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

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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 < 0.0001). Deleterious aberrations in
PALB2
resulted in the highest aGIS, followed by
BRCA2
and
ATM
. The aGIS for genotypes with >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)