PSMA-targeted Therapies Work Best in Tumors with Mutations in DNA Repair Genes, Study Suggests

Tumors with large numbers of prostate cancer cells with mutations in DNA repair genes are easier to target using prostate-specific membrane antigen (PSMA) therapies, and patients with these tumors are more likely to respond to this potential treatment’s use, a study found.

Results from the study, “Prostate-specific Membrane Antigen Heterogeneity and DNA Repair Defects in Prostate Cancer,” were published in European Urology.

PSMA is a membrane protein often found at very high levels on the surface of prostate cancer cells, especially among those forming castration-resistant prostate cancer (CRPC) tumors, an aggressive form of the disease that no longer responds to hormone therapy.

For that reason, PSMA has become a promising target of researchers working to develop a new class of medications that combine an anti-PSMA antibody with a radioactive compound. Such medications, like LuPSMA-617, use the anti-PSMA antibody to specifically spot and deliver the radioactive compound to prostate cancer cells producing PSMA in large amounts.

But this type of targeted radiation therapy does not work for all patients, and the rates of those failing to respond have amounted to about 30% in studies.

Between 30% to 60% of patients with metastatic CRPC (mCRPC) treated with these therapies, however, have reported reductions of more than 50% in PSA levels (a biomarker of prostate cancer).

“One potential explanation for these discrepancies is heterogeneity of PSMA expression,” researchers in this study wrote. “However, the extent of, implications of, and mechanisms underlying this phenomenon remain poorly understood,” mostly because prior studies used antibodies that target the intracellular part of PSMA, which has no clinical value for estimating PSMA levels.

A team of investigators at the Institute of Cancer Research in London set out to characterize the levels of PSMA found specifically on the surface of prostate cancer cells — called membranous PSMA (mPMSA) — in a group of men with mCRPC.

Because mutations in DNA repair genes lead to a high genetic variability within a single tumor, researchers also examined if these mutations affect PSMA levels and could be used to guide PSMA-directed therapies.

The study involved two groups of patients: a test group of 60 patients who provided mCRPC tissue samples, including 38 people with matched, castration-sensitive prostate cancer (CSPC) diagnostic samples; and a confirmation group of 10 patients whose tumors contained a high number of mutations in DNA repair genes.

Despite the high degree of variability in membranous PSMA levels evident among different patients and even between samples obtained from the same patient, high levels of mPSMA at diagnosis generally associated with greater cancer aggressiveness (based on the Gleason score) and poorer patient survival.

In addition, researchers found that membranous PSMA levels tended to be higher in mCRPC samples compared to CSPC samples, or samples from patients whose tumors respond to hormone therapies.

However, almost half (42%) of the CSPC samples and approximately a third (27%) of the mCRPC samples analyzed showed no signs of mPSMA. All CSPC tissue biopsies and 84% of mCRPC tissue samples had regions in which mPSMA levels were undetectable.

Investigators also found that mPSMA levels were more than four times higher in tumors containing numerous mutations in DNA repair genes, compared to those with no mutations. These findings were confirmed in the second group of study patients.

“Our new study helps to explain why some patients respond to search-and-destroy treatments and others don’t. Understanding the biology of response to these new treatments is critical to getting them into use in the clinic as soon as possible,” Johann de Bono, regius professor of cancer research at the Institute of Cancer Research, a consultant medical oncologist at the Royal Marsden NHS Foundation Trust, and the study’s corresponding author, said in a news release.

“We found that testing for DNA repair defects was a good indication of which tumors had high levels of PSMA — and so would be expected to respond to these PSMA-targeted therapies,” de Bono added. “We will need to further assess the use of DNA tests to target these treatments effectively in routine care, but we can already start to take into account DNA repair faults in our design of clinical trials” to identify likely responders.