¹⁷⁷Lu-PSMA-617

Indications

• US label (revised 07/2026): (1) with an ARPI, for adults with PSMA-positive metastatic androgen pathway modulation-naïve or -sensitive prostate cancer (mAPMN/S, the label term for metastatic hormone-sensitive disease); (2) for PSMA-positive metastatic androgen pathway modulation-resistant (castration-resistant) disease after an ARPI, either when delaying taxane chemotherapy is appropriate or after a taxane.
• EU SmPC (updated 07/2026): with ADT, with or without an ARPI, for adults with progressive PSMA-positive mCRPC already treated with an ARPI and taxane chemotherapy. Taxane-naïve and hormone-sensitive use is off-label in the EU.
• Selection: both labels require PSMA imaging but set no uptake threshold. The US label asks for an approved PSMA PET agent and points to the trial criteria; the EU label asks only for PSMA imaging.
• EANM/SNMMI 2023: strong recommendation after an ARPI and a taxane (VISION), and for men who would otherwise receive cabazitaxel after docetaxel (TheraP).
• A GnRH analogue must continue during treatment unless the patient has had orchiectomy (US label; EU SmPC).

Contraindications

• No contraindications in the US label; the EU SmPC lists only hypersensitivity. EANM/SNMMI 2023 treats most barriers as relative because the disease is life-threatening.
• Renal: the EU SmPC does not recommend treatment if baseline CLcr is <50 mL/min. The US label notes that severe impairment (CLcr 15–29 mL/min) has not been studied and mild–moderate impairment may raise toxicity.
• Baseline counts: the EU hold thresholds also apply before the first dose, so grade ≥2 cytopenia should be corrected or explained before starting.
• Dominant PSMA-negative disease: any lesion above the size limits with uptake ≤ liver (VISION rule), or FDG-positive sites with little PSMA expression (TheraP rule).
• Reduced marrow reserve (extensive prior chemotherapy, prolonged earlier cytopenia) and reduced kidney function raise the risk of higher-grade myelotoxicity. Stop large-field radiotherapy, chemotherapy and bone-seeking radiopharmaceuticals at least 4 weeks before (EANM/SNMMI 2023).

• Myelosuppression (both labels): grade 2 — withhold until grade 1 or baseline; grade ≥3 — withhold, then reduce to 5.9 GBq; recurrent grade ≥3 after one reduction — stop (US). CTCAE v5.0 grade 2 means Hb <10.0–8.0 g/dL, neutrophils <1.5–1.0 ×10⁹/L or platelets <75–50 ×10⁹/L. The EU SmPC adds: check iron, B12 and folate; growth factors and transfusion are allowed.
• Renal: a confirmed ≥40% rise in serum creatinine with a >40% fall in CLcr — withhold until improvement, then reduce by 20%. Stop for grade ≥3 renal toxicity (US) or recurrent renal toxicity (both).
• Other holds (US): grade ≥3 GI toxicity not controlled medically — withhold to grade ≤2 and reduce; grade ≥3 fatigue — withhold to grade ≤2; grade ≥2 electrolyte or metabolic abnormality — withhold to grade ≤1. The EU SmPC also holds for spinal cord compression and weight-bearing fractures until treated and stable, and stops treatment for AST or ALT >5 × ULN without liver metastases.
• Administration (US): slow IV push over about 1–10 minutes, gravity infusion over about 30 minutes, or peristaltic pump at about 25 mL/h. Flush the dedicated line with ≥10 mL saline before and after. Use the syringe or pump method for a reduced dose.
• Organ doses: in the VISION sub-study (n=29): lacrimal glands 2.1, salivary glands 0.63, kidneys 0.43 and red marrow 0.035 Gy/GBq. Over 6 cycles this is about 19 Gy to the kidneys and 1.5 Gy to marrow (EANM/SNMMI 2023).
• Dosimetry is optional. Fixed activity was licensed on the VISION data, so patient-specific dosimetry is not mandatory. Post-therapy SPECT/CT can support dosimetry or response review, and at least one post-therapy scan is expected in most EU states for treatment verification. Dosimetry-guided extra activity or cycles remain investigational (EANM/SNMMI 2023).
• Outside the label, 6–9.3 GBq per cycle and 4–10-week intervals have been used (EANM/SNMMI 2023). TheraP started at 8.5 GBq and fell by 0.5 GBq per cycle.

• Dry mouth is the commonest non-haematological effect: 39% in VISION, 61% in PSMAfore and 46% in PSMAddition, almost all grade 1–2 (US label). Dry eye occurs in <10%. Oral glutamate, atropine and pre-dosing with unlabelled ligand have been tried to cut salivary uptake, but evidence is too limited for a recommendation (EANM/SNMMI 2023).
• Myelosuppression (grade 3–4): VISION — Hb 15%, platelets 9%, leukocytes 7%, neutrophils 4.5%; PSMAfore — Hb 7%, platelets 2.7%; PSMAddition — Hb 4.3%, platelets 1.1%. VISION had deaths from bleeding with thrombocytopenia, sepsis with neutropenia, and marrow failure (US label). Check counts at the expected nadir, 2–3 weeks after each cycle, and 4–6 weeks after the last (EANM/SNMMI 2023).
• Renal: grade 3–4 acute kidney injury 3.4% in VISION, 1.3% in PSMAfore and 1.6% in PSMAddition (US label). EANM/SNMMI 2023 advises stopping if eGFR falls below 30 mL/min.
• Fatigue (51%) and nausea (35%) are common in the pooled label population (n=1320). Antiemetic prophylaxis is permitted but not required. Dexamethasone (for example 4 mg daily for 5 days) is used where swelling of cerebral, spinal or other metastases could cause pain or obstruction (EANM/SNMMI 2023).
• Tumour lysis: with high tumour burden, allopurinol may be given in the first week (EANM/SNMMI 2023).
• PSA flare: PSA becomes reliable 2–3 weeks after the second cycle; after that, a rise >25% should prompt restaging (EANM/SNMMI 2023, PCWG3).
• Late effects: MDS and secondary leukaemia have not been reported in mCRPC series but may matter as treatment moves to earlier disease (EANM/SNMMI 2023). A cumulative 44.4 GBq gives a testicular dose that can cause temporary or permanent infertility (US label).

• Follow local release rules. Depending on national law, 48–72 h inpatient isolation may be needed; where outpatient treatment is allowed, keep the patient about 2 h to watch for side effects, ensure hydration and complete the first void (EANM/SNMMI 2023). US example: NRC 10 CFR 35.75 allows release when the dose to others is unlikely to exceed 5 mSv.
• Label advice after each dose (US and EU): limit close contact (<1 m) with others for 2 days and with children and pregnant women for 7 days; no sexual activity for 7 days; sleep apart from others for 3 days, from children for 7 days and from pregnant women for 15 days.
• Drink plenty and void often, especially in the first 6–10 h, to reduce bladder dose (US label; EANM/SNMMI 2023).
• Men with female partners of reproductive potential should use effective contraception during treatment and for 14 weeks after the last dose (US label; EU SmPC). Sperm cryopreservation can be discussed before treatment (EU SmPC).
• Obtain at least one planar post-therapy scan more than 2 h after injection to exclude extravasation and confirm normal distribution (EANM/SNMMI 2023).