Overall Survival of Black and White Men with Metastatic Castration-Resistant Prostate Cancer (mCRPC): A 20-Year Retrospective Analysis in the Largest Healthcare Trust in England - Full Text Article

Abstract

Background: Prostate cancer in black men is associated with poorer outcomes than their white counterparts. However, most studies reporting this disparity were conducted in localized prostate cancer and primarily in the United States.

Methods: Data regarding prostate cancer incidence and mortality for East London between 2008 and 2010 were obtained from the UK National Disease Registration Service. We further evaluated survival outcomes of 425 cases of mCRPC in St Bartholomew’s Hospital, East London, between 1997 and 2016, and analyzed whether ethnicity impacted on responses to different treatment types.

Results: The incidence of prostate cancer in black men was higher than white men in East London. Prostate cancer-specific mortality was proportional to incidence based on ethnic groups. In the detailed analysis of 425 patients, 103 patients (24%) were black (B), and the remainder white (W). Baseline characteristics were comparable in both groups, although black patients had a lower baseline hemoglobin (p < 0.001). Median overall survival for the total cohort was 25.5 months (B) vs 21.8 months (W) (hazard ratio (HR) = 0.81, p = 0.08). There was prolonged survival in the black population in those who only received hormone-based treatment throughout their treatment course; 39.7 months (B) vs 17.1 months (W) (HR = 0.54, p = 0.019).

Conclusion: Black men may do better than white men with mCRPC, in the context of equal access to healthcare. The study also suggests a greater margin of benefit of hormone-based therapy in the black subpopulation.

Introduction

Prostate cancer is the most common cancer amongst men worldwide. Studies in the UK have reported that the incidence is twice as high in black men compared to white men, with a 30% higher mortality rate.¹ Various reasons have been cited for this, particularly in relation to socioeconomic disparity.² The involvement of biological and genetic factors, such as higher testosterone levels in black men,³ as well as higher expression levels of CYP3A4 polymorphism and 8q24 variant alleles, has also been explored.⁴

However, many of the studies conducted have focused on disparities in outcome based on localized prostate cancer and performed using data from existing registries in the United States.^5–7 Data on racial disparities in patients with metastatic prostate cancer are scarce, with available studies supporting the notion that black patients also have a worse outcome in this disease setting.⁸ While the US database registries are a valuable resource, fully adjusting for confounders based on registries is challenging,⁹ specifically with disparities in access to healthcare.

In 2018, a pooled analysis of nine phase III trials using docetaxel in metastatic castration-resistant prostate cancer (mCRPC) between 1999 and 2014 displayed data that contradicted the general opinion. Despite adverse prognostic parameters such as a higher PSA, lower hemoglobin, and higher testosterone, the black population fared at least as well as their Caucasian counterparts.¹⁰ While this was an exciting finding, the authors acknowledged that the patients in their meta-analysis were overwhelmingly white, and results from a selected trial population cannot be immediately generalizable to clinical practice.

In the United Kingdom, where the National Health System (NHS) allows for equal healthcare access, studies into ethnic disparities in prostate cancer are lacking.¹¹ In the most recent UK Office for National Statistics Census, only 3% of the population identified as black.¹² However, the black subpopulation is disproportionately concentrated in London, which comprised 13.3% of the total population of the city.¹³

Our institution is the largest NHS Hospital Trust in England, with responsibility for most of the population in East London. We cover an ethnically and socially diverse population, and regularly review outcomes of patients with prostate cancer treated in our institution. In view of the interest in differences in outcome to treatment based on race, we reviewed the outcomes of our patients with mCRPC to investigate if patients treated in the real-world setting exhibited outcomes consistent with those treated within clinical trials, in the context of equal access to healthcare.

Material and methods

Data acquisition from the National Disease Registration Service

We obtained data from Public Health England regarding the incidence and deaths from prostate cancer in the different administrative divisions (boroughs) in East London, covering the period of 2008–2010. Based on this data, we assessed relative incidence by ethnicity and corresponding prostate cancer-specific mortality (PCSM) in the region covered by our healthcare Trust.

Patient and record linkage

Information on patients with mCRPC treated between 1997 and 2016 in St. Bartholomew’s Hospital was obtained from the electronic records on the hospital network.

