TEST:

Myriad myChoice® CDx Plus

Liquid biopsy shows promise as a surrogate for tissue biopsy in determining HRR-gene alterations, genomic instability, and BRCA1 and RAD51C methylation statuses, albeit with some limitations.

Our data supports considering ascitic cytology samples suitable for HRD testing and BRCA1 and BRCA2 mutation analysis. Further studies are needed to validate the practice of using ascitic cytology as a diagnostic specimen for HRD testing when tissue is not accessible, as it could prove crucial to provide ovarian cancer patients with essential information in an early stage of the diagnostic process.

HRD positive tumours were specifically of high-grade morphology: HGSC and carcinosarcoma. The correlation of molecular status with histological features is important in order to be able to select the cases in which analysis is required. The majority of HGSCs with SET features are HRD tumours independently of BRCA status.

"Myriad Genetics, Inc...announced a collaboration with GSK aimed at improving access to homologous recombination deficiency (HRD) diagnostic testing for high-grade serous ovarian cancer (HGSOC) patients. A new sponsored testing program leveraging Myriad’s MyChoice HRD Plus and MyChoice CDx Plus Tests (collectively referred to as Myriad’s MyChoice Tests) is now available in Argentina, Brazil, Chile, Colombia, Egypt, Netherlands, Saudia Arabia, Singapore, and United Arab Emirates."

22 patients (48%) received PARPi (2 olaparib, 10 niraparib). Due to small sample, we did not find any statistical differences on PFS in the different subgroups. Contrary to expectations, we did observe a tendency of longer PFS in CRS1/2 versus CRS3 for BRCAmut and HRD tumors, indicating no added value for CRS in these situations. In contrast, a tendency of better PARPi response in the CRS3 versus CRS1/2 was noticed in HRP subgroup, suggesting that platinum sensitivity according to CRS could predict a better PARPi response in HRP population.

Neoadjuvant combination treatment of olaparib and pembrolizumab showed promising efficacy and safety in patients with HRD-positive advanced ovarian cancer.

Eight centers have been activated and other 6 are waiting for the activation with 19 patients registered and 3 screening failures. The enrollment is continuing, according to protocol timeline (12 months for enrollment, 6 months for surgery and CT and 24 months for maintenance treatment).

"Considering histological and sample conditions, success rates of up to 98% can be achieved. Our comprehensive evaluation contributes to further standardization of recommendations on HRD testing in ovarian cancer, which will have a large impact on personalized therapeutic strategies in this highly aggressive tumor type."

Comparison between the Illumina and Myriad assays showed that overall HRD status, the individual components of BRCA analysis, and HRD GIS detection results were highly concordant (>93%), suggesting the TSO 500 HRD assay will approach the analytical accuracy of the FDA-approved Myriad assay.

Introduction/Background PAOLA-1/ENGOTov25 trial showed PFS and OS benefit with PARP inhibitor (PARPi) and bevacizumab in maintenance treatment of BRCAm and homologous recombination deficient (HRD+) ovarian cancer...4% with olaparib vs placebo, respectively(HR0...There was no difference in 2yPFS with either a negative Leuven PARPi Benefit Test or a negative Myriad HRD test. Conclusion Leuven PARPi Benefit Test is an improved approach to detect benefit of PARPi in ovarian cancer patients suggesting a better predictive value compared with the Myriad test

Conclusion These results demonstrate an association between T-cell exhaustion and HRD. T-cell exhaustion is an independent predictor of disease outcome in HGSOC.

Conclusion In our cohort, BRCA1/2-mutated pts and HRD showed a trend towards a better response to NACT as opposed to BRCA-WT and HR proficient pts, according to CRS, although statistical significance is not reached due to the limited number of patients. Further research is guaranteed.

Among Japanese mHSPC patients, IDC-P demonstrates significant associations with an elevated incidence of genetic alterations and increased HRD score, emphasizing its potential clinical significance.

P3; The bevacizumab (bev)/olaparib (ola) maintenance regimen was approved for BRCA1/2-mutated (BRCAmut) and Homologous Recombination Deficient (HRD) high-grade Advanced Ovarian Cancer (AOC) first line setting, based on a significantly improved progression-free survival (PFS) compared to bev alone in the PAOLA-1/ENGOT-ov25 trial (NCT02477644), where HRD was detected by MyChoice CDx PLUS test. This benefit was significant also for BRCA1/2 wild-type tumors (40.8 versus 19.5 months, HR: 0.45 [95% CI: 0.26-0.76]). ShallowHRDv2 is a performant, clinically validated, and cost-effective test for HRD detection.

P4; N=190; Recruiting; Sponsor:Mario Negri Institute for Pharmacological Research

Background: Niraparib (nir) showed a blinded independent central review–assessed PFS benefit as a first-line (1L) maintenance therapy (MT) in the primary analysis of PRIMA (data cut 17 May 2019) across biomarker subgroups, including a substantial benefit in patients (pts) with homologous recombination–deficient (HRd) tumours... A durable PFS benefit (nir vs PBO) was observed up to 4 y after randomisation in the ITT and HRd populations, as determined by IA. Pts free from disease progression or death at the 2-y landmark had a high probability of remaining free from progression or death at 4 y, supporting the use of nir as a 1L MT.

