New liquid biopsy assay predicts treatment outcomes in mCRPC

Arun Azad, MBBS, PhD

A group of researchers in Australia showed that a multianalyte liquid biopsy assay could predict which patients with metastatic castration-resistant prostate cancer (mCRPC) would likely respond to standard treatments, according to a study published in European Urology.^1,2

Using a cell-free DNA (cfDNA) and cell-free RNA (cfRNA) next-generation sequencing liquid biopsy assay, investigators demonstrated that, “Abnormalities in the androgen receptor (AR) gene detected in the blood of men with advanced prostate cancer were associated with poor responses to available drug treatments and reduced survival. This information could be used to better guide treatment of advanced prostate cancer," senior author Arun Azad, MBBS, PhD, a medical oncologist at Peter MacCallum Cancer Centre (Peter Mac) in Melbourne, Australia, stated in a press release.

The study prospectively enrolled 67 patients with mCRPC. All patients were starting treatment with either androgen receptor pathway inhibitors (ARPIs; eg, abiraterone acetate [Zytiga] or enzalutamide [Xtandi]; n = 41), or taxane-based chemotherapy (n = 26). Using the liquid biopsy assay, which is manufactured by Predicine, researchers at Peter Mac and the Monash University School of Clinical Science, in collaboration with the Chris O'Brien Lifehouse cancer treatment center, conducted integrated cfDNA and cfRNA profiling from a single 10-ml blood tube. The investigators next examined potential links between AR aberrations and clinical outcomes using Cox regression analyses and Kaplan-Meier survival estimates.

The AR aberrations assessed included somatic mutations, copy number variation, and splice variants (AR-V7 and AR-V9). The investigators were able to successfully sequence cfRNA in 59 (88%) patients and cfDNA in all 67 patients. Overall, 36 (54%) patients had one or more AR aberrations.

AR gain was independently associated with clinical/radiographic progression-free survival (PFS; HR, 3.2, P = .01) and overall survival (OS; HR, 2.8; P = .04). Cumulative number of AR aberrations was also independently associated with PFS (HR, 3.0 for 0 vs ≥2; P = .04) and OS (HR, 2.9 for 0 vs ≥2, P = .03). The investigators also reported an association between concurrent AR gain and AR splice variant expression (AR gain/AR-V+) with shorter prostate-specific antigen PFS, regardless of whether patients received chemotherapy (HR, 3.9; p = 0.04) or ARPIs (HR, 6.7; P = .009).

The researchers validated their most significant results in an independent cohort of 40 patients with mCRPC. This included shorter OS in patients with AR gain/AR-V+ disease histology (HR, 3.3; P = .02).

“We demonstrate[d] the utility of a novel, multianalyte liquid biopsy assay capable of simultaneously detecting AR alterations in cfDNA and cfRNA. Concurrent profiling of cfDNA and cfRNA may provide vital insights into disease biology and resistance mechanisms in mCRPC,” the authors wrote in their conclusion.

Limitations of the study were noted as follow-up period and sample size.

"While advances in therapeutic strategies have significantly improved quantity and quality of life for men with mCRPC, there remains a pressing need to find predictive and prognostic biomarkers," Azad stated in the press release.

"Liquid biopsies have emerged as a minimally-invasive alternative to conventional biopsy for interrogating the prostate tumor genome. Liquid biopsies have demonstrated strong congruence with tumor biopsies, whilst simultaneously encapsulating the genomic complexity often seen in mCRPC," added Azad.

References

1. Blood test can guide treatment for most aggressive prostate cancer. Published July 7, 2020. https://bit.ly/3ecnwUs. Accessed July 8, 2020.

2. Fettkea H, Kwana EM, Docantoa MM, et al. Combined cell-free DNA and RNA profiling of the androgen receptor: clinical utility of a novel multianalyte liquid biopsy assay for metastatic prostate cancer [published online May 30, 2020]. Eur Urol. 10.1016/j.eururo.2020.03.044