PSMA Radioligand Therapy Spans Metastatic Prostate Cancer as Next-Generation Theranostics Emerge

Prostate-specific membrane antigen (PSMA)–targeted radioligand therapy is now available across the spectrum of metastatic prostate cancer, with a survival benefit established in late-line disease, high patient enthusiasm, and generally good tolerability, while new schedules, clinical settings, antigen targets, and radiopharmaceutical payloads continue to emerge, according to David VanderWeele, MD, PhD.¹

“There’s a lot of enthusiasm…for this therapy, and that’s because most patients tolerate it very well,” VanderWeele said during a presentation at the 2026 LUGPA Annual Meeting.

VanderWeele, an associate professor of medicine at Northwestern University Feinberg School of Medicine in Chicago, Illinois, focused on lutetium Lu 177 vipivotide tetraxetan (Pluvicto), using the term LuPSMA for PSMA-targeting, lutetium-based radioligand therapy. He used the Prostate Cancer Working Group 4 terminology, in which androgen pathway modulation (APM)–sensitive and APM-resistant disease replace the terms castration-sensitive and castration-resistant.

A Case for Enthusiasm

VanderWeele opened with the case of a 90-year-old patient with heart failure who had lived with prostate cancer for 6 years and APM-resistant disease for 2 years, with progression on multiple lines of androgen receptor–directed therapy. Screening PSMA PET showed highly avid disease, with a maximum standardized uptake value (SUVmax) of 101 in nodal disease and 61.6 in bone. After 4 cycles of LuPSMA, his prostate-specific antigen (PSA) level fell from 107 ng/mL to undetectable levels, and repeat PET imaging showed a complete response; the PSA remained below 0.01 ng/mL at month 15 on surveillance. “This is really why there is so much enthusiasm,” he said.

Nuts and Bolts of Administration

LuPSMA is a beta-emitting therapy that requires radiation precautions and is generally given at 200 mCi (7.4 GBq) every 6 weeks by nuclear medicine or radiation oncology teams. VanderWeele repeats PET imaging if the PSA is not decreasing after 2 cycles or is approaching zero, before deciding whether to continue. “In general, PSA is a pretty good biomarker of how well cancers respond to treatment,” he said.

Candidates need adequate bone marrow reserve and kidney function, and patients should hydrate well and void often. He recommends that patients sleep away from others and use a private bathroom for 3 days after treatment, or 7 days if they are around children or pregnant women. The need for a Foley catheter complicates radiation safety, urinary obstruction or hydronephrosis are contraindications, and toxicities can be managed with delays or a 20% dose reduction.²

Evidence Across the Metastatic Spectrum

In the phase 3 VISION trial (NCT03511664), which compared LuPSMA plus standard care with standard care alone in late-line APM-resistant disease, LuPSMA improved radiographic progression-free survival (rPFS; HR, 0.40; 95% CI, 0.29-0.57) and overall survival (OS; HR, 0.62; 95% CI, 0.52-0.74).³ “You see very good separation of the curves when you are comparing this to a control of best supportive care,” VanderWeele said.

In the phase 3 PSMAfore trial (NCT04689828), LuPSMA improved rPFS vs a change in androgen receptor pathway inhibitor (ARPI) in earlier APM-resistant disease (HR, 0.49; 95% CI, 0.39-0.61), but OS did not differ (HR, 0.98; 95% CI, 0.75-1.28), a result he noted was confounded by crossover.⁴ In the phase 3 PSMAddition trial (NCT04720157), adding LuPSMA to androgen deprivation therapy (ADT) plus an ARPI in APM-sensitive disease improved rPFS (HR, 0.72; 95% CI, 0.58-0.90), with immature OS data (HR, 0.84; 95% CI, 0.63-1.13).⁵ “You do see that separation of those curves, although it’s not nearly as dramatic when you’re adding it on top of the very effective therapies,” he said.

Based on PSMAddition, the FDA approved LuPSMA plus an ARPI in July 2026 for adults with PSMA-positive metastatic APM-naive or APM-sensitive prostate cancer.^6,7 However, VanderWeele noted that the trial did not use docetaxel-based triplet therapy as a comparator. In PEACE-1 and ARASENS, intensification beyond ADT plus docetaxel improved OS (HR, 0.75 and 0.68, respectively).

