Researchers at the Karolinska Institute have identified blood-based biomarkers that may determine which patients will benefit from continued hormone therapy for advanced prostate cancer.1 The researchers envision that their discovery may eventually result in a test that contributes to more personalized treatment of the disease.
Prostate cancer is the most common male cancer in Sweden, where approximately one in four men will be diagnosed with or progress to metastatic prostate cancer. Initial systemic hormone treatment works well for most patients with metastatic prostate cancer. But over time, the tumor develops resistance, resulting in metastatic castration-resistant prostate cancer (mCRPC).
Continued hormone treatment for mCRPC with drugs such as Zytiga (abiraterone acetate) and Xtandi (enzalutamide) provides additional clinical benefit. However, not all patients respond to such treatment. Thus, in order to avoid unnecessary side-effects and pharmaceutical expenses, it is necessary to identify those men who will benefit from the medicines before treatment is started.
“Our method can identify patients who are likely to have a poor outcome to these treatments and therefore should be offered other alternatives, if available,” says lead author Bram De Laere, PhD, a postdoctoral researcher in the department of medical epidemiology and biostatistics at the Karolinska Institute.
The researchers’ methodology is based on an analysis of prognostic biomarkers with known associations to therapy resistance in the blood of patients with mCRPC. In prostate cancer, treatment resistance can be caused by changes in genes such as the androgen receptor (AR) and a gene called TP53. Such resistance markers have most often been studied on a one-by-one basis, which has led to conflicting results among independent scientific publications.
To avoid generating additional conflicting observations, the Karolinska Institute researchers developed a method for investigating all known resistance markers in AR and TP53 simultaneously. The results showed that in the subset of patients without TP53 mutations, the number of AR resistance markers can provide independent prognostic information.
“We see that the prognosis is poorest for men with three or more resistance markers in AR,” says Johan Lindberg, PhD, senior researcher in the department of medical epidemiology and biostatistics at the Karolinska Institute, and senior author of the study. “This suggests that patients with a normal TP53 gene, without or with a small number of AR resistance markers, would benefit more from continued hormone treatment with medicines such as Zytiga and Xtandi.”
The research group is consequently introducing a new concept—the AR burden—as a measure of the number of treatment-relevant changes in the AR gene. The researchers are now working on improving their method of measurement and validating it retrospectively among patients recruited for the recently initiated ProBio clinical trial.
“Our goal is to create a test that can be used routinely in clinical practice, so that patients can receive more personalized treatment,” says Lindberg.
For further information, visit the Karolinska Institute.
- De Laere B, Rajan P, Grönberg H, Dirix L, Lindberg J. Androgen receptor burden and poor response to abiraterone or enzalutamide in TP53 wild-type metastatic castration-resistant prostate cancer. JAMA Oncol. Epub ahead of print, May 2, 2019; doi: 10.1001/jamaoncol.2019.0869.
Featured image: Johan Lindberg, PhD, (left) and Bram De Laere, PhD, Karolinska Institute.