Clinical Research as an Equalizer
Differences in outcomes and responses to treatment in diverse populations often have been attributed to biological factors. However, standardized treatment can tell a divergent story, one in which parameters, such as geographic location and financial status, play a significant role in how a person responds. This underscores the importance of a diverse study population in clinical trials, researchers say.
An example of the difference in outcomes has played out in the area of prostate cancer. One long-standing observation is Black men appear to present earlier and younger with this disease and experience a higher mortality rate, says Charles Ryan, MD, an oncologist with the University of Minnesota Medical School. “A number of biological differences have been identified between African Americans and Caucasian men with regards to a prostate cancer, but I don’t think we’ve effectively made the case to say why, biologically, African Americans had a perceived worse outcome,” he says.
Over the last several years, researchers have studied differences in outcomes of Black men based on where and how they are treated. “The question is always, is it a biological difference, which people have been trying to figure out and never anything definitive has emerged, or whether it is a societal or treatment difference, or bias in healthcare practitioners,” Ryan says.
In one study of men in the Medicare database, researchers suggested African Americans received a worse prognosis and a worse outcome when diagnosed with prostate cancer,1 Ryan says. A separate study of men in the Veterans Affairs (VA) database revealed improved outcomes. Unlike Medicare patients, the VA treats veterans according to its protocols. Their access to care is based on veteran status, not income or other factors. “The VA system analysis appeared to not erase, but lessen, the differences between African Americans and Caucasians with regards to outcome and prostate cancer,”2 he explained.
Susan Halabi, PhD, professor of biostatistics and bioinformatics at Duke University, analyzed data from nine randomized Phase III trials to compare survival rates of Black and white men. The 8,820 participants received an advanced prostate cancer diagnosis, and all were treated with chemotherapy. In comments at the meeting of the American Society of Clinical Oncology (ASCO) in 2018, Halabi said they were testing the hypothesis that Black men experience higher rates of death and incidence of prostate cancer than Caucasian men.3 “When we did the analysis, to our surprise, we found that it was contrary to what we assumed,” Halabi said.
The findings showed the median survival rate was the same in Black men and white men overall (21 months). However, Black men showed a 19% lower risk for death than white men when research adjusted for prognostic factors, such as patient age, performance status, site of metastasis, prostate-specific antigen level, and alkaline phosphatase and hemoglobin levels.4
The lower risk of death in Black men might be a reflection of “differences in the biology of the disease,” or Black men might experience higher tolerance to docetaxel-prednisone combination, Halabi said. Perhaps the selection of the men was a factor as well. “This is an open question that needs further research.”
A clinical trial is another situation in which all patients are treated the same, Ryan says. “That’s the point of the clinical trial — to treat them according to a very strict protocol,” he notes.
When studying Black men vs. Caucasian men in an arm of a prostate cancer clinical trial, the outcome of the Black men was not only “not worse” but might, in fact, have been slightly better with certain drug categories. “The aggregate effect of those analyses has been to say, ‘When we make these claims, we need to be correcting for therapy administered,’” Ryan explains. “When you correct for therapy administered and the protocol with which the therapy is delivered, these differences may go away.”
This essentially upended the long-held assumption that Black men experience categorically worse outcomes. “I think we need to say that in situations where access or other factors are integrated, there still may be significant disparities. But if we can correct access, if we can correct therapy, we may be able to correct some of these underlying challenges,” Ryan says.
This is an important lesson because it speaks to the importance of treating people according to a standard protocol. “It speaks to the importance of integrating African Americans into clinical trials, for sure,” Ryan adds.
Elisabeth Heath, MD, FACP, a medical oncologist at Barbara Ann Karmanos Cancer Institute in Detroit, recently spoke about these additional factors when talking about differences in prostate cancer patterns and response to treatment. In addition to racial disparities in prostate cancer outcomes and treatment, disparities in ethnicity, geographic location, financial status, and socioeconomic status influence treatment decision-making. Heath presented her session, “Evolution of Disparities in Prostate Cancer Treatment: Is This a New Normal?” at the 2021 ASCO Annual Meeting in June.5
Heath presented data from the National Cancer Database among 214,972 men with high-risk prostate cancer diagnosed between 2004 and 2016. “Utilization of prostatectomy, compared to radiotherapy, was associated with higher income, private insurance, and treatment at an academic center. Black men were less likely to undergo radical prostatectomy, though, over time, this difference is diminishing,” she said.
Among men who underwent radical prostatectomy, Black men experienced a 20% higher mortality rate than white men. The mortality rate for Asian men is 35% lower than for white men. “These disparities are actually greatest among those without comorbidities and those with less aggressive disease (early-stage and low-grade disease). For example, among men with Gleason 6 prostate cancer, Black men are twice as likely to die of prostate cancer compared with non-Black men. However, these data are limited by a lack of data on recurrence, cause of death, and short follow-up time,” Heath said.
Radiotherapy is used more commonly among Black men than Hispanic or white men, Heath noted. However, rates of radiotherapy non-completion were higher among Black men. Stereotactic body radiotherapy might diminish these disparities, she said.
There exist many different types of research studies with varying conclusions. “The examples I cited in the ASCO 2021 presentation were retrospective. Meta-analysis publications that concluded that there are no differences in outcomes with patients on clinical trials based on race,” Heath tells Medical Ethics Advisor. “However, these are data from patients enrolled in clinical trials. As seen in the ASCO 2021 claims data in men with castrate-sensitive prostate cancer, only one-third to one-half receive the intended treatment intensification as part of standard of care treatment. In the case of Black men, this number is again lower. The take-home message is that enrolling prostate cancer patients in clinical trials will reduce health disparity.”
