NEW YORK – Using baseline blood samples, a group of researchers have identified a gene expression signature that may predict which patients with metastatic castration-resistant prostate cancer (CRPC) are most likely to respond to treatment with the antiandrogen agents abiraterone (Janssen's Zytiga) plus prednisone (AAP) or enzalutamide (Pfizer/Astellas' Xtandi).
According to the findings published last week in the journal Prostate Cancer and Prostatic Diseases, the eight-gene expression signature, which includes expression of MSLN, ARG2, GFG8, KLK3, ESRP2, NPR3, CCND1, and WNT5A, was more strongly associated with overall survival following treatment with AAP or enzalutamide than were patients' circulating tumor cell (CTC) count or baseline clinical variables like Gleason score, PSA levels, testosterone, and hemoglobin. Â
To identify the signature, researchers collected baseline blood samples from 51 patients, 22 of whom went on to receive AAP and 29 of whom went on to receive enzalutamide. The patients were divided randomly into a 37-patient training cohort and a 14-patient test cohort.
The researchers used the CellSearch Circulating Tumor Cell Kit to measure CTCs in patients' blood samples. They then used quantitative PCR to analyze expression of 141 cancer-linked genes in CTC-enriched blood and homed in on eight that together were the most strongly associated with outcomes.
Among all the patients assessed, median overall survival was 41 months with enzalutamide and 43 months with AAP. Stratified according to the eight-gene expression panel, however, patients who were categorized as high-risk according to the panel experienced a median overall survival of 18 months when treated with either AAP or enzalutamide, whereas the median overall survival was not reached for patients who were categorized as low-risk.
Of the 41 patients who were evaluable for progression-free survival, the gene-expression panel also demonstrated predictive capabilities; patients who were high risk according to the signature experienced a median progression-free survival of five months, versus 20 months for those who were low risk according to the signature.
Interestingly, when the researchers combined the gene expression signature with patients' clinical variables, as well as their CTC count, all of the factors combined were no better at predicting response to the agents than the gene expression signature alone. To be sure, the authors of the Prostate Cancer and Prostatic Diseases paper, led by Naomi Haas and Michael LaRiviere of the University of Pennsylvania, wrote that CTC clearance is strongly correlated with overall survival and is more predictive of treatment response than PSA levels, but that approach requires patients to have received three months of treatment first.
The gene expression signature, on the other hand, relies on a baseline blood sample taken prior to treatment initiation. Should this test be validated in further research and in a larger group of people, it may be a more adequately timed and minimally invasive predictive tool given its reliance on blood samples as opposed to tumor biopsies.
"The risk group [that the signature] is able to assign patients [to] has important clinical implications that may bring actionable improvements in patient selection," wrote the authors. "[It] identifies patients likely to benefit from AAP or enzalutamide before treatment is started, on the basis of a single blood test … Ultimately, this work has the potential to inform clinicians as to which patients are most likely to benefit from second-generation antiandrogen therapy, and in turn, which patients might benefit from non-hormonal systemic treatment."
Identifying who will respond to these new antiandrogen drugs is a challenge, and research is already underway to explore avenues of treatment for those who fail treatment. Based on recent regulatory approvals, patients with metastatic CRPC who do not respond after treatment with abiraterone or enzalutamide — and whose tumors harbor homologous recombination repair gene mutations — may go on to benefit from treatment with the PARP inhibitor olaparib (Merck/AstraZeneca's Lynparza).