TEST:

Myriad myChoice® CDx

In this secondary analysis of the PAOLA-1 randomized clinical trial, patients with a BRCA-like tumor, but not those with a non-BRCA-like tumor, had a significantly longer survival after olaparib plus bevacizumab treatment than placebo plus bevacizumab treatment. Thus, the BRCA1-like classifier could be used as a biomarker for olaparib plus bevacizumab as a maintenance treatment.

P2, N=15, Terminated, University of Oklahoma | N=45 --> 15 | Trial completion date: Nov 2024 --> Feb 2024 | Active, not recruiting --> Terminated; Funder terminated funding.

Assays for GI assessment not only show a high concordance with each other but also in correlation with Myriad myChoice. Thus, almost all of the assays included here can be used effectively to assess HRD-associated GI in the clinical setting. This is important as PARPi treatment on the basis of these tests is compliant with European Medicines Agency approvals, which are methodologically not test-bound.

The myChoice® CDx Nordic core facility has been well received among the Nordic countries and provides new insights on the influence of national guidelines on HRD testing. Overall, we experienced an efficient turnaround time and a high fraction of conclusive results. Interestingly, prior somatic BRCA testing is redundant when assessing HRD status through myChoice® CDx test since somatic BRCA screening is already a significant component of the myChoice® CDx test. Thus, it should be considered to omit prior somatic BRCA testing to ensure a rationalised HRD diagnostic flow optimised for clinical use.

The SeqOne assay offers a clinically validated approach to detect HRD.

P3; Not yet recruiting --> Recruiting

BRCA mutation is one cause of HRD and appears that SET morphology associated with HGSC is unique to BRCA-mutation and not under the umbrella of other causes and effects of HRD. HRD in HGSC may produce its own molecular surrogate that is yet to be discovered. Definitive determination of which platform is superior for clinical validation of HRD assessment as a surrogate to Myriad MyChoiceDX gold standard requires matched analysis against Myriad and patient's progression free survival.

Further investigation of HRD and EC-specific GIS cut-off value are highly warranted and may help to improve outcome in this specific EC subgroup. Patients with p53abn tumors may benefit from PARP inhibition and HRD testing may provide key information for patient selection.

In patients with advanced ovarian cancer who are BRCA WT, HRD does not seem to predict cytoreductive surgical outcome or pre-treatment disease volume, although patients with HRI were less likely to be offered PCS. Larger, prospective cohort with HR status on all comers with HGSOC, will help to determine the significance of HR status when deciding on PCS or ICS.

The incidence of ST response to maintenance olaparib is high and appears to be modulated by maintenance sequence (primary vs recurrent therapy). Response to most recent chemotherapy could be incorporated into prospective data as a surrogate for predicting response to PARP inhibitors. Efforts to increase utilization of PARP inhibitor therapy in the primary maintenance setting are warranted.

Multi-gene NGS tumour testing was capable of identifying all clinically relevant germline variants. Although paired multi-gene tumour-germline testing is required to determine variant origin, over 40% of individuals in this study could have avoided germline testing following negative tumour results. These results suggest that streamlining genetic testing for EOC patients via primary multi-gene tumour testing is possible with further investigation.

39). Conclusion The MEDx HRDetectCDx demonstrated high consistency with Myriad test and was prospectively validated for predictive value in 1L maintenance therapy with niraparib in the real-world setting.

Further investigation of HRD and EC-specific GIS cut-off value are highly warranted and may help to improve outcome in this specific EC subgroup. Patients with p53abn tumors may benefit from PARP inhibition and HRD testing may provide key information for patient selection.

GREAT cohort: Main clinical and tumor biological patient characteristicsConclusion Characteristics and treatment of the 1507 pts included in the real-life GREAT prospective study are representative of the standard AOC population. The clinically and biologically annotated GREAT cohort with collection of tumor samples offers a unique opportunity for evaluating new tumor targets for future drug development.

J.P. Morgan 42nd Annual Healthcare Conference Presentation

The myChoice CDx was able to detect most germline BRCA1/2 pathogenic variants in tumour DNA, although a proportion of pathogenic large rearrangements were not reported. If Myriad's myChoice CDx is used for tumour BRCA1/2 testing, our data supports a testing strategy of germline and tumour BRCA1/2 testing in all patients diagnosed with epithelial ovarian cancer aged < 79 years old, with germline BRCA1/2 testing only necessary for patients aged ≥ 80 years old with a tumour BRCA1/2 pathogenic variant.

