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JAMA Oncol
JAMA Oncol
JAMA Oncology
2374-2437
2374-2445
American Medical Association

38696212
10.1001/jamaoncol.2024.0851
cld240005
Research
Letters
Research Letter
Online First
Comments
Genetic Testing in Men With Metastatic Castration-Resistant Prostate Cancer
Genetic Testing in Men With mCRPC
Letters
Barata Pedro C. MD MSc 1
Assayag Jonathan PhD 2
Li Benjamin PhD 3
Siu Gordon MSc 3
Niyazov Alexander PharmD MPH 3
1 University Hospitals Seidman Cancer Center, Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio
2 Pfizer Inc, Kirkland, Quebec, Canada
3 Pfizer Inc, New York, New York
Article Information

Accepted for Publication: February 23, 2024.

Published Online: May 2, 2024. doi:10.1001/jamaoncol.2024.0851

Open Access: This is an open access article distributed under the terms of the CC-BY-NC-ND License. © 2024 Barata PC et al. JAMA Oncology.

Corresponding Author: Pedro C. Barata, MD, MSc, University Hospitals Seidman Cancer Center, Case Comprehensive Cancer Center, Case Western Reserve University, 11100 Euclid Ave, Lakeside Ste 1200, Room 1215, Cleveland, OH 44106 (pedro.barata@uhhospitals.org).
Author Contributions: Drs Barata and Niyazov had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Barata, Assayag, Niyazov.

Acquisition, analysis, or interpretation of data: Assayag, Li, Siu, Niyazov.

Drafting of the manuscript: Barata, Assayag, Niyazov.

Critical review of the manuscript for important intellectual content: All authors.

Statistical analysis: Barata, Assayag, Li, Siu.

Obtained funding: Niyazov.

Administrative, technical, or material support: Assayag, Niyazov.

Supervision: Barata, Assayag, Niyazov.

Conflict of Interest Disclosures: Dr Barata reported receiving personal fees from EMD Serono, Exelixis Inc, Pfizer Inc, Caris Life Sciences, UroToday, AstraZeneca, Myovant Sciences Ltd, Merck & Co Inc, Targeted Oncology, Bristol Myers Squibb, MJH Life Sciences, SeaGen Inc, Bayer AG, and Eisai Inc outside the submitted work. Dr Assayag reported owning stock in Pfizer Inc. Dr Li reported owing stock in Pfizer Inc. Dr Niyazov reported owning stock in Pfizer Inc. No other disclosures were reported.

Funding/Support: The study was supported by Pfizer Inc.

Role of the Funder/Sponsor: The sponsor was involved in the study design, assisted with the analysis and interpretation of data, and checked study data during a review of the manuscript. The sponsor had no role in the conduct of the study, collection or management of the data, preparation or approval of the manuscript, and decision to submit the manuscript for publication.

Data Sharing Statement: See the Supplement.

Additional Contributions: Medical writing support, including assisting authors with the development of the outline and initial draft and incorporation of comments, and editorial support, including fact checking, referencing, figure preparation, formatting, proofreading, and submission were provided by Allison Alwan TerBush, PhD, and Rosie Henderson, MSc (both of Onyx, London, UK) with financial support from Pfizer Inc according to Good Publication Practice guidelines.

2 5 2024
2 5 2024
e24085123 12 2023
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Copyright 2024 Barata PC et al. JAMA Oncology.
https://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article distributed under the terms of the CC-BY-NC-ND License.
jamaoncol-e240851.pdf

This cross-sectional study assesses homologous recombination repair mutation genetic testing and associated characteristics among men with metastatic castration-resistant prostate cancer (mCRPC).
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pmcIn metastatic castration-resistant prostate cancer (mCRPC), germline or somatic homologous recombination repair (HRR) gene mutations can be found in approximately 25% to 30% of tumors. Certain HRR mutations have prognostic value and become increasingly relevant as predictive biomarkers for therapies, notably poly(ADP [adenosine diphosphate]-ribose) polymerase inhibitors (PARPi). Genetic testing can inform treatment decisions for patients with mCRPC and was recommended in national guidelines in 2018. Little is known about genomic testing rates following the integration of PARPi into guidelines. We assessed patterns of HRR mutation genetic testing and the characteristics associated with testing among US patients with mCRPC.

Methods

This cross-sectional retrospective study was based on anonymized secondary data reported at the aggregated level and not at the patient level. The study was exempt from Institutional Review Board approval. We followed the STROBE reporting guideline.