These patients were referred from one of five local hospitals, where the initial prostate cancer diagnosis was established. Patients were discussed in a multi-disciplinary meeting that includes urologists, clinical and medical oncologists, and nurse specialists. Patients with metastatic disease were referred directly to the Medical Oncology clinic. A total of 538 cases of mCRPC were identified during this 20-year period. Amongst these, 85 patients had received docetaxel in the castrate-sensitive setting—to avoid bias from this minority subset of patients, they were excluded from further analysis. A total of 28 patients were of Asian background and hence excluded, leaving us with a total of 425 patients (Supplementary Fig. 1). Ethnicity was regularly recorded as part of the demographic information collected by the Trust.


Fig. 1 Median overall survival (in months) for total cohort of patients divided by ethnicity. OS calculated from diagnosis of metastatic castration-resistant prostate cancer.

Following the results from these 425 patients, we reviewed survival data from a largely distinct and more contemporary cohort of 134 patients, who received enzalutamide in our Trust between 2016 and 2018. The cut-off date for data analysis for this separate cohort was August 2019

Statistical analysis

Statistical analyses were conducted using Intercooled Stata 8.2 (State College, TX, USA). Survival was calculated from the date of diagnosis of mCRPC to date of death or when censored. The date of diagnosis of mCRPC was the date of documented radiological or biochemical progression despite maximum androgen blockade.¹⁴ Treatment-related outcomes were calculated from the date of start of treatment for mCRPC. χ2 and Mann–Whitney U tests were used to compare the baseline clinical characteristics between black and white men. Kaplan–Meier graphs, log-rank tests, and univariate Cox proportional hazards models were employed to investigate the relationship between ethnicity and median overall survival (OS). Outcomes derived from the univariate proportional hazards model are unadjusted for other covariates, unless stated otherwise.

We also performed subgroup analyses of patients who received (a) chemotherapy, (b) taxane vs alkylating agents, and (c) hormone-based treatment only.

Results

Incidence and prostate cancer mortality rates in East of London

Table 1 details the ethnic composition, prostate cancer incidence, and PCSM rates by ethnicity in five major boroughs in East London between 2008 and 2010. There was significant ethnic diversity. While the black population made up only 6–17% of the population in the individual boroughs, they accounted for a disproportionate number of new diagnoses of prostate cancer, i.e., 18–53% of new cases. However, deaths resulting from prostate cancer by ethnicity were consistent with the proportions of new diagnoses made during this period.

Table 1 Relative incidence and mortality of patients with prostate cancer in different boroughs in East London between 2008 and 2010.


This led us to hypothesize that while the incidence of prostate cancer was higher in the black subpopulation, the PCSM does not differ when adjusted by stage of cancer presentation in the context of equal access to healthcare. We proceeded to collect and analyze 20 years of patient data from Barts Health NHS Trust, which serves the majority of East London.

Baseline characteristics of patients in Barts Health NHS Trust

Among the 425 patients with mCRPC in our dataset, a significant minority of our patients (103, 24%) were black (B). The baseline characteristics of our patients were similar between the black and white (W) subgroups in the context of age, baseline biochemical markers and disease sites, proportion enrolled into clinical trials, and performance status. The hemoglobin prior to starting treatment was lower in the black subpopulation. Treatment choices did not appear to differ between the two groups (Table 2).

Table 2 Baseline characteristics by racial group.



Overall survival in total cohort

The median OS amongst the black population was 25.5 (21.0–35.8) months against the 21.8 (19.2–24.0) months in the white group [log-rank p = 0.08, hazard ratio (HR) = 0.81 (95% confidence interval, 0.64–1.03)]. The Kaplan–Meier Survival Curve for the patients categorized by ethnicity is shown in Fig. 1. The first-line treatment received by patients in the mCRPC setting is detailed in Table 3.

Table 3 First-line treatments regimens in mCRPC setting.


Of the 425 patients, 306 (72%) patients received chemotherapy at some point of their treatment of mCRPC. The proportion of patients who received chemotherapy as part of their treatment were balanced in both groups, 72.7% (W) vs 69.9% (B). Chemotherapy was administered either before or after further hormone-based treatment. An equal proportion received chemotherapy (7.8%) as first-line treatment for mCRPC. In this patient cohort, survival was comparable in both groups (median OS 23.8 months in black population vs 22.8 months in white population, p = 0.82, HR 0.97) (Fig. 2A).

