ABSTRACT
Introduction
The homologous recombination repair (HRR) pathway is a frequently mutated pathway
in advanced prostate cancer. The clinical course of patients with HRR gene alterations
who have metastatic hormone sensitive prostate cancer (mHSPC) has not been fully characterized.
Here, we examine the outcomes of men with mHSPC with HRR alterations.
Methods
We conducted a single-center retrospective analysis of men with mHSPC who underwent
next generation sequencing. The primary objective was to assess the time from diagnosis
of mHSPC to metastatic castrate resistance prostate cancer (mCRPC) in patients with
pathogenic HRR alterations compared to individuals lacking these alterations. Key
secondary objectives included time to mCRPC in prespecified cohorts, PSA response,
and overall survival.
Results
151 men with mHSPC were identified for the study. 24% (N = 37) had pathogenic HRR
gene alterations detected with the most common alterations found in BRCA2 (n = 15), ATM (n = 10), and CDK12 (n = 7). Time to mCRPC was significantly decreased in patients with HRR gene alterations
versus those without such alterations (12.7 vs. 16.1 months, HR 1.95, P = .02). In multivariate analysis, the effect of HRR gene alterations on time to CRPC
remained significant when adjusting for age, mHSPC therapy, the volume of disease,
the presence of visceral metastases, and PSA (adjusted HR 1.69, P = .02). Stratified by specific HRR gene alteration, patients with BRCA2 or CDK12 had significantly decreased time to mCRPC compared to other HRR alterations.
Conclusion
HRR gene alterations are associated with the worse outcomes in mHSPC with significantly
shorter time to mCRPC. Given the established role of Poly (ADP-ribose) Polymerase
(PARP) inhibitors in mCRPC, these data highlight an opportunity to examine PARP inhibitors
earlier in the clinical course for prostate cancer patients. Ongoing prospective studies
will further validate the role of PARP inhibitors in mHSPC patients.
Keywords
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Article info
Publication history
Published online: June 29, 2022
Accepted:
June 21,
2022
Received in revised form:
June 19,
2022
Received:
May 7,
2022
Identification
Copyright
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