Biomarker-Directed Therapy in Black and White Men With Metastatic Castration-Resistant Prostate Cancer

Key Points Question Do disparities exist in the application of precision medicine for Black and White men with metastatic prostate cancer? Findings In this cohort study of 962 men with metastatic castration-resistant prostate cancer, mismatch repair deficiency or microsatellite instability-high was significantly more frequent in Black men than White men. However, Black men were significantly less likely to receive molecularly matched targeted therapy than White men. Meaning These findings suggest that although precision medicine in metastatic prostate cancer has become more common, opportunities remain to improve access to precision medicine to benefit Black men with prostate cancer.


Introduction
2][3] Furthermore, environmental factors can interact with genetic factors to induce adverse tumor biology. 4[8][9] Recently, molecular profiling has identified biomarkers associated with response to targeted therapies in prostate cancer.4][15][16] Other examples of molecular alterations associated with response include mismatch repair deficiency (MMRD) and tumors with high microsatellite instability (MSI-H). 17,18cause Black men have been underrepresented in prostate cancer molecular profiling studies, 19,20 the underlying tumor genomic landscape for Black men is not entirely known.Since molecular profiling is becoming increasingly important in metastatic prostate cancer, we aimed to investigate the proportion of Black and White men with actionable molecular data and access to targeted therapies for these 2 groups in a contemporary, clinical-genomic database.

Methods
This cohort study was either exempt from institutional review board (IRB) review or IRB-approved at all participating centers, per individual institutional policy.The University of Michigan IRB determined that informed consent was not required because no identifiable patient information was collected.
Reporting follows the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline.

Study Design and Patient Population
The Prostate Cancer Precision Medicine Multi-Institutional Collaborative Effort (PROMISE) is a consortium of academic cancer centers who have established a large, diverse, inclusive, and wellannotated repository of deidentified genomic and clinical data for men with advanced prostate cancer. 21All patients have undergone germline or somatic molecular profiling, including but not limited to 1 or more of the following blood or tissue-based assays: tumor DNA sequencing (eg, cellfree circulating tumor DNA or tumor tissue sequencing), germline DNA sequencing, or transcript profiling studies.Comprehensive clinical data are collected from the time of initial patient diagnosis to time of last follow-up or death.Data are deidentified locally and submitted to a secure database

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Biomarker-Directed Therapy in Black and White Men With Metastatic Castration-Resistant Prostate Cancer maintained at the University of Michigan.Data collection began April 2020.Data cutoff for this analysis was December 12, 2021.For this analysis, patients were required to have a diagnosis of metastatic castration-resistant prostate cancer (mCRPC) and evaluable race and ethnicity information.Two cohorts of patients were defined based on race and ethnicity: non-Hispanic Black (hereafter, Black) and non-Hispanic White (hereafter, White).

Data Elements and Outcome Definitions
Data elements included demographics (including race and ethnicity, as captured by the PROMISE database survey instrument) and clinical and disease characteristics.Prostate-specific antigen (PSA) status was collected from the first systemic therapy given for mCRPC.Molecular testing variables included specimen source, type and timing of molecular testing performed, and reported molecular aberrations.
The primary outcome was the proportion of Black and White men with actionable molecular data.Actionable molecular data was defined as the presence of MMRD or MSI-H, HRRD, or high tumor mutational burden (TMB-H) of 10 mutations per megabase or greater.The presence of any of the following molecular alterations was sufficient for inclusion in the MMRD or MSI-H cohort: MSI; loss of MSH2, MSH3, MSH6, MLH1, MLH3, PMS1, and PMS2 on immunohistochemistry; loss of function of MSH2, MSH3, MSH6, MLH1, MLH3, PMS1, and PMS2 on somatic or germline sequencing; or MLH1 promoter hypermethylation.HRRD was defined as a pathogenic alteration in any of the following genes: BRCA1, BRCA2, ATM, BRIP1, BARD1, CDK12, CHEK1, CHEK2, FANCL, PALB2, PPP2R2A, RAD51B, RAD51C, RAD51D, or RAD54L.For patients with more than 1 test result, the presence of an actionable alteration on any test result was used for categorization.
Secondary outcomes included the proportion of Black and White men with other molecular alterations, the type and timing of molecular testing performed, and the use of biomarker-directed therapy.Biomarker-directed therapy was defined as checkpoint inhibitor immunotherapy for MMRD or MSI-H, PARP-inhibitor or platinum-based therapy for HRRD, and checkpoint inhibitor immunotherapy for TMB-H.Disease-related outcomes included PSA declines, site-reported best radiographic response, and overall survival (OS).PSA declines were calculated as the percentage decline from baseline to nadir PSA, and PSA response (yes vs no) was categorized as at least 50% PSA decline.Response rates were calculated as the percentage of patients with either complete or partial radiographic response (sitereported) for each category of therapy.Survival was calculated from the time of site-reported mCRPC until death or censored at date of last contact.OS probabilities for Black and White cohorts were estimated with the Kaplan-Meier method.Patient characteristics were summarized using the median and IQR for noncategorical variables, and categorical variables were described with the proportions in each category.Differences between the Black and White cohorts for categorical or binary variables were evaluated using χ 2 tests, and 95% CIs for proportions were constructed using the Wilson method.Overall survival probabilities for the Black and White cohorts were estimated using the Kaplan-Meier method, and differences in OS across groups were evaluated using the log-rank test.Statistical significance was defined as 2-sided P < .05.Analyses were conducted using R statistical software version 4.1.2(R Project for Statistical Computing).Data were analyzed from December 2021 to May 2023.