"Our results show that the majority of HGSCs with SET features are homologous recombination deficient tumors independently of the BRCA status and highlight the importance of the homologous recombination repair tumor testing especially in BRCA wild-type tumors. Recognition of transitional cell variant of HGSCs may help to identify patients most likely to benefit from PARP inhibitors."

Percentages of BRCAwt/GIS-, BRCAwt/GIS+, BRCAm, and invalid cases were almost identical. In conclusion, Sophia DDMTM Dx HRD solution shows a high interlaboratory agreement, providing clinically relevant molecular information, and improving the interaction between referral and reference centers.

The subset of platinum-sensitive ovarian clear cell carcinomas includes a majority with pure ovarian clear cell carcinoma features that lack the homologous recombination deficiency phenotype.

A robust correlation between the Leuven HRD and Myriad test was observed. For HRD+ tumours, the academic Leuven HRD showed a similar difference in PFS and OS as the Myriad test.

Background: In the PAOLA-1/ENGOT-ov25 trial (NCT02477644), maintenance ola (a PARP inhibitor) + bevacizumab (bev) led to prolonged progression-free and overall survival vs placebo (pbo) + bev in AOC pts, specifically those with homologous recombination-deficient (HRD+) tumors (Ray-Coquard et al. In this post hoc exploratory analysis of PAOLA-1, the efficacy of subsequent CT at relapse appeared dependent on whether progression occurred during or after the end of ola treatment. Efficacy was reduced when relapse occurred during ola but was comparable between pts who progressed after ola vs pbo + bev pts. Clinical trial information: NCT02477644.

Acknowledging limitations of small subgroup sizes, non-BRCA HRRm gene panels were not predictive of PFS benefit with maintenance olaparib plus bevacizumab versus placebo plus bevacizumab in PAOLA-1, irrespective of the gene panel tested. Current gene panels exploring HRRm should not be considered a substitute for HRD determined by BRCA mutation status and genomic instability testing in first-line high-grade ovarian cancer.

In our cohort, rare histotypes of ovarian carcinomas are characterized by morphological and molecular heterogeneity resulting in different clinical behaviour. The evaluation of molecular markers could improve potential novel target therapy for these uncommon tumors.

tBRCAm status by central labs and HRD status by Myriad MyChoice HRD Plus.*Kaplan–Meier estimates.CI, confidence interval; HR, hazard ratio; ITT, intent-to-treat. Conclusions The 5-y updated descriptive PFS rates suggest the benefit of adding olaparib to bev is sustained beyond end of treatment and may indicate the potential of cure in HRD+ newly diagnosed advanced OC, supporting use of maintenance olaparib + bev as a standard of care in pts with HRD+ tumours, regardless of tBRCAm status.

Conclusions This post hoc analysis of 5-y OS suggests that adding maintenance ola to bev should be considered for all HRD+ pts with newly diagnosed AOC, irrespective of their clinical risk status. Particular benefit was observed in HRD+ lower-risk pts who achieved 5-y OS rates of 88.3%.

Background Niraparib (nir) showed a blinded independent central review–assessed PFS benefit as a first-line (1L) maintenance therapy (MT) in the primary analysis of PRIMA (data cut 17 May 2019) across biomarker subgroups, including a substantial benefit in patients (pts) with homologous recombination–deficient (HRd) tumours...Pts free from disease progression or death at the 2-y landmark had a high probability of remaining free from progression or death at 4 y, supporting the use of nir as a 1L MT. Table: 33O HRd Nir PBO Landmark time from randomization Events/total pts 2-y probability from landmark, % (95% CI) Events/total pts 2-y probability from landmark, % (95% CI) 0 137/247 51 (44–57) 98/126 29 (21–37) 1 y 69/159 62 (54–70) 33/57 50 (36–62) 2 y 26/110 74 (64–82) 11/34 60 a ITT Landmark time from randomization Nir PBO Events/total pts 2-y probability from landmark, % (95% CI) Events/total pts 2-y probability from landmark, % (95% CI) 0 332/487 36 (31–40) 199/246 22 (17–28) 1 y 124/244 54 (47–60) 54/92 46 (36–56) 2 y 42/152 67 (57–76) 15/51 64 a a 95% CI were not calculated at time points with <10 pts.

of events / no. of pts (%) 5 y OS rate, % HR (95% CI) Ola + bev Pbo + bev Ola + bev Pbo + bev ITT 288/537 (53.6) 158/269 (58.7) 47.3 41.5 0.92 (0.76–1.12) HRD+§ 93/255 (36.5) 69/132 (52.3) 65.5 48.4 0.62 (0.45–0.85) tBRCAm§ 48/157 (30.6) 37/80 (46.3) 73.2 53.8 0.60 (0.39–0.93) HRD+ excluding tBRCAm§ 44/97 (45.4) 32/55 (58.2) 54.7 44.2 0.71 (0.45–1.13) HRD-/unknown§ 195/282 (69.1) 89/137 (65.0) 30.6 34.9 1.14 (0.89–1.48) HRD-§ 140/192 (72.9) 58/85 (68.2) 25.7 32.3 1.19 (0.88–1.63) *tBRCAm status by central labs; HRD status by Myriad myChoice HRD Plus; §Preplanned exploratory analysis Conclusions Despite a high proportion of pts in the control arm receiving a PARP inhibitor post-progression, ola + bev provided a clinically meaningful improvement in OS for 1L HRD+ pts with and without a tBRCAm, confirming ola + bev as standard of care in this setting.