Outcomes Among African American and Non-Hispanic White Men With Metastatic Castration-Resistant Prostate Cancer With First-Line Abiraterone

Key Points Question How do outcomes associated with first-line abiraterone therapy differ by race in a real-world cohort of patients with metastatic castration-resistant prostate cancer (mCRPC)? Findings In this propensity score–adjusted cohort study of 3808 patients with mCRPC, among men receiving first-line abiraterone, African American men had significantly longer median overall survival compared with non-Hispanic White men (23 vs 17 months). Among non-Hispanic White men, first-line abiraterone was associated with significantly lower median overall survival than enzalutamide (17 vs 20 months). Meaning Abiraterone in mCRPC was associated with differential outcomes by race, possibly driven by decreased benefit among non-Hispanic White men.


Introduction
Despite multiple agents receiving approval for treatment of metastatic castration-resistant prostate cancer (mCRPC), African American men are underrepresented in seminal phase 3 trials in mCRPC. 1 Given that African American men are more likely to develop and die from metastatic prostate cancer than non-Hispanic White men, identifying optimal treatment strategies for African American men with mCRPC is a key public health priority. 2,35][6][7] African American patients treated with abiraterone in the Abi-Race prospective trial had longer median time to prostate-specific antigen progression than non-Hispanic White patients (16.6   vs 11.5 months, respectively) and higher rates of at least 50% prostate-specific antigen decline (74% vs 66%, respectively); however, these differences were not statistically significant. 7It is unclear whether these outcomes extend to contemporary real-world cohorts, particularly given availability of other effective therapies, such as enzalutamide.We investigated differences in outcomes associated with first-line abiraterone between African American and non-Hispanic White men with mCRPC in a national real-world cohort, which to our knowledge represents a larger sample size with greater power than that of similar investigations to date.Moreover, through comparing abiraterone with enzalutamide, our study is the first to our knowledge to evaluate for an association between race and androgen receptor signaling inhibition therapy and thereby examine both the prognostic value of race among abiraterone-treated patients and the predictive value of race on abiraterone vs enzalutamide outcomes.

Data Source
This retrospective cohort study used the nationwide Flatiron Health electronic health record-derived deidentified database, a longitudinal data set consisting of deidentified patient-level structured and unstructured data curated via technology-enabled abstraction.During the study period, data originated from approximately 280 cancer clinics (approximately 800 sites of care).The framework and methodology used by the Flatiron Health database to generate its mCRPC cohort is detailed extensively elsewhere. 8Briefly, CRPC status is identified through an algorithm incorporating physician documentation of hormone-resistant status and resistance to androgen deprivation therapy through certain prostate-specific antigen elevation parameters.Lines of therapy are documented in the database relative to the index date of mCRPC diagnosis, in which the first line of treatment was defined as the first therapeutic agent initiated after mCRPC diagnosis plus any other agents initiated within 28 days of the first agent.The University of Pennsylvania institutional review board approved the protocol with a waiver of informed consent, given use of deidentified data.This report followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline for cohort studies.

JAMA Network Open | Oncology
Castration-Resistant Prostate Cancer Outcomes With First-Line Abiraterone by Patient Race

Study Population and Covariates
The study population included patients with newly diagnosed mCRPC who were receiving first-line systemic therapy between January 1, 2012, and December 31, 2018.Patients were excluded if they had no documented first-line therapy, a greater than 90-day gap between mCRPC diagnosis and first structured electronic health record activity, or nonmetastatic CRPC; or had received first-line agents not listed in National Comprehensive Cancer Network guidelines 9 for mCRPC (eFigure 1 in the Supplement).Follow-up was censored at death or last confirmed electronic health record activity.
Race and ethnicity categorizations in the Flatiron Health database are modeled after the US Office of Management and Budget standards for race and ethnicity, 10 which inform census categories and Food and Drug Administration guidelines for collecting race and ethnicity information in clinical trials.
Race and ethnicity information was self-reported by patients and then documented by clinical teams directly within the electronic health record or within a practice management system from which data were then imported into the electronic health record.

