Real-world clinical practice gaps in timely homologous recombination repair gene mutation (HRRm) testing and poly (ADP-ribose) polymerase inhibitor (PARPi) treatment of patients with metastatic castration resistant prostate cancer (mCRPC).
Authors: Shore Neal D. , Vasudevan Anupama , Li John , Qureshi Husain , Sathyan Pratheesh , Aton Lindsay , Blanc Simon , Varughese Prateesh , Tierno Marni Brisson 
Published: February 2025

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Background:
Testing for HRRm is standard of care for all mCRPC patients to identify those eligible to receive PARPi targeted therapy. Our previous real-world analysis of testing and treatment patterns (1/1/2020 – 12/31/2021) revealed 40.8% of mCRPC patients did not receive HRRm testing while 33.2% of HRRm positive (HRRm+) patients did not receive a PARPi. The approval of novel hormonal therapies (NHT) in combination with PARPi for first line treatment of mCRPC prompted us to expand our analysis, to determine timing of HRRm testing in relation to line of therapy (LOT) initiated, LOT when NHT and/or PARPi were received, and breakdown of HRRm+ genes in PARPi treated and untreated cohorts.
Methods:
The IntegraConnect – Precision Q de-identified database that includes electronic health and practice management data from 500 US sites of care was utilized to select a real-world cohort of newly diagnosed or treated mCRPC patients between 1/1/2020 - 12/31/2023. Patient charts were manually reviewed by medical curators to extract data including frequency and timing of germline and somatic testing for HRRm, testing success rate and results, and LOT where NHT and/or PARPi were received in the HRRm+ cohort.
Results:
Of the 1022 mCRPC total patients, 63.6% (n=650) received HRRm testing [21.2% germline (n=138); 58.8% somatic (n=382); 3.4% (n=22) germline + somatic; 16.6% (n=108) unknown]. Timing of HRRm testing revealed 19% (n=122) were tested at time of diagnosis, 41% (n=265) during or after first LOT, 22% (n=145) during or after second LOT, and 18% (n=118) at 3+ LOT. Only 9% (n=56) of patients had testing failures with 38% (n=21) originating from somatic tissue testing. Of the 38% (n=226) of HRRm+ patients, 58.4% (n=132) received a PARPi, including 13 patients receiving PARPi in >1 LOT and 23% (n=33) receiving PARPi/NHA combination therapy. 65% (n=95) of patients received PARPi therapy after >3 LOT. The HRRm+ genes in the PARPi treated cohort included
BRCA2
(33.6%; n=51),
ATM
(30.9%; n=47),
CHEK2
(13.2%; n=20),
BRCA1
&
CDK12
(6.6%; n=10),
PALB2
(5.3%; n=8),
RAD54L
(2%; n=3),
BRIP1
,
CHEK1
, &
RAD51B
(0.7%; n=1). Of the 94 patients who did not receive PARPi therapy, 15.9% (n=17), 29% (n=31) and 3.7% (n=4) were
BRCA2
,
ATM
, and
BRCA1
mutation positive, respectively.
Conclusions:
This extended real-world analysis confirms clinical practice gaps with HRRm testing and receipt of matched PARPi therapy in mCRPC. 81% of patients do not receive HRRm testing at the time of mCRPC diagnosis and only 35% of HRRm+ patients receive PARPi prior to third LOT. It is particularly concerning that not all
BRCA1/2
and
ATM
positive patients receive PARPi therapy. Continuing education and standardized testing practices may be needed to address these gaps.