Assessing genomic instability (GI) by shallow whole-genome sequencing (sWGS) to predict PARP inhibitor (PARPi) response in metastatic castration-resistant prostate cancer (mCRPC).
Authors: Peter Slootbeek, Yarah M. Quint, Julian J.R. Kokke, Samhita Pamidimarri Naga, Iris Kloots, Maria Victoria Luna-Velez, Marjolijn J.L. Ligtenberg, Richarda M. de Voer, Niven Mehra
Journal: Journal of Clinical Oncology (2025)

194 Background: The heterogeneous efficacy of PARPi in patients with mCRPC and homologous recombination deficiency (HRd)-associated genetic alterations has emphasized the need for a more accurate selection of responding patients. sWGS offers a cost-effective method to identify HRd through GI analysis. However, the correlation between GI from sWGS and specific genotypes, along with its predictive value for PARPi response, remains unreported. Methods: A total of 289 samples from 267 patients were analyzed for GI by sWGS. Of these, 121 were newly sequenced with a mean depth of 2.05x and 168 were in silico down-sampled to 2x. Eighty-four percent of the samples were collected in the CRPC setting. Copy number analysis was performed using iChorCNA with a 50 Kb window size, and multiple genome-wide copy number plots were generated per sample with varying tumor content and ploidy. Two researchers independently selected the optimal plot, with discordant cases reviewed by a third, to quantify large-scale transitions and telomeric allelic imbalances per sample, which together constituted an adjusted GI score (aGIS). Results: The median aGIS of all samples was 21 (interquartile range [IQR] 16 – 30). Samples with HRd-associated genetic alterations (43%) had a higher median aGIS (26) than to those without (19, P &lt; 0.0001). Deleterious aberrations in PALB2 resulted in the highest aGIS, followed by BRCA2 and ATM . The aGIS for genotypes with &gt;3 samples are detailed (Table). Out of the 267 patients, 71 received PARPi. Their median aGIS was 27 (IQR: 19–37). The 33 patients with ≥50% PSA decline had a higher aGIS than the 37 without (aGIS 35 vs 22, P = 0.0001). In 60 patients with radiologic assessment, 22 had a partial response, 27 stable disease, and 11 progressive disease. The median aGIS for these groups were 32 (IQR: 25.5–49), 26 (IQR: 17.5–35), and 21 (IQR: 16.5–26.5), respectively, with a significant difference between partial and progressive disease (P = 0.0053). The Cox proportional hazards model did not show a significant effect of aGIS on progression-free survival (P = 0.144). Still, patients with the highest 25% aGIS had a median progression-free survival of 11 months, compared to 4 months for the lowest 25%, and 8 months for the remaining. Conclusions: The quantity of large-scale transitions and telomeric allelic imbalances, from sWGS, correlates with HRd-associated genetic alterations. In PARPi-treated patients, this aGIS is significantly associated with biochemical and radiologic response, even after selection by genotyping. These findings support the development of an sWGS-adjusted GI score for predicting PARPi response in mCRPC. Aberration in: N Median aGIS (IQR) PALB2 4 30.5 (15 – 44.75) BRCA2 50 29 (22 – 38.75) ATM 37 28 (20 – 34) BARD1 4 26.5 (15.5 – 34.5) RAD51B 5 26 (25 – 26) CDK12 20 18.5 (10.75 – 20.25) CHEK2 5 16 (12 – 17)