Study Sheds Light on Genetic Variations in Advanced Prostate Cancer

Clara Hwang, MD

Black men with metastatic castration-resistant prostate cancer (mCRPC) had a higher frequency of mismatch repair deficiency (MMRD) or high microsatellite instability (MSI-H) and lower frequency of PTEN and TMPRSS alterations compared with White men, according to a retrospective cohort study. However, no differences were seen in regard to clinical outcomes, even with Black men receiving targeted therapy less frequently than White men.

The study included 962 eligible patients with mCRPC, comprising 204 Black patients and 758 White patients. Data collected by the Prostate Cancer Precision Medicine Multi-Institutional Collaborative Effort (PROMISE) consortium from April 2020 to December 2021 was utilized. Investigators assessed the primary end point of frequency of actionable molecular data and secondary end points of frequency of other alterations, the type and timing of genomic testing performed, and use of targeted therapy.

At a median follow-up from mCRPC of 26.6 (14.2-44.7) months, the prevalence of actionable alterations was comparable across groups, seen in 65 Black men (32.8%) and 215 White men (29.1%; P =.35). However, MMRD or MSI-H was more prevalent among Black men (9.1%) vs White men (4.9%; P =.04).

Actionable alterations were seen in 65 Black patients (32.8%) and 215 White patients (29.1%); P =.35), which was comparable. On the other hand, MMRD or MSI-H was found to be more common in Black men (n = 18; 9.1%) than White men (n = 36; 4.9%; P =.04). PTEN alterations occurred less frequently in Black men (15.7%) vs White men (26.3%; P =.003), as did TMPRSS alterations (7.1% vs 21.0%; P <.001). No other disparities were observed in the 15 most frequently altered genes, including TP53, AR, CDK12, RB1, and PIK3CA.

Findings also showed that blood-based molecular testing was seen more frequently among Black men (48.7%) vs White men (36.4%; P <.001). Additionally, matched targeted therapy was less frequently administered to Black men compared with White men (33.5% vs 53.5%; P =.008). However, no differences were noted in response to targeted therapy or survival between the 2 cohorts.

In an interview with Targeted Oncology^TM, Clara Hwang, MD, medical oncologist, senior staff physician at Henry Ford Health, discussed the notable differences in molecular alterations observed in the retrospective cohort study among Black men with mCRPC compared with White men.

Prostate cancer, bladder cancer, men's health care: © Tom - stock.adobe.com

Targeted Oncology: Can you explain the background of this research? How did you come up with the main question asked in the study?

Hwang: The motivation was the known disparities between Black and White men with prostate cancer. We know that Black men are more likely to get prostate cancer and also more than twice as likely to die from prostate cancer. There are multiple reasons for this. What we were looking for in this study was to see if these disparities persisted in the application of precision medicine to prostate cancer.

In terms of why we would want to apply precision medicine for prostate cancer, now, the many guidelines recommend genetic testing for patients with advanced prostate cancer. That is because we have targeted therapies that we can offer to men with prostate cancer that are beyond the standard-of-care. For example, we can give pembrolizumab [Keytruda] to patients who have mismatch repair deficiency, we can give [poly-ADP ribose polymerase (PARP)] inhibitors to patients who have BRCA or other [homologous recombination repair (HRR)] defects, and this is beyond your standard-of-care.

The group that I am working with is called the PROMISE consortium, and it is a clinical genomic database. We capture both clinical and genomic information from these patients. We compared the data that we had for the Black vs the non-Hispanic White population.We looked specifically at patients who have metastatic castration-resistant prostate cancer. Then, we specifically compared Black vs White patients in this patient population.

What were the methods and designs used?

It was a retrospective chart review. Essentially, it has more than 1500 patients, so it is a large, consortium-driven database. We compared the populations based on race, and we looked at number 1, whether patients had what we call actionable mutations. We basically looked at 3 categories of action of a mutation. As I mentioned, both MSI-H/mismatch repair deficiency would qualify for patients for pembrolizumab, so that was 1. We looked at HRR deficiency, because that would qualify patients for PARP inhibitors or platinum therapy. Then, we also looked at TMB status, a high tumor mutational burden, which would qualify patients for pembrolizumab. We looked at those 3 categories of action of mutations. Then, we compared rates in the Black vs White population. We also looked to see whether patients received targeted therapy. We compared other things as well, but those were the 2 main things.

Can you elaborate on the findings that were discovered?

Overall, we did not find differences in the rates of actionable mutations between Black and White men with metastatic prostate cancer. However, what we did find was that the rates of MSI-H/mismatch repair deficiency were higher in Black patients. They were about 5% vs 10%, as I recall. Other than that, we did not really see any significant differences in terms of the molecular findings.

The other major finding that I would say that we reported on was the fact that despite Black men having higher rates of mismatch repair deficiency, overall, if we looked at patients who had actionable mutations, Black men were less likely to get targeted therapy.

What is the importance of this research and what are the next steps?

First, even though we saw that there were differences in delivery of precision medicine to Black patients, we did not see differences in survival. We did not see any differences with respect to cancer outcomes, which I think is very reassuring. However, I think it does speak to the fact that there is still room to make progress in terms of making sure we have equal or equitable access to care because I do think that access to precision medicine is important for all patients with advanced prostate cancer.

What are some ways we could improve patients' access to precision medicine?

When we were looking at the data, we did know that some patients did, for example, get targeted therapies on clinical trials. I think that is 1 thing, [we must] make sure we have access to clinical trials widely available. I think that will help a lot. Other than that, [we must] make sure that oncologists everywhere are kept up to date in terms of thinking about targeted therapy for their patients.

For community oncologists, what are the main takeaways from this research?

Number 1, we should definitely be looking for these types of molecular alterations and knowing, for example, that Black men are more likely to have a molecular alteration that would make them eligible for pembrolizumab. I think that is important to remember. Then, looking for these mutations early enough in the disease course where we can still offer patients these targeted therapies.

REFERENCE:
Hwang C, Henderson NC, Chu SC, et al. Biomarker-directed therapy in black and white men with metastatic castration-resistant prostate cancer. JAMA Netw Open. 2023;6(9):e2334208. Published 2023 Sep 5. doi:10.1001/jamanetworkopen.2023.34208