P2; Recruiting --> Active, not recruiting | Trial completion date: Jun 2026 --> Nov 2024 | Trial primary completion date: Jun 2025 --> Nov 2023

P1/2; Trial completion date: May 2025 --> Nov 2026 | Trial primary completion date: May 2025 --> Nov 2026

Mutations in the TP53 gene and genes (APC/CTNNB1) related to the Wnt pathway are associated with metastatic visceral dissemination and early death. These genomic alterations could be considered as markers to identify prostate cancer patients at a high risk of life-threatening disease who might benefit from more intensified treatment or new targeted therapies.

RADD demonstrates the ability to determine a quantitative analysis of DNA damage and repair in ovarian cancer samples. Considering its rapid turnaround time and correlation with HR status, RADD has potential use in determining clinical trial candidates stratified by HR status. Additionally, RADD correlates with known predictive biomarker CD39 for response with immunotherapy.

P2; N=45; Recruiting; Sponsor:University of Oklahoma

Finally, our AT confirms its capability of determining HRD status, with the advantage of being faster, cheaper, and easier to carry out. Our results showed a prognostic value for the HRD score.

False-positive rates were 31.6% (6/19) for AmoyDx GI status and 31.9% (7/22) for OncoScanâ„¢, while false-negative rates were 0% (0/28, AmoyDx) and 11.1% (2/18, OncoScanâ„¢) compared with the Myriad MyChoice GI status. While substantial concordance between Myriad MyChoice and alternative assays was demonstrated, prospective validation of the analytical performance and clinical relevance of these assays is warranted.

"Myriad Genetics, Inc...and Personalis, Inc...announced a non-exclusive collaboration through which Myriad will market the Personalis®ImmunoID NeXT ultra-comprehensive biomarker discovery platform to its pharmaceutical partners who use the MyRisk® Hereditary Cancer Test, BRACAnalysis CDx® and/or MyChoice® CDx cancer tests."

Our data shows that the implementation of in-house HRD testing in diagnostic laboratories is technically feasible and can be reliably performed with commercial assays. Also, the turnaround time is compatible with clinical needs, making it an ideal alternative to offer to a broader number of patients while maintaining high-quality standards at more accessible price tiers.

The pharmacological costs were calculated following treatment protocol of GeparSixto where TNBC patients received neoadjuvant paclitaxel plus Myocet®-nonpegylated liposomal doxorubicin (PM) or PM plus carboplatin (PMCb), both arms including bevacizumab. The most efficient scenarios are the functional RAD51 test and all comers. Both tBRCA1/2 and genomic HRD by Myriad Mychoice® scenarios provide worse health outcomes at a higher cost, based on the data of the GeparSixto trial. This study highlights the potential overall benefit of functional HRD biomarkers to predict PARPi sensitivity.

High correlation of HRD score was observed between Myriad and our WES-based scarHRD test (coefficient 0.82, p<0.001) in the linear regression model. In compared to positive HRD status of Myriad test, the sensitivity,specificity, PPV and NPV was 93.5%, 76.9%, 90.6% and 83.3% respectively in our WES-based scarHRD test. The percentages of EOC patients with positive HRD statusof our test/ Myriad test were higher in advanced FIGO stage (Early vs Advanced: 0% vs 76.2%; p = 0.018)/ (Early vs Advanced: 0% vs 73.8% , p =0.025), and sensitive platinum-response (Sensitive vs Resistant: 84.6% vs 55.6%, p = 0.033)/(Sensitive vs Resistant: 84.6% vs 50%, p = 0.013).

"GIS was positive in 40% of the BRCA1/2-negative cases. The RediScore bioinformatics algorithm developed for GIS calculation in combination with NGS BRCA1/2 analysis is a viable and effective approach for HRD calculation in patients with ovarian cancer, offering a positive prediction for PARP inhibitor responsiveness in 55% of the patients."

P1/2, N=0, Withdrawn, City of Hope Medical Center | N=57 --> 0 | Not yet recruiting --> Withdrawn

P2; Trial completion date: Jun 2026 --> Dec 2026 | Trial primary completion date: Jun 2024 --> Dec 2024

Of 40 patients enrolled, thirty were included for analysis. Reason for exclusion included insufficient tissue for HR profiling (n=4), inadequate assessment during surgery (n=4), unconfirmed primary site (n=2). Pattern of tumour spread was indeterminate in 12 patients and infiltrative in 13 patients.

As expected CCNE1 amplifications are mutually exclusive from BRCA mutations, however 20% were HRD according to GIS. We observed unexpected high rates of CRS3, and significantly improved outcomes compared to non-CCNE1amp HRDneg tumors.