In her ASCO presentation, Heath spoke about considering the effect of ethnicity. Lumping Hispanic populations together does not account for the meaningful differences in cancer rates among Hispanic populations. For example, “it is important to distinguish Hispanic populations (who descend from Spanish-speaking countries, such as Mexico) and Latino groups (who descend from Latin American countries, such as Brazil).”
“Ethnicity remains a difficult topic to address,” Heath says. “Clinical trials are primarily focused on addressing race.”
Ryan and Heath discussed Heath’s presentation in a video. Ryan said he thought Heath was constructing “multivariate determinants of potential outcome” she wanted to study.6
Heath agreed. “[B]ecause we know no matter how you tease it out, each one man always has all those factors going on,” she said. What makes it important is recognizing the parameters. “Every time we think disparity, we think Black, white. I look at the sort of Latino, Hispanic … just the ethnicity question is so underexplored. The heterogeneity there is tremendous, and we just kind of clump everybody.”6
The factors driving the disparity gap are complex and multifaceted. “It is difficult to isolate one specific biological difference when the everyday challenges of access to care or ZIP code also dictate the care that a prostate cancer patient receives,” Heath tells Medical Ethics Advisor. “Our approach to reduce the disparity gap has to be equally aggressive and multifaceted. Otherwise, the gap will continue to grow.”
To help close the gap, Heath recommends IRBs ask if eligibility criteria should be broadened to include specific groups as well as asking how investigators plan to recruit special populations.
However, showing consistent results through standardization of treatment can be undermined by disparities in clinical trial enrollment. Heath also addressed this in her presentation. Nationwide, 6.2% of clinical trial participants are African American, she said. This is substantially lower than the general population, or among cancer patients.
“In addition, in prostate cancer, Latino and Asian men are also underrepresented,” Health explained. “Further, only 12% of the sample in the TCGA [The Cancer Genome Atlas] are from African Americans, thus limiting the ability to provide generalizable genomic data.”
Globally, the data are no better, she continued. “Among 72 global Phase III and III prevention, screening, and treatment trials in prostate cancer from 1987 to 2016, 96% of enrolled men were white. Further, African countries and Caribbean countries were underrepresented.”
A growing number of programs are addressing this underrepresentation. Partnering Around Cancer Clinical Trials is a multilevel, multisite intervention addressing patients and physicians.7 Genentech’s Advancing Inclusive Research Site Alliance is a partnership with several community-based research hospitals that is set up to increase representation and to test enrollment approaches.8
Advancing People of Color in Clinical Trials Now! (ACT Now!) studied a “culturally tailored website designed to influence clinical trial decision-making among people of color.” ACT Now! used a community steering committee (CSC) to apply a community-based participatory research approach. The CSC gave input through the study conception, development, implementation, and enrollment.9
The study included two randomized groups. The intervention group accessed the ACT Now! website, while the control group was exposed to a standard clinical recruitment website. Researchers measured the groups’ clinical trial literacy and willingness to enroll in a clinical trial before and after exposure to the website. Surveys were given at baseline, at one month post-intervention, and a three-month follow-up. As of December 2019, 100 participants had been enrolled.
It is too early to say if these efforts are working, Ryan says, although the topic is front and center at academic sites, including his own. “There’s a lot of research money going into looking at disparities and outcomes. It’s a topic that is top of mind for a lot of people right now.”
Overall, the conversation is not just about race, and not just about one group of people. “Disparity is not only in race, but ethnicity, geography, socioeconomic, and so on,” Heath says. “When we discuss and focus on one particular group, it may appear as if the other groups are not getting equal attention. The goal is to engage more researchers and stakeholders in the community to be involved in the conversation so that all groups can be represented.”
The discussion does not discount biological differences either, Ryan says, because they do exist in prostate cancer among people of different racial backgrounds. Researchers recently reviewed tumor genomic data and found “clinically significant alterations may occur at different frequencies across races.” Black men with metastatic prostate cancer were more likely than either white or Asian men to experience tumor mutations in AR, along with mutations in DNA-repair genes, and actionable genetic mutations.10
“Still, we cannot say that all the differences in outcomes are due to biological differences,” Ryan says. “In fact, we might be getting to the point of saying most of the differences in outcome are not related to biology but are related to access or patterns of care … and the conversation continues.”
- Schmid M, Meyer CP, Reznor G, et al. Racial differences in the surgical care of Medicare beneficiaries with localizedprostate cancer. JAMA Oncol 2016;2:85-93.
- National Cancer Institute. VA study finds no disparities in prostate cancer deaths with equal access to care. Feb. 18, 2020.
- The ASCO Post. Susan Halabi, PhD, on prostate cancer: Overall survival for Black vs white men. June 2018.
- The ASCO Post. 2018 ASCO: Black men with advanced prostate cancer treated with chemotherapy may have equal or better survival than white men. June 1, 2018.
- Wallis CJD. ASCO 2021: Differences in the pattern of and response to treatment: Not just race. UroToday. June 2021.
- Ryan C, Heath E. Differences in the pattern of and the response to treatment not just race — Elisabeth Heath. UroToday. June 27, 2021.
- Eggly S, Hamel LM, Heath E, et al. Partnering around cancer clinical trials (PACCT): Study protocol for a randomized trial of a patient and physician communication intervention to increase minority accrual to prostate cancer clinical trials. BMC Cancer 2017;17:807.
- Genentech. Advancing Inclusive Research.
- Chung A, Seizas A, Williams N, et al. Development of “Advancing People of Color in Clinical Trials Now!”: Web-based randomized controlled trial protocol. JMIR Res Protoc 2020;9:e17589.
- Mahal B, Alshalalfa M, Chowdhury-Paulino I, et al. Racial differences in genomic profiling of prostate cancer. N Engl J Med 2020;383:1083-1085.
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