A new study led by Terry Fox-funded researchers and published in the Journal of Nuclear Medicine found that a blood-based tumour DNA test, used alongside PSMA PET scans, could help predict which patients with advanced prostate cancer are most likely to benefit from a combination of radioligand therapy and immunotherapy, while also providing an early indication of whether the treatment is working.
The findings could help doctors better personalize care and monitor treatment responses, helping more patients receive the right treatment at the right time while avoiding unnecessary side-effects from therapies unlikely to benefit them.
The research draws on a clinical trial (PRINCE), which tested lutetium-PSMA (LuPSMA) with pembrolizumab for advanced prostate cancer. LuPSMA is a radioligand therapy that delivers radiation directly to prostate cancer cells, while pembrolizumab is an immunotherapy drug.
The cross-institutional team of researchers, including first author Dr. Sophie Tolmeijer, a postdoctoral researcher in the Wyatt Lab at the University of British Columbia (UBC), investigated whether radiation damage from LuPSMA could help the immune system recognize and attack cancer cells. Although LuPSMA is now a standard treatment for metastatic prostate cancer, patient responses vary considerably.
Together with researchers in Canada and Australia, the team investigated ways to predict and track patient responses to LuPSMA.
Researchers analyzed blood samples and PET scans from 37 PRINCE trial participants. Samples were collected before treatment, 12 weeks after treatment began, and when the cancer started growing again. The team measured circulating tumour DNA (ctDNA), which is tumour DNA shed into the bloodstream, as well as individual tumour cells in the blood, and compared the results with patients’ scans.
Patients who had low levels of ctDNA and tumours that displayed high PSMA intensity on their scans before treatment experienced the best outcomes. In contrast, patients whose tumours had alterations in key tumour-suppressor genes, including TP53, RB1 or PTEN, had more aggressive disease, benefited from treatment for less time and had shorter survival.
“Radioligand therapy has changed care for men with advanced prostate cancer, but we still can’t reliably say who will benefit. This work shows that a blood test for tumour DNA and PSMA PET imaging tell us complementary things, both before treatment and within the first few months. Our hope is that combining them in future will help oncologists match each patient to the right treatment sooner, and avoid treatment that isn’t working,” explains Dr. Alexander Wyatt, associate professor at UBC co-lead of the study.
The researchers also found that the presence of ctDNA in the blood after 12 weeks was a strong indicator of the depth and duration of a patient’s response. In some cases, the blood test detected early signs of cancer progression even when scans suggested that the tumours were shrinking.
When the cancer returned, tumours often had lower levels of PSMA, the protein targeted by LuPSMA. Cancer cells with alterations in key tumour-suppressor genes had also frequently increased in number, providing insight into how resistance to the treatment combination may develop.
Together, these findings could help inform treatment decisions and support new approaches to treatment monitoring. Better biomarkers could help doctors focus this intensive treatment combination on patients who are most likely to benefit, while sparing others unnecessary side effects and costs and allowing them to move to alternative treatments sooner.
Blood-based monitoring could also help make care more accessible. Unlike PSMA PET imaging, which requires patients to visit specialized centres, blood samples can be collected locally and sent elsewhere for analysis. With further study, ctDNA testing could offer a more widely available approach to routine monitoring, particularly for patients who live far from specialized imaging facilities.
Understanding how resistance develops could also inform future clinical trials. The loss of PSMA and the growth of cancer cells with alterations in key tumour-suppressor genes point to potential resistance mechanisms that researchers may be able to target with new treatment combinations.
This research was funded by a Terry Fox New Frontiers Program Project Grant: Targeting Tumour Plasticity in Advanced Prostate Cancer.
The biomarker analysis was also supported by the Prostate Cancer Foundation.
A version of this article originally appeared on the Department of Urologic Studies at UBC site.