Baseline Characteristics
Of 1619 individuals in the overall database, a total of 962 patients with mCRPC met inclusion criteria (eFigure 1 in the Supplement), including 204 Black patients (

Molecular Testing Characteristics
We compared molecular testing practices in the Black and White cohorts ( did not find any significant differences in testing practices between the Black and White cohorts.

Genomic Characterization of Tumors and Actionable Alterations
The primary objective of our study was to estimate the proportion of Black and White men with mCRPC who were reported to have actionable alterations based on MMR or MSI status, HRRD, or

Use of Biomarker-Directed Therapies
Certain molecular alterations qualify patients for biomarker-directed therapies.We evaluated the use of biomarker-directed therapy in the MMRD or MSI-H, HRRD, and TMB-H cohorts (

Disease-Related Outcomes
There were no differences seen in response to biomarker directed therapy (eTable 2 in Supplement 1).PSA response rates to immunotherapy were 100% (95% CI,

Discussion
In this cohort study, we present one of the largest studies examining differences between Black and White men in a contemporary mCRPC molecular profiling cohort to our knowledge.We found no differences between the Black and White cohorts for our primary outcome, proportion of patients with actionable molecular data; however, MMRD or MSI-H was more common in Black men.
Despite this, receipt of immunotherapy in these Black men was approximately 30% lower than for White men, suggesting a barrier by race in the receipt of matched molecular immunotherapy in the US.
We identified differences in rates of MMRD or MSI-H and PTEN alterations between the Black and White cohorts.MMRD or MSI-H was more common in Black men, while PTEN alterations and TMPRSS2 translocations were less frequent in Black men.Other studies have reported a lower frequency of PTEN loss and TMPRSS2-ERG translocations in genetic analyses of primary prostate cancers from Black men, [23][24][25] strengthening the reliability of these findings.[29] Figure Our finding that MMRD or MSI-H was more frequent in Black men than White men is concordant with a prior report of higher rates of MMRD tumors in men of African ancestry. 30MMRD was associated with adverse clinical and pathologic features but unexpectedly associated with good response to hormonal therapy. 31MMRD or MSI-H is conventionally associated with benefit from immunotherapy, 17 presumably related to genomic instability and the occurrence of immunogenic tumor neoantigens.Genomic instability can arise from defects in other DNA repair pathways, such as HRR.One such gene, CDK12, has been associated with response to immunotherapy in prostate cancer. 31,32Prostate cancers in Black men and men of African ancestry have been reported to have higher rates of DNA repair deficiency 33,34 and increased TMB 35 compared with men of European ancestry.While our study did not replicate all these findings, our data contribute to a growing body of literature pointing to greater genomic instability and possibly better outcomes for immunotherapy for Black men with prostate cancer.Increased genomic instability may be a contributing factor to the observation that tumors in Black men are associated with heightened immune activation and increased cytokine signaling. 36An upregulated inflammatory response and tumoral immunogenicity could also explain the greater observed survival benefit of sipuleucel-T therapy in Black men compared with White men. 6These data, along with the potential for durable responses, emphasize the need to screen for actionable molecular alterations that are associated with benefit from immunotherapy, especially in Black men.
Molecular testing and treatment patterns were similar between Black and White cohorts with 2 notable exceptions.Tissue-based molecular testing was less common for Black patients, and Black men were less likely to receive biomarker-directed therapy than White men.Differences in receipt of targeted therapy were not explained by a difference in clinical trial participation or discussion at molecular tumor boards.Lower use of immunotherapy and platinum chemotherapy contributed to the overall lower utilization of biomarker-directed therapy in the Black cohort.Clinical benefit from standard therapies likely influences the decision to use targeted therapy and seems justified when considering survival was the same between Black and White cohorts, with and without the use of biomarker-directed therapy.In our cohort, clinical markers of aggressive disease (eg, higher grade, presence of de novo and visceral metastases) were seen more commonly in Black men than White men.Despite this, there were no differences in OS between the Black and White cohorts.This finding is concordant with several reports of equal or better outcomes for Black patients when treated with docetaxel, 7 sipuleucel-T, 37 radium-223, 38 and abiraterone, 8 which are standard therapeutic options for men with mCRPC.
The finding that Black men were more likely to receive blood-based vs tissue-based genomic testing may be explained by the lower rates of prostatectomy in Black men 29 leading to greater challenges with tissue-based biomarker testing.When prostatectomy tissue is not available, bloodbased testing may be preferred as more convenient, less invasive, and less expensive than tissue-based testing. 39ltiple variables, [40][41][42][43] including disparities in socioeconomic factors and health care access, negatively impact the care of Black men with prostate cancer.The finding that Black men were less likely to receive targeted therapies, even when undergoing molecular testing, raises the question of whether these factors played a role in this observed disparity.Resource availability at different treatment sites (proposed to be a legacy of structural racism) may influence practice patterns.
Potential unconscious bias among health care practitioners is another factor that may affect the delivery of biomarker-directed therapy.Patient behavior and decision-making influence treatment delivery.Mistrust has been reported to influence cancer treatment decisions, including patients with prostate cancer undergoing genomic testing. 44Patient financial barriers and comorbidities may also contribute to observed treatment differences.Each of these potential variables is worthy of future study.Understanding the reasons behind observed differences in practice patterns is critical to implementing effective interventions to reduce cancer disparities.For example, community outreach or engaging trusted messengers may be used to address medical mistrust, while expanding insurance coverage, financial navigation, and assistance programs may be used to address resource disparities.