Pharmacogenomics is recognized as an important factor accounting for differences in response to treatment based on ethnic background. We analyzed the survival benefit of the class of chemotherapy received within each ethnic group. In the white subpopulation, there was no difference in survival regardless of whether the patient received docetaxel or alkylating chemotherapy as first-line cytotoxic treatment for mCRPC (HR 1.03, p = 0.87) (Fig. 2B). In the black subpopulation, there was a suggested benefit of administering alkylating chemotherapy in mCRPC (median OS 30.1 vs 20.3 months, HR for death 0.71), although this difference was not statistically significant (p = 0.17, Fig. 2C).


Fig. 2 Median overall survival (in months) for patients who received chemotherapy during treatment for mCRPC. A OS for patients who received chemotherapy from start of treatment for mCRPC (n = 306). B OS for white patients who received chemotherapy separated by type of chemotherapy received. C OS for black patients who received chemotherapy separated by type of chemotherapy received. Hazard ratio for death in B and C takes docetaxel cohort as reference.

Cohort of patients who remained chemotherapy-naive

A total of 106 patients did not receive chemotherapy at any point during their treatment, because of patient choice, comorbidities, and/or poor performance status. As such, their treatment options were effectively confined to hormone-based therapy.

In this subgroup of patients, black patients fared significantly better with a median OS of 39.7 vs 17.1 months in white patients (p = 0.019, HR 0.54), as shown in Fig. 3. The choice of their first-line hormone-based treatment in mCRPC is shown in Table 3.

Due to this significant difference in survival, we analyzed whether there was a difference in baseline characteristics between the white (n = 76) and black (n = 30) patients in this subgroup that may have contributed to this observation. There was a greater proportion of black patients with ECOG Performance Status 0 in this subgroup, 30% (B) vs 22.5% (W). However, there was also a greater proportion of those with an ECOG PS of 3, 15% (B) vs 5% (W). In terms of baseline biochemical parameters, there was no significant difference in PSA (Mann–Whitney U test, unpaired p = 0.984), LDH (p = 0.187), ALP (p = 0.285), or albumin (p = 0.610) between the two groups. Median Hb was lower in the black subpopulation (12.4, W vs 10.7, B, p = 0.007). In summary, the baseline characteristics of the patients were unlikely to have contributed to this finding.

Patients who received novel antiandrogen agents— a contemporary analysis

We recognize that the treatment landscape of mCRPC has changed with the introduction of novel antiandrogen agents. There was an under-representation of patients (n = 9) receiving these agents between 1997 and 2016, as abiraterone and enzalutamide only received marketing authorization in the United Kingdom in 2016.

We explored whether our findings, in the context of ethnicity-based outcomes, remain applicable with the introduction of novel antiandrogens. We reviewed survival data from a largely distinct and more contemporary cohort of patients, who received enzalutamide in our Trust. The cut-off date for data analysis for this separate cohort was August 2019.

A total of 134 patients had received enzalutamide in our Trust (93, W vs 41, B). This included patients who received docetaxel in the hormone-sensitive setting. Survival was evaluated from the start of enzalutamide treatment. There was no difference in OS from start of enzalutamide treatment (p = 0.91) based on ethnicity. Even after dividing these patients into cohorts who received enzalutamide before or after chemotherapy, no survival difference was observed between black and white men (Supplementary Fig. 2A–C).

Discussion

Black men with prostate cancer have been associated with poorer outcomes, and efforts have been made to investigate the reasons behind this. There is growing recognition in the United States that this difference is attributable to access to healthcare, and studies have been conducted in the localized prostate cancer setting to prove that the black race is not associated with inferior stage-for-stage mortality.^15,16

Acknowledging that socioeconomic differences could account for outcomes, two recent studies have investigated outcomes of mCRPC using the Veterans Health Administration (VHA) database and found that black patients did better in this setting when they received abiraterone¹⁷ or radium-223.¹⁸

