High PSMA Predicts Targeted Therapy Response in Prostate Cancer

BARCELONA—High prostate-specific membrane antigen (PSMA) on whole-body positron emission tomography (PET) scans predicts a higher likelihood of favorable response to lutetium-177 (177Lu)–PSMA-617 than to cabazitaxel in patients with metastatic castration-resistant prostate cancer that has progressed after docetaxel.

The researchers also assessed a prognostic biomarker, fluorodeoxyglucose (FDG) PET. A high volume of disease on FDG-PET (metabolic tumor volume [MTV] > 200 mL) was associated with a worse prognosis regardless of randomly assigned treatment, reported the lead researcher, James Buteau, MD, a nuclear medicine physician from the Peter MacCallum Cancer Centre, Melbourne, Australia.

These are the latest results of the TheraP trial presented at European Association of Nuclear Medicine (EANM) 2022. The findings have implications for clinical practice. “In this study, we show that PSMA-PET — a full body scan — done prior to treatment with 177Lu-PSMA-617, predicts how the treatment will go,” remarked Buteau, who presented the findings.

“It’s a window into the future, so we can peek through and see how treatment will go for different patients, because the scans can help us decide who should definitely get treatment with 177Lu-PSMA-617, and who might benefit more from other treatments,” he added. “With FDG-PET, we also identify which patients will do worse and may benefit more from other strategies, like therapy combinations.”

The findings may help clinicians decide which treatment to give first. “If you have a choice between cabazitaxel or 177Lu-PSMA-617, then these biomarkers show which patients should definitely go on to get the 177Lu-PSMA-617,” said Buteau, whose abstract was awarded one of the top three scientific presentations at this year’s meeting.

Therapy with 177Lu-PSMA-617 should be prioritized for patients showing high PSMA concentrations, he summarized, while high FDG volume warrants more research for treatment intensification.

Which Patients Will Most Benefit From 177 Lu-PSMA-617?

The TheraP study was the first randomized controlled trial to compare 177Lu-PSMA-617 with cabazitaxel in men with metastatic castration-resistant prostate cancer. A total of 200 patients were randomly assigned 1:1 to 177Lu-PSMA-617 (8.5 GBq intravenously every 6 weeks, decreasing by 0.5 GBq each cycle for up to 6 cycles) or to cabazitaxel (active chemotherapy at 20 mg/m3 intravenously every 3 weeks, up to 10 cycles).

Previously published findings show that 177Lu-PSMA-617 improved the prostate-specific antigen (PSA) ≥50% response rate (PSA50-RR), along with improved PSA progression-free survival (PFS), and radiographic PFS compared with cabazitaxel in this patient group. It showed that 66% vs 37% of patients met PSA50-RR.

In the study presented here today, Buteau analyzed the PSMA and FDG-PET scans obtained before administration of treatments to the 200 randomly assigned patients. “The study effectively aimed to validate prior biomarker work, targeting the top one third of patients with these imaging parameters,” said Buteau.

For the PSMA predictive biomarker, the PSA50-RR in patients with a mean standardized uptake value of 10 or greater was 91% with 177Lu-PSMA-617 vs 47% with cabazitaxel.

“What’s remarkable is these are deep PSA drops. Over 60% of them had an over 90% drop in PSA value. In comparison to people who had a mean SUV less than 10, for which 52% responded [with PSA 50] on 177Lu-PSMA-617 in vs 32% on cabazitaxel,” he reported.

These results translate to an odds ratio (OR) of 2.2 in patients with a mean SUV of less than 10 or less but an OR of 12.2 in those with mean SUV of 10 or greater.

“So the higher PSMA intensity, then the better the response,” said Buteau.

When the FDG volume was greater, the patients did worse: The PSA50-RR (all patients combined) was 38% when MTV was 200 mL or less vs 56% when MTV was less than 200 mL.

“So all in all, FDG-PET helps to identify men who might do better from combinations or more intensive treatments, and might be seen as a stepping stone in guiding future trials rather than changing management,” concluded Buteau.

Radiographic PFS shows that patients with lower volume do a lot better than those with higher volume of FDG-avid disease, he added.

Earlier this year, the U.S. Food and Drug Administration approved 177Lu-PSMA-617 for clinical use in men with metastatic castration-resistant prostate cancer. “Now, for the many nuclear medicine centers that may want to provide this treatment, this study helps with selection of patients who are most likely to respond,” explained Buteau. “It’s about resource allocation as well.”

Irene Burger, MD, nuclear medicine physician form Kantonsspital Baden, Switzerland, commented on the work for Medscape Medical News. “I think this is important work because it guides us in optimizing patient selection for treatment. PSMA PET is good to define those with high expression so we can get enough radiation doses to the tumor, but we should also consider metabolic activity.” She added, “With improved patient selection, I’m convinced that we can improve the efficacy of our novel drugs.”

“These show that with reasonably high PSMA expression with low FDG uptake, you can preselect patients that will a greater than 95% chance of good response. To know this before you start treatment is tremendously helpful to give the appropriate therapy for a patient.”

Drs Buteau and Burger have no relevant disclosures.

European Association of Nuclear Medicine (EANM) 2022. Presented October 16, 2022.

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