2 (olaparib + bev vs pbo + bev) was 74% vs 60%; among HRD+ stage IV pts, 53% vs 30%. Among HRD+ stage III pts with no residual disease after upfront surgery, HR (95% CI) for PFS was 0.15 (0.07–0.30) and for PFS2 was 0.22 (0.06–0.67). Among HRD+ stage III pts with residual disease after upfront surgery or who received neoadjuvant chemotherapy, or HRD+ stage IV pts, HR (95% CI) for PFS was 0.38 (0.27–0.53) and PFS2 was 0.68 (0.46–1.03).In the PAOLA-1 study, maintenance olaparib + bev provided a PFS and PFS2 benefit over pbo + bev in HRD+ pts, irrespective of

...AstraZeneca and Merck, known as MSD outside the United States and Canada, today announced that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has adopted a positive opinion recommending LYNPARZA for the maintenance treatment of adult patients with advanced (FIGO stages III and IV) high-grade epithelial ovarian, fallopian tube or primary peritoneal cancer who are in response (complete or partial) following completion of first-line platinum-based chemotherapy in combination with bevacizumab and whose cancer is associated with homologous recombination deficiency (HRD)-positive status defined by either a BRCA1/2 mutation and/or genomic instability....The positive opinion was based on a biomarker subgroup analysis of the Phase 3 PAOLA-1 trial, whichwas published in The New England Journal of Medicine....The addition of LYNPARZA to bevacizumab improved progression-free survival (PFS) to a median of 37.2 months vs. 17.7 months with bevacizumab alone in patients with HRD-positive advanced ovarian cancer.

Olaparib + bev provided a statistically significant reduction in the risk of second progression or death vs placebo + bev (ITT analysis; HR 0.78; 95% CI 0.64 -0.95; P=0.0125).... Adding maintenance olaparib to bev provided a benefit beyond first progression, with a substantial PFS2 benefit in tBRCAm and HRD-positive pts. The statistically significant improvement in PFS2 seen with olaparib + bev vs placebo + bev was supported by a similar TSST benefit.

In PAOLA-1, maintenance bev alone achieves a substantial ORR in pts with residual disease after initial therapy. Adding olaparib improved ORRs compared with bev. In both maintenance arms, BRCAm and HRD-positive pts are deriving the greatest benefit.

Data for 380 patients with complete baseline data from SOLO1 (n = 254 olaparib, n = 126 placebo) were pooled with data from 222 BRCA-mutated patients with complete baseline data in PAOLA-1 (n = 151 olaparib plus bevacizumab, n = 71 bevacizumab plus plaebo).....The results of the PAIC suggest that the combination of olaparib plus bevacizumab leads to a potentially meaningful improvement in PFS versus olaparib alone in women with BRCA-mutated newly diagnosed ovarian cancer.

Addition of olaparib to bev maintenance therapy following 1L PCh plus bev led to a statistically significant and clinically meaningful PFS benefit in pts with advanced OC. The PFS benefit in pts with a tBRCAm and in HRD-positive pts was substantial.

...- other epithelial non mucinous ovarian cancer in a patient with germline BRCA 1 or 2 deleterious mutation I-3-3 at an advanced stage: FIGO stage IIIB, IIIC, or IV of the 1988 FIGO classification....

Adding bevacizumab to olaparib was associated with a numerical improvement in PFS compared with olaparib alone (hazard ratio [HR] 0.71; 95% confidence interval [CI] 0.45-1.09). Statistically significant improvements in PFS were seen with olaparib alone versus placebo plus bevacizumab (HR 0.48; 95% CI 0.30-0.75), olaparib plus bevacizumab versus placebo (0.23; 0.14-0.34), and placebo plus bevacizumab versus placebo (0.65; 0.43-0.95). Results of this hypothesis-generating PA-ITC analysis support the use of maintenance olaparib alone or with bevacizumab in patients with newly diagnosed, advanced ovarian cancer and a BRCAm.

The percentage of BRCA1m pts who received olaparib plus bev and were progression-free at 1 and 2 years was 95% and 73% (vs. 70% and 29% for placebo plus bev) and for BRCA2m pts was 89% and 84% (vs. 84% and 53%)