To our knowledge, ours is the first real-world dataset focused on the mCRPC disease setting unrestricted by treatment type, demonstrating that black men do not fare worse in the context of equal access to healthcare. Falling just short of conventional statistical significance, our data suggest that black patients may do better. Furthermore, the black subpopulation had a lower pre-treatment hemoglobin, which is an independent adverse prognostic factor in mCRPC.¹⁹ The HR of 0.81 favoring black men in our analysis of OS stands in contrast to popular opinion, and corroborates the findings of the large study of pooled trial data conducted by Halabi et al.¹⁰ Despite their larger numbers, our findings mitigate several shortcomings of their meta-analysis, with a demographic reflective of East London (24% of our patients were black vs 6% in the metaanalysis) and a fitness-level representative of the prostate cancer population (13% of our patients had documented ECOG PS ≥ 2).

The strong suggestion of better survival data in black patients who only received hormone-based therapy pointed to a greater margin of benefit of these drugs. A separate retrospective study using data from the VHA database showed chemotherapy-naïve, patients with mCRPC who were treated with abiraterone or enzalutamide lived longer than their white counterparts.¹⁷ This supports a prior study suggesting that black patients have a better PSA response rate than Caucasians treated with abiraterone.²⁰ This may be attributable to differences in androgen biosynthesis and metabolism, androgen receptor expression, and signaling patterns between black and white patients.^21,22 A clinical trial, AbiRace (NCT01940276), which prospectively stratifies abiraterone treatment based on ethnicity, is currently underway and may provide clarification.

Our findings suggested a survival benefit derived from alkylating agents, particularly in the black subpopulation. The implications of cancer pharmacoethnicity have been discussed for a long time, particularly in relation to ethnic differences in single nucleotide polymorphisms.²³ More recently, a study has demonstrated a high prevalence of DNA-damage repair genes in ethnic minorities, which could explain the response observed in the black population receiving alkylating agents in our patient cohort.²⁴ While we accept that the survival benefit demonstrated by alkylating agents was not statistically significant compared to docetaxel, we propose that this class effect be explored in further studies to consolidate on prior studies that have demonstrated the efficacy of alkylating agents^25–27 in mCRPC. These agents may be particularly relevant in the treatment course of patients with DNA repair deficits, similar to the cohort that may benefit from PARP inhibitors such as rucaparib and olaparib.

Our work was limited by its retrospective nature, and the absence of baseline criteria such as Gleason Score and baseline comorbidities. However, we have shown that both cohorts were closely matched across a very broad range of characteristics that are individually prognostic in mCRPC^28,29 Our survival data reflect all-cause mortality rather than PCSM. While it would have been useful to compare the two, most men with mCRPC die from their cancer. Hence, the lack of PCSM is unlikely to have influenced the outcome of our analysis. Baseline non-cancer comorbidities are also usually more prevalent in black men with prostate cancer, which would have put this cohort at a disadvantage in the context of assessing survival.³⁰

We also recognize variations in treatment options in mCRPC across different regions and countries and hence the results may not be immediately generalizable. For instance, Sipuleucel-T, which is licensed in the United States for mCRPC, does not have marketing authorization in Europe. Conversely, diethylstilbestrol is used in the United Kingdom while not in the United States.

We acknowledge that there has been a change in the treatment landscape for metastatic prostate cancer, most notably with the introduction of novel antiandrogens. Our review of a separate cohort of 134 patients who received enzalutamide in our hospital, including those who have received docetaxel chemotherapy in the castrate-sensitive setting, supports our hypothesis that black patients do not do worse than white patients with mCRPC. Larger patient numbers, longer follow-up, and more detailed analysis of this group will be required. Nonetheless, many treatments in our study are still relevant today and our study consolidates on the real-world efficacy of many mCRPC treatments— both cytotoxic and hormone-based agents (such as parenteral oestrogen³¹ and corticosteroids³²), which remain widely used in many countries.

Conclusion

Our data suggest that black men with mCRPC do not do worse than white men. In making this conclusion, we appreciate that ethnicity is a complex entity, and that any proposed relationship between ethnicity, social class, educational level, and other determinants of health can never be fully adjusted for. Despite falling short of statistical significance in some areas, our retrospective analysis generates some interesting hypotheses and prompts further research into exploring differential responses to therapies in specific ethnic groups. As the first European study to our knowledge exploring differences in outcome based on race, it contributes to the ongoing discussion about the relative influence of socioeconomics and pharmacogenomics on racial disparity in prostate cancer outcomes.

