Dr Calais on Individualizing PSMA-Targeted Therapy Sequencing in Prostate Cancer

“I think going upfront with six cycles continuously may be too much in some patients that respond very well.”

Jeremie Calais, MD, PhD, a professor of nuclear medicine and theranostics at Gustave Roussy and Université Paris-Saclay and an adjunct professor at UCLA Health, discussed individualizing the timing and delivery of prostate-specific membrane antigen (PSMA)–targeted radioligand therapy as its use expanded across prostate cancer disease settings.

Since the initial FDA approval of lutetium Lu 177 vipivotide tetraxetan (Pluvicto), subsequent label expansions have allowed additional patient populations to receive the radioligand therapy. The FDA’s original approval in March 2022 indicated lutetium Lu 177 vipivotide tetraxetan for the treatment of adult patients with PSMA-positive metastatic castration-resistant prostate cancer (mCRPC) who have previously received other anticancer therapies, such as androgen receptor (AR) pathway inhibition and taxane-based chemotherapy. The first label expansion in March 2025 allowed for the agent to be given to patients with mCRPC who received prior AR inhibition and are considered appropriate to delay taxane chemotherapy.

Then in July 2026, the FDA approved lutetium Lu 177 vipivotide tetraxetan plus an AR pathway inhibitor for the treatment of adult patients with PSMA-positive metastatic androgen pathway modulation–naive/sensitive prostate cancer, commonly known as metastatic hormone-sensitive prostate cancer.

Data from the phase 3 VISION (NCT03511664), PSMAfore (NCT04689828), and PSMAddition (NCT04720157) supported the original approval, first label expansion, and second label expansion, respectively. Calais emphasized that these studies involved different patient populations and argued that treatment approaches should reflect those differences.

In earlier disease, Calais questioned whether every patient required six consecutive treatment cycles with lutetium Lu 177 vipivotide tetraxetan. He suggested that patients with favorable responses might benefit from a pause after 2, 3, or 4 cycles, followed by an adjustment in treatment delivery. He presented this as a potential individualized approach rather than a uniform strategy for all patients.

Calais also cautioned against assuming that earlier availability made PSMA-targeted therapy appropriate for every patient in that setting. He identified disease volume and the level of PSMA expression on PET imaging as important considerations when deciding where radioligand treatment belonged within the overall sequence.

He described a broader assessment that incorporated molecular findings, circulating tumor DNA levels, fluorodeoxyglucose PET findings, and differences between high-volume and low-volume disease. Calais emphasized that these features could distinguish patients whose treatment needs differed despite sharing a prostate cancer diagnosis or eligibility for a PSMA-targeted approach.

Accordingly, Calais rejected the concept of one optimal sequence for every patient. He acknowledged that clinicians still needed to determine which sequence best suited each patient, disease type, and phenotype identified through available testing. He also highlighted uncertainty about how dosing should be modified across these different clinical circumstances.

For patients with very aggressive disease, Calais favored chemotherapy before PSMA-targeted treatment. Similarly, when testing identified an actionable mutation with an associated treatment, he favored using the corresponding targeted option first.

Calais framed these preferences within an evolving understanding of treatment selection. He emphasized matching sequencing and treatment delivery to the individual patient, while acknowledging that the best approach across distinct disease presentations and testing profiles remained an area of ongoing learning.