Tolerability and Patient Selection

“In general, [radioligand therapy] is tolerated quite well,” VanderWeele said, adding that dry mouth is by far the most common symptomatic toxicity, followed by nausea and other gastrointestinal effects. He suspects these effects may be more frequent in patients with lower-volume disease, in whom less tumor is available to absorb the therapy. In PSMAddition, grade 3 or higher adverse effects occurred in 51% of patients in the LuPSMA arm (n = 564) vs 43% in the control arm (n = 565), and dry mouth occurred in 46% vs 4%, respectively; dose reductions, delays, and discontinuations were driven mainly by changes in blood counts, liver function tests, and amylase/lipase levels.⁵ “Not a lot of patients are stopping because of dry mouth,” he noted.

VanderWeele considers LuPSMA a good option for patients who have already received, do not want, or are not fit for chemotherapy, and a great option when screening PET shows high uptake (SUVmax >20; SUVmean >10). “All these patients should get a [PSMA PET] scan beforehand,” he said. It is a less suitable option for patients with renal dysfunction, cytopenias, or urinary obstruction. Because PSMAddition has not shown an OS benefit and used doublet therapy as its control, he prefers chemotherapy for patients with aggressive disease, such as high-volume APM-sensitive disease or multiple tumor suppressor gene alterations. “I still think there’s a real role for chemotherapy for those with aggressive disease,” he said.

What Comes Next for Theranostics

Beyond current approvals, VanderWeele described how each component of a theranostic agent is being reengineered. Alpha emitters such as actinium-225 and lead-212 deliver much larger particles than beta emitters, although he cautioned that dry mouth is a major concern with actinium-based agents. Alternative PSMA-targeting molecules include PSMA-I&T, PNT2002, and the antibody J591; he explained that antibodies circulate longer and reach the salivary glands less readily, potentially reducing dry mouth but raising concern for myelosuppression.

New antigens under investigation for adenocarcinoma include KLK2, STEAP1/2, ACP3, B7-H3, and GRPR, and DLL3 is being explored for small cell prostate cancer. Randomized trials are testing radioligand therapy earlier, including in high-risk localized disease and oligometastatic APM-sensitive disease, in which the BULLSEYE and LUNAR studies have reported progression-free survival improvements (HR, 0.07 and 0.37, respectively).¹ In earlier APM-resistant disease, the phase 3 SPLASH trial of PNT2002 improved rPFS vs an ARPI switch (HR, 0.71; 95% CI, 0.55-0.92).

VanderWeele described a rapidly growing field, with work under way “both with the agents at hand, looking at new settings, and lots and lots of new agents coming.”

References

1. VanderWeele D. Seeing and treating: the PSMA theranostic revolution. Presented at: 2026 LUGPA Annual Meeting; November 5-7, 2026; Chicago, IL.
2. Calais J, et al. J Nucl Med. 2024.
3. Sartor O, de Bono J, Chi KN, et al. Lutetium-177–PSMA-617 for metastatic castration-resistant prostate cancer. N Engl J Med. 2021;385(12):1091-1103.
4. Morris MJ, Castellano D, Herrmann K, et al. 177Lu-PSMA-617 versus a change of androgen receptor pathway inhibitor therapy for taxane-naive patients with progressive metastatic castration-resistant prostate cancer (PSMAfore): a phase 3, randomised, controlled trial. Lancet. 2024;404(10459):1227-1239.
5. Tagawa ST, et al. Lancet. 2026.
6. FDA approves lutetium Lu 177 vipivotide tetraxetan with androgen receptor pathway inhibitor therapy for metastatic androgen pathway modulation-naïve or -sensitive prostate cancer. FDA. July 31, 2026. Accessed November 6, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-lutetium-lu-177-vipivotide-tetraxetan-androgen-receptor-pathway-inhibitor-therapy
7. FDA approves lutetium Lu 177 vipivotide tetraxetan for PSMA+ mHSPC. OncLive. July 31, 2026. Accessed November 6, 2026. https://www.onclive.com/view/fda-approves-lutetium-lu-177-vipivotide-tetraxetan-for-psma-mhspc