The presence and amount of full-length androgen receptor biomarker detected in the circulating tumor cells of people with metastatic castration-resistant prostate cancer can inform prognosis, a prospective study reveals.
Investigators report significant differences in prostate-specific antigen 50 (PSA50) values, PSA progression-free survival, clinical and/or radiologic progression-free survival, as well as overall survival, based on baseline levels of the amplified androgen receptor full-length (AR-FL) marker. The findings suggest quantification of AR-FL could serve as a clinically useful molecular biomarker in addition to AR-V7 status.
Prognosis differed among the 48% of patients with no detectable AR-FL marker, the 26% with amplification values below a median, and the remaining 26% with values above the median. The study included 202 men tested before starting hormonal treatment with either abiraterone or enzalutamide.
“Despite androgen deprivation, the androgen receptor continues to play a crucial role in prostate cancer,” Emmanuel S. Antonarakis, MBBCh, of Johns Hopkins University in Baltimore, said at in a press briefing held at the 2017 genitourinary cancers symposium sponsored by the American Society of Clinical Oncology, ASTRO, and the Society of Urologic Oncology. Dr. Antonarakis presented the findings on behalf of lead author John Silberstein, MD, and their coinvestigators.
Researchers found an inverse association with higher level of AR-FL and PSA50 responses. Also, men who did not achieve a PSA50 response had a mean of 55.4 transcripts, compared with 6.7 transcripts for those who did. Analyzed another way, the AR-FL–negative patients had a 62% PSA response rate, compared with 54% among the AR-FL–positive patients with amplification below the median and 28% for AR-FL–positive patients with values above the median.
In a multivariate analysis, controlling for AR-V7 and clinical variables, AR-FL remained prognostic for inferior PSA progression-free survival (hazard ratio, 1.06, P = .04). “A similar picture was seen with radiographic progression-free survival,” Dr. Antonarakis said. The best prognosis was for patients with undetectable AR-FL and the worst was for patients with detectable values above the median (HR, 1.04). However, AR-FL only trended toward significance (P = .13).
Similarly, for overall survival, AR-FL–negative patients had the best prognosis and patients with AR-FL above median had the worst in the multivariate analysis (HR, 1.07). “AR-FL reached borderline clinical significance,” he said (P = .06).
The presence of AR-V7 was independently prognostic in the multivariate analysis as well. “In conjunction with AR-V7, AR-FL quantification could serve as an additional biomarker to detect abiraterone or enzalutamide sensitivity or resistance,” Dr. Antonarakis said.
The current research builds on previous findings in this patient population. For example, genetic aberrations in circulating tumor DNA were associated with treatment resistance and inferior outcomes, including a worse progression-free survival, Dr. Antonarakis said (Clin. Cancer Res. 2015;21:2315-24). Other researchers demonstrated similar outcomes, both worse progression-free survival and overall survival among patients who had amplification or mutation of AR, compared with wild type, Dr. Antonarakis said.
These investigators used cell-free DNA to quantify AR, and the current study assessed circulating tumor cell–derived AR.
“Our vision is, very shortly in the future, we will have a liquid biopsy in patients to fully characterize their full complement of AR – patients with copy number gains, mutations in their genes, and splicing variance in the clinic,” Dr. Antonarakis said. It’s important to consider all three factors, he added.
Did you see any patients who were AR-V7 positive but AR-FL negative? study discussant Angelo Demarzo, MD, PhD, of Johns Hopkins University in Baltimore asked. “We have yet to find a patient like this. AR full length so far is always present when AR-V7 is positive,” Dr. Antonarakis replied. He added, however, “There is a subset of patients who are AR-V7 negative who have a high burden of AR full length, and they will still have a high risk.”