Assessment of
PARP1
mRNA expression as prognostic of aggressive pathology and adverse outcomes, and as predictor of response to PARP inhibition in castration-sensitive prostate cancer.
Authors: Antonarakis Emmanuel S. , Alshalalfa Mohammed , Teply Benjamin A. , Hao Yangyang , Proudfoot James A. , Davicioni Elai , Schaeffer Edward M. , Karnes R. Jeffrey , Spratt Daniel Eidelberg , Hwang Justin , Lotan Tamara L. , Marshall Catherine Handy 
Published: February 2025

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Background:
While several PARP inhibitors are approved in combination with hormonal therapies for metastatic castrate resistant prostate cancer (CRPC), their use in castrate sensitive prostate cancer (CSPC) is understudied. We previously reported that olaparib monotherapy (without ADT) shows significant clinical activity in
BRCA2
-altered patients with biochemically recurrent (BCR) prostate cancer. Here, we explored prognostic and predictive PARP-related mRNA biomarkers derived from primary prostate tumors.
Methods:
We characterized the expression of 16 PARP transcripts using a cohort of 52,266 radical prostatectomy (RP) specimens (2016-2024) undergoing Decipher prostate genomic classifier testing (Veracyte Inc). Transcriptome-wide mRNA expression data as well as baseline clinical/pathologic factors were retrieved from the Decipher GRID database (NCT02609269). Associations between high PARP expression (top 25%), baseline factors, and gene signatures were examined using logistic regression. We assessed the association between PARP expression and distant metastases in 3 retrospective cohorts (n= 545, 855, and 325). Finally, we evaluated PARP expression in our prior phase II trial (NCT03047135, n=39) of olaparib monotherapy in the setting of BCR following RP.
Results:
Higher mRNA levels of
PARP1
,
2
,
8
and
14
showed strong associations (all
P
<0.001) with known adverse prognostic factors such as very-high Decipher score (>0.85), high Gleason grade (GG5) and non-organ confined disease (EPE, SVI and LNI), while higher
PARP6
and
7
expression were associated with more favorable disease characteristics. High
PARP1
expression was positively correlated with DNA-repair deficiency (r=0.77) and tumor immune microenvironment (r=0.62) signatures. In 3 independent retrospective cohorts of intermediate-high risk PCa patients, higher
PARP1
expression was strongly associated with development of distant metastases after RP (HR 1.70, 1.81, and 1.67 respectively; all
P
<0.05). Finally, in our phase II trial of patients with BCR who received olaparib monotherapy,
PARP1
(but not
PARP2
) expression from RP was 1.5-fold higher in samples with
BRCA2
mutations (median 0.416 vs 0.276,
P
=0.01) and was associated with overall improved PSA progression-free survival (continuous variable, HR 0.55,
P
=0.01) and longer time to next systemic treatment (continuous variable, HR 0.66,
P
=0.02).
Conclusions:
High
PARP1
mRNA expression, measured at RP, is associated with aggressive disease biology and greater risk of metastasis. However, high
PARP1
(but not
PARP2
) levels are associated with improved response to PARP inhibition in the setting of BCR prostate cancer. Future trials testing PARP (including PARP1-selective) inhibitors in the CSPC space should consider measuring
PARP1
mRNA levels in addition to
BRCA1/2
mutation status. Clinical trial information:
NCT02609269
,
NCT03047135
.