The use of biomarkers in genitourinary cancers offers exciting potential in understanding which patients may do better with androgen-targeting therapies.
William Oh, MD
The use of biomarkers in genitourinary cancers offers exciting potential in understanding which patients may do better with androgen-targeting therapies. Progress in developing biomarker tests is frustratingly slow, according to William K. Oh, MD.
For example, the presence or absence of the androgen-receptor splice variant 7 messenger RNA (AR-V7) is predictive of success in treatment with enzalutamide (Xtandi) and abiraterone (Zytiga) in cases of castration-resistant prostate cancer (CRPC). This was demonstrated by study results published in the New England Journal of Medicine (NEJM) in 2014, said Oh, chief of the division of hematology and medical oncology and professor of medicine and urology at the Mount Sinai School of Medicine in New York.
“What this showed was that if you had AR-V7 in your circulating tumor cells, you were very unlikely to respond to enzalutamide or abiraterone,” Oh said in an interview with OncologyLive® during the 1st Annual International Congress on Oncology Pathology™: Towards Harmonization of Pathology and Oncology Standards, which Physicians’ Education Resource® (PER®) hosted in New York City in June. Oh discussed predictive markers in advanced prostate cancer during the conference.
“That was exciting because, if we could [identify] patients who wouldn’t respond to these drugs, we could minimize exposure of a very expensive, toxic treatment for patients who would not otherwise respond. Three years later, we still don’t have this test in widespread clinical use. This is partly because it has been hard to replicate and hard to commercialize,” he said.
The NEJM study investigated AR-V7 and its relationship to enzalutamide and abiraterone resistance in CRPC. It demonstrated that patients who had AR—V7 in their circulating tumor cells did not respond to either drug. However, when patients did not have the AR-V7 biomarker, they had a high chance of responding to treatment.
When investigators looked at prostate-specific antigen (PSA) response rates among patients who were AR-V7—negative, they noted that 68% of patients had a reduction in PSA (95% CI, 52%-81%); among patients who were AR-V7–positive, none had a PSA response (95% CI, 0%-19%). Seventeen percent of patients who started the study as AR-V7– negative but became AR-V7–positive by the end of the study had a PSA response (95% CI, 4%-58%).
What also has been an important finding in recent years is that even after patients progress to CRPC, androgen receptor signaling remains a critical driver of the disease. The NEJM study hypothesized that because AR-V7 does not have the ligand binding domain for either enzalutamide or testosterone molecules, it remains capable of promoting tumor cell growth. This would explain why abiraterone and enzalutamide are unsuccessful treatments for patients who are AR-V7-positive.
Despite the evidence in favor of screening for the AR-V7 biomarker, it has been difficult to replicate an AR-V7 test and distribute it widely to clinical practice. Oh noted that commercial tests for biomarkers, in general, must be easily accessible and relatively inexpensive, and the average doctor needs to be able to obtain them. This is not currently the case for an AR-V7 test.
“If AR-V7 testing became more widely available, which it may later this year, then maybe patients who have high levels of AR-V7 would be better candidates for chemotherapy instead of an androgen receptor-targeted treatment,” Oh said.
Antonarakis ES, Lu C, Wang H, et al. AR-V7 and resistance to enzalutamide and abiraterone in prostate cancer. N Engl J Med. 2014;371(11):1028-1038. doi:10.1056/NEJMoa1315815.