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Biomarker-Directed Therapy in Black and White Men With Metastatic Castration-Resistant Prostate Cancer

Limitations
This study has some limitations.We did not address actionable molecular data outside of MMRD or MSI-H, TMB-H, HRRD in this study, nor did we analyze how practice patterns changed over time.The rarity of AR-V7 testing limited our ability to compare frequencies or understand how this biomarker is used in practice.Other variables that influence whether patients receive targeted therapies include comorbidities, performance status, and socioeconomic factors, which are not captured in our database.Lack of information on insurance coverage and income constrained analysis of disparities related to social determinants of health.The PROMISE database uses database-reported race and ethnicity, which should be distinguished from genetic ancestry.Additionally, there is a potential for selection bias related to molecular testing completion as a requirement for inclusion in the PROMISE precision medicine database.

Conclusions
In this cohort study of Black and White men with mCRPC, despite similar overall rates of actionable alterations, we found that Black men were more likely to have MMRD or MSI-H status as well as having less frequent PTEN alterations.We also found that Black men were less likely to receive biomarker-directed therapy.These findings underscore the need for further study for how the

JAMA Network Open | Oncology Biomarker
-Directed Therapy in Black and White Men With Metastatic Castration-Resistant Prostate Cancer

Table 1 .
Baseline Patient and Disease Characteristics of the Study Cohort (continued)

Table 2 .
Molecular Testing Characteristics Reported in Prostate Cancer Precision Medicine Multi-Institutional Collaborative Effort Database in Black vs White Men With mCRPCWhen reviewing treatment patterns in the MMRD or MSI-H, HRRD, and TMB-H cohorts, we discovered the use of biomarker-directed therapy that was not approved by the US Food and Drug Administration.Therefore, we compared the use of clinical trials in the Black and White cohorts in an exploratory analysis.We found that 14 of 215 White patients (6.5%) and 2 of 65 Black patients (3.1%) received biomarker-directed therapy in a clinical trial.

Table 3 .
Actionable Alterations in Black vs White Men With mCRPC

Table 4 .
BDT in Black and White CohortsBiomarker-Directed Therapy in Black and White Men With Metastatic Castration-Resistant Prostate Cancer platinum therapy was 25.0% (95% CI, 1.3%-78.1%) in the Black cohort and 31.6%(95%CI,18.0%-48.8%)intheWhitecohort (P > .99).Similarly, no difference was seen in survival between the Black and White cohorts.Median OS from development of mCRPC was 41.5 (95% CI, 34.7-51.3)monthsforBlack men and 44.7 (95% CI, 41.1-51.5)monthsforWhite men (P = .14).No difference was seen when comparing survival outcomes for patients who received biomarker-directed therapy with those who did not(Figure).The median a Among 18 Black patients and 36 White patients.b Among 46 Black patients and 179 White patients.c Among 8 Black patients and 21 White patients.d Among 65 Black patients and 215 White patients.JAMA Network Open | Oncology JAMA Network Open.2023;6(9):e2334208.doi:10.1001/jamanetworkopen.2023.34208(Reprinted) September 18, 2023 7/13 Downloaded From: https://jamanetwork.com/ on 09/29/2023 . Kaplan-Meier Estimate of Overall Survival for Black and White Cohorts With and Without Biomarker-Directed Therapy (BDT) Downloaded From: https://jamanetwork.com/ on 09/29/2023 environment, social determinants of health, health care infrastructure, practitioner biases, and patient behavior interact to produce the cancer disparities and increased prostate cancer mortality that affect Black men.Serial NGS Testing in Black and White Cohorts eTable 1. Frequency of Gene Alterations in Black and White Men With mCRPC eFigure 3. OncoPrint of Black and White Cohorts eTable 2. Response Rates to Biomarker Directed Therapy