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ASCO 2019 Annual Meeting

ASCO 2019: More Than Skin Deep: Investigating Disease Biology, Treatment Response, and Side Effect Differences by Race

Chicago, IL (UroToday.com) Dan George, MD, gave a presentation on the race differences in prostate cancer at ASCO 2019. There are significant health disparities among racial groups with prostate cancer, as can be seen in figure 1. The mortality rates also vary in the US, with the south-east section showing a greater rate of mortality compared to the rest of the US (Figure 2). This geographical area also has a higher rate of African-American ancestry than other areas in the US.

Figure 1-Prostate cancer health disparities among racial groups:
ASCO 2019_More Than Skin Deep_1.png


Subgroup analysis from the COU-302 trial demonstrated that black patients might respond better to abiraterone.1 In a case-controlled analysis of PSA response on abiraterone by race, it was shown that African Americans have a greater PSA response rate than White Americans (Figure 3). This led Dr. George to conduct a prospective parallel group multicenter trial of abiraterone by race (study design in figure 4). Many correlative analyses were performed including DNA isolation and characterization of single-nucleotide polymorphisms (SNP), genome-wide analysis (GWAS), lipidomics and hormonal levels, plasma samples were taken to explore additional biomarkers, and tissue was archived for measuring somatic alterations.

Figure 2 – Age standardized mortality rates for prostate cancer in 2014:
ASCO 2019_More Than Skin Deep_2.png

Figure 3 – Case controlled analysis of PSA response on Abiraterone by race:
ASCO 2019_More Than Skin Deep_3.png

Figure 4 – Abiraterone race study design:

ASCO 2019_More Than Skin Deep_4.png
The baseline characteristics of the study participants are shown in table 1, and the adverse effects caused by abiraterone in all patients are shown in table 2. Laboratory adverse events occurred in more than 20% of patients, with hyperglycemia, hypokalemia, and hypomagnesemia being more common in African American patients than in White American patients. The radiographic progression-free survival was similar for both races, as shown in Figure 5. African American men did demonstrate a longer median PSA progression-free survival than White men (16.6 months vs. 11.5 months). Similar to the retrospective studies, PSA declines after 3 months on treatment with abiraterone was better in African Americans. Lastly, overall survival was quite similar in White and Black men. An interesting finding was that the proportion of bone scan flares was higher in the African American population (22% vs. 6%).

A confirmatory study, with a similar design, is now being performed, with apalutamide and abiraterone +prednisone given to all patients (Figure 6). The reason for the differences in response rate to abiraterone in African American and White men could be explained due to the different metabolism of abiraterone. Abiraterone acetate has been shown to be converted to D4A by the enzyme 3ßHSD. D4A blocks multiple steroidogenic enzymes as well as antagonizes the androgen receptor. There is variation throughout the population in the levels of D4A2 and the levels could be significantly different in Black and White men.

Table 1- Baseline characteristics:
ASCO 2019_More Than Skin Deep_5.png
Table 2 – Adverse effects caused by abiraterone in all patients:
ASCO 2019_More Than Skin Deep_6.png

Figure 5 – Radiographic progression-free survival:
ASCO 2019_More Than Skin Deep_7.png
Figure 6 – Confirmatory study design of apalutamide and abiraterone+prednisone by race:ASCO 2019_More Than Skin Deep_8.png

When analyzing the effect that docetaxel had on African men, a recently published meta-analysis including phase three trials in men with metastatic castrate-resistant prostate cancer (mCRPC) showed that there is greater overall survival for Black vs. White men.3 Similar data have been shown in mCRPC men treated with abiraterone or enzalutamide, with Black men demonstrating better overall survival than White men.4

In conclusion, prospective race-based trials in prostate cancer suggest that response, toxicity, and survival may vary by race. Future phase three studies should mandate proportional enrollment of minority patients or post-approval race-based studies should be performed. There is a need to understand the biologic determinant of sensitivity and resistance to hormonal interventions in prostate cancer by race.

Presented by: Daniel J. George, MD, Professor of Medicine and Surgery, Divisions of Medical Oncology and Urology in the Duke University School of Medicine and leads the Duke Prostate and Urologic Cancer Center. 

Written by: Hanan Goldberg, MD, Urologic Oncology Fellow (SUO), University of Toronto, Princess Margaret Cancer Centre @GoldbergHanan at the 2019 ASCO Annual Meeting #ASCO19, May 31- June 4, 2019, Chicago, IL USA

References:
  1. Efstathiou E. et al. AACR 2014
  2. Zhenfeo L. et al. Nature 2015
  3. Halabi S et al. Overall Survival of Black and White Men With Metastatic Castration-Resistant Prostate Cancer Treated With Docetaxel. JCO 2019
  4. McNamara et al. GCS 2019