From January 1, 2014, to December 31, 2022, data for patients with mCRPC treated in the US were obtained from the Flatiron Health Enhanced Datamart, a database capturing longitudinal data of patients with cancer who receive treatment in community- and academic-based integrated care delivery networks. Patients with a confirmed diagnosis of mCRPC underwent testing for HRR mutations, including (1) a next-generation sequencing, specifically any somatic HRR, tissue, or circulating tumor DNA test, or (2) a somatic or germline BRCA test. Timing of HRR testing relative to mCRPC diagnosis and initiation of first-line therapy was determined from the first HRR test result available. A multivariable stepwise logistic regression model was used to identify factors associated with HRR testing.

Results

A total of 9395 patients with mCRPC (median age, 74 [range, 37-88] years; 928 [9.9%] Black and 5975 [63.4%] White; 8042 [85.6%] treated in a community setting; 4622 [49.2%] with socioeconomic score ≤3) were included. Overall, 3538 patients (37.7%) received HRR testing. The proportion of patients tested peaked in 2020 (596 of 1073 [55.5%]) and decreased in 2022 (327 of 662 [49.4%]) (Figure 1A). From 2014 to 2019, 1546 of 2090 patients (74.0%) underwent HRR testing more than 12 weeks after initiating first-line therapy (Figure 1B). Conversely, by 2022, 304 of 662 patients (45.9%) were tested within 12 weeks of initiating first-line therapy. Of the 3428 BRCA tests (96.9% of tested patients), 1592 (46.4%) were somatic, 751 (21.9%) were germline, and 1085 (31.7%) were both. Logistic regression analysis identified diagnosis before 2018 (odds ratio [OR], 0.30 [95% CI, 0.28-0.33]), no prior treatment for localized disease (OR, 0.64 [95% CI, 0.56-0.73]), Eastern Cooperative Oncology Group performance status of 1 (OR, 0.78 [95% CI, 0.70-0.87]) or 2 or greater (OR, 0.52 [95% CI, 0.45-0.61]), and de novo disease (OR, 0.65 [95% CI, 0.57-0.75]) as associated with lower odds of receiving HRR testing (Figure 2).

Figure 1. Homologous Recombination Repair Mutation Testing Rates and Timing of Testing Among Patients Diagnosed With Metastatic Castration-Resistant Prostate Cancer (mCRPC) Each Year

1L indicates first-line therapy.

Figure 2. Baseline Demographic and Disease Characteristics Associated With Homologous Recombination Repair (HRR) Mutation Testing Among Patients With Metastatic Castration-Resistant Prostate Cancer (mCRPC)

Median PSA levels were measured at time of mCRPC diagnosis. ECOG PS indicates Eastern Cooperative Oncology Group performance status; PSA, prostate-specific antigen; OR, odds ratio; and SES, socioeconomic score.

aRepresents quintiles based on US census data. 1 represents the lowest quintile; 5, the highest quintile. Factors associated with these categories are household income, home value, median rent, educational level, percentage of population considered working class, percentage of population living under 150% of the federal poverty line, and percentage of population unemployed.

bOwing to release of olaparib data by de Bono et al, 2018 was chosen as cutoff.

Discussion

Most patients (5857 [62.3%]) diagnosed with mCRPC between 2014 and 2022 in the US did not receive HRR testing. Positive associations were observed with the timing of testing relative to initiation of first-line therapy, and to a lesser extent, testing rates. The small decline in testing rates after 2020 may be attributable to the COVID-19 pandemic. Racial and socioeconomic disparities in testing access and cancer outcomes have been well documented and are reflected in this study. Lower socioeconomic index and Medicaid insurance were associated with lower odds of testing. Treatment outside academic centers and older age were also associated with lower testing rates.

Study limitations included incomplete information on the type of test and the number of genes included in each test. Furthermore, most patients were from a community setting, and these testing rates may not reflect rates in academic centers. While the use of genomic-based therapies was not the focus of this study, the low testing rates observed in our cross-sectional study would be further compounded by low utilization of targeted therapies among patients who are known to be eligible. These findings highlight disparities in receiving HRR testing in the US. Continued efforts to address barriers to HRR testing are needed.

Supplement. Data Sharing Statement
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References

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2 Shao C, Chang MS, Lam FC, . A systematic review and meta-analysis on the prognostic value of BRCA mutations, homologous recombination gene mutations, and homologous recombination deficiencies in cancer. J Oncol. 2022;2022 :5830475. doi:10.1155/2022/5830475 35909902
3 de Bono J, Mateo J, Fizazi K, . Olaparib for metastatic castration-resistant prostate cancer. N Engl J Med. 2020;382 (22 ):2091-2102. doi:10.1056/NEJMoa1911440 32343890
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5 Hwang C, Henderson NC, Chu SC, . Biomarker-directed therapy in Black and White men with metastatic castration-resistant prostate cancer. JAMA Netw Open. 2023;6 (9 ):e2334208. doi:10.1001/jamanetworkopen.2023.34208 37721753
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