Statistical Analysis
Data analysis was performed between January 1, 2020, and June 1, 2021.The primary exposure was receipt of abiraterone for first-line therapy, either with androgen deprivation therapy alone or in combination with other systemic therapies.Propensity score-based inverse probability of treatment weighting (IPTW) was applied to reduce imbalance in measured confounders between patients receiving first-line abiraterone vs other first-line therapies (eFigure 2 in the Supplement).Patientlevel covariates measured at mCRPC diagnosis included age, race and ethnicity, Elixhauser comorbidities, 11 prostate-specific antigen level, docetaxel treatment in the metastatic hormonesensitive setting, insurance type, and opioid use as a proxy of disease severity, 12 given that prior research has demonstrated that pain is a predictor of overall survival in men with mCRPC and that opioid use correlates with higher pain scores. 13Practice-level covariates included treatment setting (academic vs community), geographic region, and abiraterone prescribing rate.Abiraterone prescribing rate was defined as the proportion of first-line treatment initiations containing abiraterone per practice and was used to account for any variation in baseline practice patterns 14 that might influence patient receipt of abiraterone as part of first-line therapy.A secondary analysis assessed exposure to first-line enzalutamide treatment, using the same propensity score-based methodology and covariates.
The primary outcome was overall survival from start of first-line treatment.IPTW-adjusted Kaplan-Meier curves compared treatment-specific overall survival between African American and non-Hispanic White patients to estimate the marginal association between race and overall survival after balance was achieved in measured confounders.Cox proportional hazards regressions estimated IPTW-adjusted hazard ratios (HRs) and 95% CIs.Stratified analyses investigated overall survival within each race group, with first-line single-agent enzalutamide as the comparator.A 2-sided P value of .05 was considered statistically significant.All models included race-treatment interactions to determine whether differences in outcomes by race varied by treatment group.
Stata/IC version 15.1 (StataCorp) was used for data analysis.

Discussion
In this real-world analysis of nearly 4000 patients with mCRPC who were receiving first-line treatment, abiraterone was associated with superior overall survival for African American men compared with non-Hispanic White men.Race-stratified analyses using enzalutamide as a comparator suggested that this overall survival disparity may have been due to decreased benefit associated with abiraterone among non-Hispanic White men.In contrast, among patients receiving first-line enzalutamide, there was no racial difference in overall survival.Favorable outcomes for African American men receiving abiraterone were previously observed in retrospective studies, 4,5 but no significant race-based differences in abiraterone effectiveness were found in prospective data. 6,7It is unclear, however, whether the lack of significant differences in these prospective studies was due to insufficient power.Our study suggests that abiraterone is associated with better outcomes for African American vs non-Hispanic White men in real-world practice and extends prior analyses by investigating race-specific overall survival in a large real-world cohort.Our study demonstrated a significant race-treatment interaction association, which to our knowledge has not been reported by prior randomized studies investigating abiraterone and enzalutamide.Although there may not be a comparative advantage for abiraterone over other first-line mCRPC agents among African American men, other agents may be favored above abiraterone among non-Hispanic White men.Beyond the context of androgen receptor signaling inhibitors, there is emerging evidence for race-treatment interaction associations in the mCRPC setting with respect to sipuleucel-T therapy, for example, 15 which likewise underscores the need to further explore the interplay between race and treatment as it relates to variation in mCRPC outcomes.
Future investigation into drivers of differential outcomes between mCRPC agents should move beyond studying race itself because race may not account for all underlying factors, including socioeconomic differences, that contribute to disparate outcomes. 16,17To that end, genetic variants are being explored as factors in mCRPC treatment response.The HSD3B1(1245A>C) gene variation has higher single-nucleotide variation allelic frequency among male individuals of European (32%) vs African American (15%) ancestry 18,19 and has been shown to increase 3βHSD1 enzyme quantity within androgen receptor signaling pathways. 201][22] If future randomized trials confirm this treatment-related association, precision oncology treatment strategies may have important applications in mCRPC and contribute to decreasing disparities in outcomes, but only in concert with systematic efforts to increase representation of non-White populations in cohort studies and clinical trials.

Limitations
Because this cohort study was a real-world analysis, a key limitation was the inability to fully account for socioeconomic factors and biases that, in conjunction with race, contribute to receipt of a given therapy and outcomes disparities. 2,17Likewise, certain covariates may have been incompletely coded owing to inconsistent electronic health record documentation (eg, comorbidities), and other variables affecting prognosis and outcomes were not collected or easily analyzable in this database (eg, treatment adherence, burden of metastatic disease, family history, genetic risk factors).
However, this missingness is common with observational data sets, and we have no evidence that it was unbalanced between African American and non-Hispanic White men.In addition, our analysis included a relatively short median follow-up of 13 months.Finally, non-Hispanic White men disproportionately outnumbered African American men in the study sample.However, the sample proportion of African American men exceeded typical representation of African American men in CRPC trials by more than 3-fold. 1 Despite these limitations, to our knowledge this is the largest realworld study to date investigating differential outcomes with abiraterone use by race in the mCRPC setting.
Role of the Funder/Sponsor: The Prostate Cancer Foundation had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
In this propensity scoreadjusted cohort study of 3808 patients with mCRPC, among men receiving first-line abiraterone, African American men had significantly longer median overall survival compared with non-Hispanic White men (23 vs 17 months).Among non-Hispanic White men, first-line abiraterone was associated with significantly lower median overall survival than enzalutamide (17 vs 20 months).Meaning Abiraterone in mCRPC was associated with differential outcomes by race, possibly driven by decreased benefit among non-Hispanic White men.

Figure 1 .
Figure 1.Overall Survival by Race, African American vs Non-Hispanic White Men

Figure 2 .
Figure 2. Overall Survival by Race and Treatment, First-Line Abiraterone vs First-Line Enzalutamide