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Updated: Jun 10, 2026
Microarray-based Identification of Individual HERV Loci Expression: Application to Biomarker Discovery in Prostate Cancer
Published on: November 2, 2013
Durable benefit from poly(ADP-ribose) polymerase inhibitors in metastatic prostate cancer in routine practice:
D Triner1, R P Graf2, R W Madison2
1Department of Urology, Michigan Medicine, Ann Arbor, USA.
Background:
Controlled trials have consistently demonstrated the efficacy of poly(ADP-ribose) polymerase inhibitors (PARPis) in patients with metastatic castration-resistant prostate cancer (mCRPC) and BRCA1 or BRCA2 alterations (BRCAalt). However, the reported efficacy of PARPi for alterations in other homologous recombination repair (HRR) genes is less consistent. We sought to evaluate the routine practice effectiveness of PARPi between and within these groups.
Design:
Patient-level data from a deidentified nationwide (USA-based) cancer clinico-genomic database between January 2011 and September 2023 were extracted. Patients with mCRPC and comprehensive genomic profiling by liquid biopsy [circulating tumor DNA (ctDNA)] or tissue (tumor) biopsy and who received single-agent PARPi were included and grouped by BRCAalt, ATMalt, other HRR, or no HRR. We further subcategorized BRCAalt into homozygous loss (BRCAloss) and all other deleterious BRCAalt (otherBRCAalt).
Results:
A total of 445 patients met inclusion criteria: 214 with tumor and 231 with ctDNA. BRCAalt had more favorable outcomes to PARPi compared with ATM, other HRR, and no HRR groups. Within the BRCAalt subgroup, compared with other BRCAalt, BRCAloss had a more favorable time to next treatment (median 9 versus 19.4 months, P = 0.005), time to treatment discontinuation (median 8 versus 14 months, P = 0.006), and routine practice overall survival (median 14.7 versus 19.4 months, P = 0.016). Tumor BRCAloss prevalence (3.1%) was similar to ctDNA prevalence in liquid biopsy specimens with high tumor fraction (>20%). BRCAloss was not detected in orthogonal germline testing.
Conclusions:
PARPi routine practice effectiveness between groups mirrors prospective trials. Within the BRCAalt group, BRCAloss had the best outcomes. Unless the ctDNA tumor fraction is very high, somatic tissue testing (archival or metastatic) should be prioritized to identify patients who may benefit most from PARPi. When tissue testing is not clinically feasible, sufficient ctDNA tumor fraction levels for detection are enriched at clinical timepoints associated with tumor progression.
Insights
Poly(ADP-ribose) polymerase inhibitors (PARPi) show effectiveness in metastatic castration-resistant prostate cancer (mCRPC) with BRCA alterations. Homozygous BRCA loss (BRCAloss) within this group yields superior outcomes, highlighting the importance of precise genetic profiling for PARPi therapy.
Area of Science:
- Oncology
- Genetics
- Pharmacology
Background:
- Poly(ADP-ribose) polymerase inhibitors (PARPis) are effective in metastatic castration-resistant prostate cancer (mCRPC) with BRCA1/2 alterations (BRCAalt).
- Efficacy of PARPi in patients with other homologous recombination repair (HRR) gene alterations is less consistent.
- This study evaluates the real-world effectiveness of PARPi in mCRPC patients with various HRR alterations.
Purpose of the Study:
- To assess the routine practice effectiveness of PARPi in mCRPC patients.
- To compare PARPi effectiveness across different HRR alteration groups (BRCAalt, ATMalt, other HRR, no HRR).
- To investigate outcomes within the BRCAalt subgroup, differentiating homozygous loss (BRCAloss) from other BRCAalt.
Main Methods:
- Utilized deidentified patient-level data from a US cancer clinico-genomic database (2011-2023).
- Included mCRPC patients with comprehensive genomic profiling (liquid or tissue biopsy) who received single-agent PARPi.
- Grouped patients by HRR alteration status, with BRCAalt further subcategorized into BRCAloss and other BRCAalt.
Main Results:
- BRCAalt patients demonstrated more favorable outcomes with PARPi compared to ATMalt, other HRR, and no HRR groups.
- Within BRCAalt, BRCAloss showed significantly better time to next treatment, time to treatment discontinuation, and overall survival than other BRCAalt.
- Tumor BRCAloss prevalence was comparable between tissue and high-fraction ctDNA liquid biopsies; BRCAloss was not detected in germline testing.
Conclusions:
- PARPi effectiveness in routine practice aligns with findings from prospective trials.
- BRCAloss within the BRCAalt group is associated with the best outcomes.
- Somatic tissue testing is preferred for identifying optimal PARPi candidates, unless ctDNA tumor fraction is very high. High ctDNA fractions are enriched at tumor progression points.
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