Reflexive paired somatic and germline testing at time of medical oncology referral in mCSPC: Impact on timely treatment.
Authors: Gagnon Richard , Hoag Emma , Olsen Alexandra , Attwell Andrew J. , Fundytus Adam Michael , Vergidis Joanna , Parimi Sunil , Sonke Eric , Alimohamed Nimira S. , Yip Steven , Maurice Dror Corinne , Chi Kim N. , Hinkley Madison , Lavoie Jean-Michel 
Published: February 2025

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Background:
Use of PARP inhibitors (PARPi) improves outcomes in patients with metastatic castrate-resistant prostate cancer (mCRPC) harboring germline or somatic homologous recombination repair (HRR) mutations. To ensure timely PARPi initiation, genetic results should be available at castrate resistance, with testing initiated in the metastatic castration-sensitive (mCSPC) setting. Relying on ad hoc, provider-initiated testing risks biomarker unavailability when treatment decisions are made, leading to suboptimal therapies. This study evaluates a program of reflexive paired germline and tumor testing for mCSPC patients at medical oncology referral (typically following initial management and androgen deprivation therapy [ADT] by urology or radiation oncology) as a potentially effective time point for genetic testing.
Methods:
This was a single cancer centre, retrospective review of mCSPC patients offered simultaneous germline and tumor tissue next-generation sequencing at medical oncology referral. We examined test completion rates, timing of results relative to key disease timepoints (ADT initiation, first-line mCRPC treatment), and the frequency of detected pathogenic mutations. Timing of results was analyzed separately for all patients, those with HRR mutations, and those with timely referrals to medical oncology, defined as <90 days from ADT start.
Results:
Of 218 mCSPC patients, 212 (97.2%) completed germline or tumor tissue sequencing with interpretable results from at least one assay. Germline results were obtained in 171 patients (78.4%) and tumor tissue results in 194 (88.9%). HRR mutations were detected in 29 patients (13.3%): 15 germline, 10 somatic, and 4 of unknown origin. Median time from ADT initiation to germline and tumor tissue genetic results was 165 and 120 days, respectively. Germline results were available for 144 patients (84.2%) and tumor tissue results for 176 (90.7%) before initiation of first-line mCRPC treatment. Among the 29 patients with identified HRR mutations, 19 (76%) had germline results and 17 (81%) had tumor tissue results before first-line mCRPC treatment. In the subgroup of 175 patients referred to medical oncology within 90 days of ADT initiation, 136 patients (98.6%) had germline results and 148 (99.3%) had tumor tissue results before first-line mCRPC treatment.
Conclusions:
Reflexive paired genetic testing at medical oncology referral is effective in identifying HRR mutations and optimizing PARPi use based on current mCRPC indications. Ensuring timely patient identification through clear and accessible genetic testing pathways will help maximize therapeutic options for patients with advanced prostate cancer. If PARPi or other targeted agents demonstrate benefit in earlier disease states, this process may need to be shifted further upstream, requiring close multidisciplinary collaboration.