Improved prediction of PARPi responders in ovarian cancer patients using the Leuven PARPi benefit test

Poly (ADP-ribose)-polymerase inhibitors (PARPis) like olaparib have transformed the treatment landscape for high-grade serous ovarian cancer, with multiple trials showing significant improvement in progression-free survival (PFS).1 Although PFS benefits with PARPis appear to be consistent in patients who are homologous recombination deficiency-positive (HRD+), it is less consistent among those who are HRD-negative (HRD-).1 The existing tests for HRD have shown some success in identifying potential responders to PARPi but further improvements are still necessary.1

The Leuven HRD test is an academic laboratory-developed HRD test previously designed to predict PARPi response based on DNA obtained from formalin-fixed paraffin-embedded (FFPE) ovarian cancer samples that offers highly similar results to the commercial Myriad MyChoice® CDx test.1 Using a capture-based probe design, targeted sequencing of key homologous recombination  repair (HRR) genes such as BRCA1/2, RAD51C/D, BARD1 was compared against a genome-wide panel.1 A HRD score was generated based on the detection of loss of heterozygosity (LOH), telomeric allelic imbalance (TAI) and large-scale transitions (LSTs).1 Tumor samples with an HRD score of ≥56 and/or BRCA mutation were defined as Leuven HRD+.1 Based on biopsy samples from 468 ovarian cancer patients randomized to receive  bevacizumab + placebo or bevacizumab + olaparib from the phase 3 PAOLA-1 trial, Leuven HRD+ samples were shown to respond better to olaparib compared to HRD- samples and the results were similar to the commercial test (overall percent agreement: 91%).1

However, as the Leuven HRD test uses a statistical cut-off, there remains a question of defining whether a patient is a good responder if the HRD score falls just below the threshold.1 Moreover, whether the computation of genome-wide LOH, TAI and LST is comprehensive enough to define HRD-positivity and response to PARPi remains unclear.1 At the ESGO 2024 Congress, Dr. Liselore Loverix, presented the Leuven PARPi benefit test which sought to address these challenges.1 Although the newly developed method uses the same technical test as the Leuven HRD test, changes were made to the bioinformatic pipeline, resulting in a final, binary classification of patients into having a yes or no response to PARPi therapy.1

In the validation study for the Leuven PARPi test, exceptional responders (PFS ≥2 years, progression after stopping PARPi) and poor responders (PFS <2 years, progression during PARPi treatment) were identified from the pool of patients in the PAOLA-1 trial.1 A total of 396 samples with good single nucleotide polymorphism (SNP) profiles were identified, 198 samples were used as a training cohort, while the other 198 samples were used as an independent validation cohort.1 In the training cohort, the detection of BRCA1/2 and 6 HRR mutations, 44 copy-number features of specific genes and allele-specific copy number analysis of tumors (ASCAT) features were found to have an important role in predicting PARPi response.1 The bioinformatics pipeline also incorporated the location of BRCA mutations and LOH events, as it was found that not all BRCA mutations affect PARPi response in the same manner, and that LOH events do not happen randomly across the genome.1 Based on the data from this training cohort, patients were then classified as Leuven PARPi benefit-positive or negative.1

In the validation cohort, all patients who were classified as PARPi test-positive showed improved PFS with olaparib + bevacizumab compared to placebo added to bevacizumab (PFS at 2 years: 78% vs. 32%; HR=0.32, 95% CI: 0.181-0.566) which aligned with the results when patients were classified using the Myriad MyChoice® CDx test (PFS at 2 years: 69% vs. 32%;  HR=0.41, 95% CI: 0.248-0.661).1 However, among BRCA wild-type samples, the Leuven PARPi benefit test had a better prediction of olaparib-responders, resulting in a larger PFS benefit (olaparib vs. placebo PFS at 2 years: 71% vs. 22%; HR=0.18, 95% CI:  0.068-0.487) compared to the Myriad test (olaparib vs. placebo PFS at 2 years: 54% vs. 29%; HR=0.39, 95% CI: 0.189-0.799).1 As expected, patients who were not responsive to PARPi did not show any PFS benefit with olaparib compared with placebo (PFS at 2 years: 23% vs. 28.5%; HR=1.01, 95% CI: 0.637-1.610), similar to HRD- patients identified with the Myriad test (PFS at 2 years: 25% vs. 31%; HR=1.11, 95% CI: 0.630-1.960).1

In summary, the Leuven PARPi benefit test provides an alternative approach to predict PARPi benefit in first-line high-grade serous ovarian cancers, using the same technical backbone as the Leuven HRD test but with a different bioinformatic pipeline.1 This includes copy-number features of specific genes, domains of BRCA variants, and specific LOH regions across the genome of ovarian cancer cells.1 Compared to the Myriad test, the Leuven PARPi benefit test may be a stronger predictor for progression during PARPi maintenance.1

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