Researchers have developed a blood test that can identify mutations in the androgen receptor (AR) gene that drive resistance to abiraterone acetate, an androgen synthesis inhibitor. If validated, the test could identify prostate cancer patients who will not respond to the treatment.
Anti-androgen therapy with enzalutamide or abiraterone is now a mainstay for the treatment of metastatic castration-resistant prostate cancer (CRPC), yet 30% to 60% of patients do not respond and resistance to therapy within 12 months of starting treatment is common.
“This new study finds that by analyzing tumor DNA present in the bloodstream, we should be able to personalize treatment with abiraterone, so that only those who will benefit from the drug will receive it,” said Paul Workman, FMedSci, chief executive of the Institute of Cancer Research, London, in a press release.
The results of the study were published in Science Translational Medicine.
Alessandro Romanel, PhD, of the Centre for Integrative Biology at the University of Trento, Italy, and colleagues used next-generation sequencing to analyze tumor DNA in the blood samples of 97 patients with CRPC who were treated with abiraterone (274 total samples). Enough tumor DNA was detected in 80 patients to identify AR gene aberrations (217 samples).
The 45% of patients with a detectable increase in AR copy number or presence of AR (T878A or L702H) point mutations prior to abiraterone treatment were 4.9 less likely to have a greater than 50% decline in prostate-specific antigen (PSA) and 7.8 times less likely to have a greater than 90% decline in PSA.
Patients with these AR gene aberrations also had significantly worse progression-free (hazard ratio [HR], 3.73; P = 5.6 × 10−7) and overall survival (HR, 7.33; P = 1.3 × 10−9) compared with patients with normal AR gene variants in their tumor DNA.
In an accompanying editorial, Michael T. Schweizer, MD, medical oncologist at the Fred Hutchinson Cancer Center in Seattle, and Emmanuel S. Antonarakis, MD, assistant professor of oncology at Johns Hopkins University, noted that “determining which biomarkers are the most powerful predictors of response or resistance to the next-generation AR-directed drugs will require additional prospective studies with clearly defined hypotheses and statistical plans.”