ideasIdea

Neoadjuvant PSMA radioligand therapy before prostatectomy

For men with high-risk prostate cancer that hasn't spread yet, giving a dose or two of PSMA-targeted radioactive treatment before surgery, rather than only using it after the cancer has spread, might kill hidden cancer cells surgery alone would miss. It is still experimental and hasn't yet been shown to help patients live longer or avoid the cancer coming back.

Lutetium-177-PSMA-617 is approved for metastatic castration-resistant prostate cancer, but its combination of tumour-targeted radiation and imageable gamma emission has prompted interest in moving it earlier, to localised high-risk disease, on the theory that it could eliminate occult micrometastases before they become detectable. The LuTectomy trial (NCT04430192, Peter MacCallum Cancer Centre) tested this in 20 men with high-risk localised prostate cancer and high PSMA expression on PSMA PET, giving one cycle (10 patients) or two cycles (10 patients) of approximately 5 GBq 177Lu-PSMA-617 six weeks before robotic radical prostatectomy. The trial delivered a median tumour absorbed dose of 35.5 Gy across all lesions (19.6 Gy to the prostate), was well tolerated with no grade 3/4 toxicity, and did not compromise surgical safety; 45% of patients achieved a 50% or greater PSA decline, and 80% showed a partial histological response (stromal fibrosis, reduced tumour cell density), but no patient achieved a pathological complete response with a single or double cycle.

Because monotherapy did not achieve pathological complete responses, follow-on trials are testing combinations and longer regimens. The German NEPI trial (randomised, EudraCT 2021-004894-30, 46 patients) is comparing androgen deprivation therapy plus two cycles of 177Lu-PSMA-617 with or without the checkpoint inhibitor ipilimumab, with pathological complete response as a co-primary endpoint. In the United States, the PRELUDE trial (NCT06798558, Hackensack University Medical Center and others) is a phase 2 study giving two cycles of 177Lu-PSMA-617 before prostatectomy and following patients for two years for biochemical recurrence.

No trial has yet reported a survival, metastasis-free survival, or biochemical-recurrence benefit from this strategy, and neoadjuvant radioligand therapy is not recommended by any current guideline; a 2025 review explicitly states the approach 'does not yet have data to support any benefit' in these harder outcomes and remains investigational.

Hypothesis

Giving one or two cycles of lutetium-177-PSMA-617 before radical prostatectomy in men with high-risk localised prostate cancer will reduce micrometastatic disease burden and improve long-term biochemical-recurrence-free survival compared with prostatectomy alone, without making surgery less safe.

Rationale

The LuTectomy trial demonstrated that neoadjuvant 177Lu-PSMA-617 delivers substantial targeted radiation dose (median 35.5 Gy to lesions) with minimal toxicity and no impairment of surgical safety, and produced partial histological responses in 80% of patients, but achieved zero pathological complete responses with up to two cycles, showing monotherapy alone is probably insufficient. Whether the observed PSA declines and histological changes translate into fewer biochemical recurrences or better long-term survival is unverified; a 2025 review states this explicitly.

Proposed test

The randomised NEPI trial (EudraCT 2021-004894-30, 46 patients), testing androgen deprivation plus 177Lu-PSMA-617 with or without ipilimumab with pathological complete response as a co-primary endpoint, and the US phase 2 PRELUDE trial (NCT06798558) following patients for two-year biochemical recurrence, are the next steps toward establishing whether this strategy has a genuine oncological benefit; a phase 3 trial with metastasis-free or overall survival as the primary endpoint would be required to change practice.

Maturity

early clinical

Who acts

research

Cost to try

Medium ($1M to $50M)

Years to first evidence