Radioligand therapy
Radioligand therapy attaches a radioactive particle to a molecule that homes in on a tumour, so the radiation is delivered from the inside of the cancer rather than from an external beam.
Overview
Radioligand therapy (RLT) with beta-emitters is the most clinically mature branch of theranostics. Lutetium-177 vipivotide tetraxetan (Pluvicto, 177Lu-PSMA-617) is approved by the FDA and EMA for PSMA-positive metastatic castration-resistant prostate cancer, on the strength of the VISION trial (median overall survival 15.3 vs 11.3 months, HR 0.62; radiographic progression-free survival 8.7 vs 3.4 months, HR 0.40; Sartor et al., NEJM 2021) and the earlier-line PSMAfore trial (rPFS 9.3 vs 5.6 months, HR 0.41), which supported the FDA's March 2025 label expansion into taxane-naive mCRPC. Lutetium-177 dotatate (Lutathera) is approved for gastroenteropancreatic neuroendocrine tumours on the basis of NETTER-1 (Strosberg et al., NEJM 2017) and has since been extended to a first-line setting by NETTER-2 (Lancet 2024).
A competitive multi-agent PSMA-RLT field is emerging behind Pluvicto: 177Lu-PSMA-I&T (PNT2002, Lantheus/POINT Biopharma) reported the SPLASH trial, and Telix's antibody-based rosopatamab tetraxetan (TLX591-Tx) is in the ProstACT Global phase 3 programme. On the neuroendocrine side, 177Lu-edotreotide (ITM-11) and FAP-targeted 177Lu-FAP-2286 are in later-phase development.
What remains unsolved: a 2026 GRADE-assessed meta-analysis of six randomised trials (Mubarika et al., Int Urol Nephrol 2026) found the primary intention-to-treat overall-survival benefit of 177Lu-PSMA over standard of care was not statistically significant (HR 0.81, 95% CI 0.62-1.06), with a benefit only apparent after adjusting for control-arm crossover (HR 0.76, 95% CI 0.59-0.96) — a reminder that trial-design choices, not just the isotope, drive the reported benefit. Optimal sequencing against androgen-receptor pathway inhibitors, taxanes and alpha emitters is still being worked out in trials such as PSMAddition and ENZA-p, and lutetium-177's roughly 0.5-2 mm beta path length is thought to undertreat isolated tumour cells and micrometastases, motivating the move to alpha emitters.
Notes
top- A 2026 GRADE meta-analysis found the ITT overall-survival benefit of 177Lu-PSMA vs standard of care was not significant (HR 0.81, 95% CI 0.62-1.06) until adjusted for crossover (HR 0.76, 95% CI 0.59-0.96); trial design materially changes the reported effect size.
- Optimal sequencing of RLT against ARPIs, taxanes and alpha emitters is unresolved; PSMAddition and ENZA-p are testing earlier and combined use.
- 177Lu's beta path length (roughly 0.5-2 mm) is thought to leave isolated tumour cells and micrometastases undertreated, which is the main argument for moving to alpha emitters.
Patients newly diagnosed with an advanced grade 2 or 3 neuroendocrine tumour of the gut or pancreas that shows somatostatin receptors on imaging can now receive lutetium dotatate as their first treatment, gaining more than a year of additional disease control and a much higher chance of tumour shrinkage. It does not settle whether radioligand therapy is better than other first-line options such as capecitabine-temozolomide or everolimus, and long-term marrow safety with earlier use needs surveillance.
Men with metastatic castration-resistant prostate cancer that has progressed after hormonal therapy and chemotherapy, and whose tumours show PSMA on a PET scan, can now receive lutetium-PSMA, which extends life, controls pain and is usually better tolerated than further chemotherapy. It has established a new treatment class in which a scan decides who gets the matching radioactive drug, and it is now being tested earlier in the disease (PSMAfore, PSMAddition).
Lutetium-177 dotatate is a standard treatment for progressive small bowel neuroendocrine tumours after somatostatin analogues, and NETTER-2 has since moved it into first-line use for higher-grade tumours.