Acknowledgments: This work uses data that have been provided by patients and collected by the NHS as part of their care and support. The data are collated, maintained, and quality assured by the National Cancer Registration and Analysis Service, which is part of Public Health England (PHE).

Funding: No funding was received specifically for this project. KN is currently funded by a Cancer Research UK Clinical Research Training Fellowship (Award Number 549580).

Author contributions: Conception and design: KM, LH, and JS. Acquisition of data: KN, PW, and JS. Analysis and interpretation of data: KN, PW, and JS. Drafting of the manuscript: KN and JS. Critical revision of the manuscript for important intellectual content: KN, KM, LH, and JS. Statistical analysis: KN and PW. Supervision: JS.

Compliance with ethical standards

Conflict of interest The authors declare that they have no conflict of interest.

Ethical statement Patient outcomes are regularly reviewed in our hospital Trust consistent with the NHS Clinical Governance Framework. In accordance with criteria outlined by the Health Research Authority, NHS Research Ethics Committee approval was not required for this work.

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Kenrick Ng^1,2 Peter Wilson¹ Katherine Mutsvangwa¹ Luke Hounsome³ Jonathan Shamash¹

1. Department of Medical Oncology, Barts Health NHS Trust, London, UK
2. UCL Cancer Institute, University College London, London, UK
3. National Cancer Registration and Analysis Service, Public Health England, London, UK