CR 38.4%, PR 53.5%. SD: 2% and progression 6.1%. Allergic reaction to chemotherapy occurred in 22% of the total.38% of patients received PARPi as first-line maintenance.In the group of patients who progressed to first line (49% of our series), PFS was higher in those with somatic line pathogenic variants, presenting a median of 18 months versus 10 months, (p=0.015).

This test identifying ovarian cancer patients with positive homologous recombination deficiency (HRD) status by detecting BRCA1 and BRCA2 (sequencing and large rearrangement) variants and assessing genomic instability with 3 biomarkers: loss of heterozygosity, telomeric allelic imbalance and large-scale state transitionsResults Our results show 70.3% patients without HRD and 29.7% with HRD, with the most common histological type of ovarian carcinoma in which it occurs is High grade serous carcinomaTable. Frequency of homologous recombination deficiency according to the histological subtypeConclusion HRD status and frequency are important for postoperative therapy of women with ovarian cancer, as well as for survival and mortality indicators.

We investigated differences in progression-free (PFS) and overall (OS) survival in the olaparib+bevacizumab and placebo+bevacizumab arms between HRD-positive and HRD-negative pts. No significant difference in PFS or OS was observed between treatment arms in pts with HRD-negative test (HR PFS, 1.04; 95% CI, 0.71-1.52; p=0.8; HR OS, 1.19; 95% CI, 0.78-1.80; p=0.4). Conclusion The analytical performance and the potential clinical relevance results of SOPHiA DDM™ Dx HRD Solution from PAOLA-1 samples support the value of combining low-pass whole genome and targeted sequencing in a unique workflow for reliable and decentralized HRD testing and future patient stratification.

The worldwide approval of the combination maintenance therapy of olaparib and bevacizumab in advanced high-grade serous ovarian cancer requires complex molecular diagnostic assays that are sufficiently robust for the routine detection of driver mutations in homologous recombination repair (HRR) genes and genomic instability (GI), employing formalin-fixed (FFPE) paraffin-embedded tumor samples without matched normal tissue. The "NOGGO GIS v1 assay" performed using highly robust hazard ratios for progression-free survival (PFS) and overall survival (OS), as well a significantly lower dropout rate than the Myriad MyChoice clinical trial assay supporting the clinical utility of the assay. We also provide proof of a modular and scalable routine diagnostic method, that can be flexibly adapted and adjusted to meet future clinical needs, emerging biomarkers, and further tumor entities.

Introduction Recently the PAOLA-1/ENGOT-ov25 phase-3 study (Ray-Coquard ESMO-2022) showed that the addition of olaparib maintenance to 1st-line platinum-based therapy and bevacizumab improved survival of advanced ovarian cancer (AOC) patients with HRD positive tumors independently of BRCA status (Myriad myChoice test). Conclusion/Implications The ENGOT HRD initiative is a unique collaboration of European academic laboratories involved in gynaecology oncology translational research. A total of 8 innovative HRD tests achieved a clinical validation from AOC tumor samples of the phase 3 PAOLA-1 study.

The proposed test efficiently separates HRD-positive from HRD-negative patients, predicts response to PARP inhibition, and can be easily deployed in a clinical laboratory for routine practice. The performance is similar to the available commercial test, but its lower failure rate allows an increase in the number of patients who will receive a conclusive laboratory result.

Turnaround reporting time was MMC 30 (IQR 27–35) versus WGS 42 (IQR 33–47) days (n=11). Conclusions WGS is feasible in the NHS for detecting HRD and has similar performance to MMC with improved HRD gene mutation detection and discovery of additional biomarkers.

P3; Trial completion date: May 2038 --> Aug 2038 | Trial primary completion date: May 2033 --> Aug 2033

HRD status determined with both assays was associated to Progression-Free Survival (PFS) after first line bevacizumab and platinum-based therapy and Overall Survival (OS) in univariate and multivariate analysis.Results and DiscussionsHRD status obtained by OCA was compared with the reference Myriad assay in 86/97 samples for which both test results were available...In univariate analysis for OS, OCA was prognostic (HR=0.44, p=0.016) but not Myriad (HR 0.71, P=0,3). Multivariate analysis for OS was not performed due to low number of events.ConclusionThese data suggest the feasibility of OCA testing for assessing HRD status, with a good concordance with the gold standard assay and association with clinical outcome.

Over 6% of PVs detected in the ovarian tumors analyzed were LRs. It is imperative for laboratories to utilize testing methodologies that will accurately detect LRs at a single exon resolution to optimize the identification of patients who may benefit from PARP inhibitor treatment.