1. Ben-Shlomo Y, Evans S, Ibrahim F, Patel B, Anson K, Chinegwundoh F, et al. The risk of prostate cancer amongst black men in the United Kingdom: the PROCESS cohort study. Eur Urol. 2008;53:99–105.
2. Evans S, Metcalfe C, Ibrahim F, Persad R, Ben-Shlomo Y. Investigating black-white differences in prostate cancer prognosis: a systematic review and meta-analysis. Int J Cancer. 2008;123:430–5.
3. Ellis L, Nyborg H. Racial ethnic variations in male testosterone levels—a probable contributor to group-differences in health. Steroids. 1992;57:72–5.
4. Okobia MN, Zmuda JM, Ferrell RE, Patrick AL, Bunker CH. Chromosome 8q24 variants are associated with prostate cancer risk in a high risk population of African ancestry. Prostate. 2011;71:1054–63.
5. Presley CJ, Raldow AC, Cramer LD, Soulos PR, Long JB, Yu JB, et al. A new approach to understanding racial disparities in prostate cancer treatment. J Geriatr Oncol. 2013;4:1–8.
6. Tyson MD II, Castle EP. Racial disparities in survival for patients with clinically localized prostate cancer adjusted for treatment effects. Mayo Clin Proc. 2014;89:300–7.
7. Wang C, Kamrava M, King C, Steinberg ML. Racial disparity in prostate cancer-specific mortality for high-risk prostate cancer: a population-based study. Cureus. 2017;9:e961.
8. Thompson I, Tangen C, Tolcher A, Crawford E, Eisenberger M, Moinpour C. Association of African-American ethnic background with survival in men with metastatic prostate cancer. J Natl Cancer Inst. 2001;93:219–25.
9. Park HS, Lloyd S, Decker RH, Wilson LD, Yu JB. Limitations and biases of the surveillance, epidemiology, and end results database. Curr Probl Cancer. 2012;36:216–24.
10. Armstrong AJ, Halabi S, Luo J, Nanus DM, Giannakakou P, Szmulewitz RZ, et al. Prospective multicenter validation of androgen receptor splice variant 7 and hormone therapy resistance in high-risk castration-resistant prostate cancer: the PROPHECY study. J Clin Oncol. 2019;37:1120–9.
11. Lloyd T, Hounsome L, Mehay A, Mee S, Verne J, Cooper A. Lifetime risk of being diagnosed with, or dying from, prostate cancer by major ethnic group in England 2008-2010. BMC Med. 2015;13:171.
12. Gov.UK. Population of England and Wales.
13. Gov.UK. Regional Ethnic Diversity.
14. European Association of Urology guideline version 2015. http://www.uroweb.org/guidelines/.
15. Dess RT, Hartman HE, Mahal BA, Soni PD, Jackson WC, Cooperberg MR, et al. Association of black race with prostate cancer-specific and other-cause mortality. JAMA Oncol. 2019;5:975–83.
16. Paller CJ, Wang L, Brawley OW. Racial inequality in prostate cancer outcomes-socioeconomics. Not Biol JAMA Oncol. 2019;5:983–4.
17. McNamara MA GD, et al. Overall survival by race in chemotherapy-naïve metastatic castration-resistant prostate cancer (mCRPC) patients treated with abiraterone acetate or enzalutamide. J Clin Oncol. 2019;37:212.
18. Zhao H, Howard LE, De Hoedt A, Terris MK, Amling CL, Kane CJ, et al. Racial discrepancies in overall survival among men treated with (223)Radium. J Urol. 2020;203:331–7.
19. Dai D, Han S, Li L, Guo Y, Wei Y, Jin H, et al. Anemia is associated with poor outcomes of metastatic castration-resistant prostate cancer, a systematic review and meta-analysis. Am J Transl Res. 2018;10:3877–86.
20. Ramalingam S, Humeniuk MS, Hu R, Rasmussen J, Healy P, Wu Y, et al. Prostate-specific antigen response in black and white patients treated with abiraterone acetate for metastatic castrateresistant prostate cancer. Urol Oncol. 2017;35:418–24.
21. Edwards A, Hammond HA, Jin L, Caskey CT, Chakraborty R. Genetic variation at five trimeric and tetrameric tandem repeat loci in four human population groups. Genomics. 1992;12:241–53.
22. Karakas C, Wang C, Deng F, Huang H, Wang D, Lee P. Molecular mechanisms involving prostate cancer racial disparity. Am J Clin Exp Urol. 2017;5:34–48.
23. O’Donnell PH, Dolan ME. Cancer pharmacoethnicity: ethnic differences in susceptibility to the effects of chemotherapy. Clin Cancer Res. 2009;15:4806–14.
24. Lopez RFA, Goel S, Peeke S, Sharma J, Shenoy N. Genomic profiling of prostate cancer at a diverse academic center. J Clin Oncol. 2020;38; abstr. 64.
25. Ladoire S, Eymard JC, Zanetta S, Mignot G, Martin E, Kermarrec I, et al. Metronomic oral cyclophosphamide prednisolone chemotherapy is an effective treatment for metastatic hormonerefractory prostate cancer after docetaxel failure. Anticancer Res. 2010;30:4317–23.
26. Shamash J, Jacob J, Agrawal S, Powles T, Mutsvangwa K, Wilson P, et al. Whole blood stem cell reinfusion and escalated dose melphalan in castration-resistant prostate cancer: a phase 1 study. Clin Cancer Res. 2012;18:2352–9.
27. Shamash J, Dancey G, Barlow C, Wilson P, Ansell W, Oliver RT. Chlorambucil and lomustine (CL56) in absolute hormone refractory prostate cancer: re-induction of endocrine sensitivity an unexpected finding. Br J Cancer. 2005;92:36–40.
28. Belderbos BPS, de Wit R, Hoop EO, Nieuweboer A, Hamberg P, van Alphen RJ, et al. Prognostic factors in men with metastatic castration-resistant prostate cancer treated with cabazitaxel. Oncotarget. 2017;8:106468–74.
29. Halabi S, Small EJ, Kantoff PW, Kattan MW, Kaplan EB, Dawson NA, et al. Prognostic model for predicting survival in men with hormone-refractory metastatic prostate cancer. J Clin Oncol. 2003;21:1232–7.
30. Putt M, Long JA, Montagnet C, Silber JH, Chang VW, Kaijun L, et al. Racial differences in the impact of comorbidities on survival among elderly men with prostate cancer. Med Care Res Rev. 2009;66:409–35.
31. Norman G, Dean ME, Langley RE, Hodges ZC, Ritchie G, Parmar MK, et al. Parenteral oestrogen in the treatment of prostate cancer: a systematic review. Br J Cancer. 2008;98:697–707.
32. Venkitaraman R, Thomas K, Huddart RA, Horwich A, Dearnaley DP, Parker CC. Efficacy of low-dose dexamethasone in castration refractory prostate cancer. BJU Int. 2008;101:440–3.