European Nuclear Medicine Guide
Radiopharmaceutical: [177Lu]Lu-PSMA small-molecule inhibitors ([177Lu]Lu-PSMA-617), [177Lu]Lu-DOTAGA-(l-y)fk(Sub-KuE) aka [177Lu]Lu-PSMA I&T).
Radionuclide: Lutetium-177 is a medium-energy β-emitter with a maximum energy of 0.5 MeV, a maximal tissue penetration of 2 mm, and a half-life of 6.7 days. Lutetium-177 also emits low-energy γ-rays at 208 and 113 keV with 11% and 6.4% abundance, respectively, and this allows scintigraphy and subsequent dosimetry with the same therapeutic compound.
Activity: according to guidelines, the administered activity proposed is 2–6 cycles of 3.7–9.3 GBq at 6–8 week intervals.
Administration: intravenous (i.v.)
The EANM procedure guidelines for radionuclide therapy with 177Lu-labelled PSMA-ligands (177Lu-PSMA-RLT) contain recommendations for its clinical application [1].
Prostate-specific membrane antigen (PSMA) (also known as glutamate carboxypeptidase II) is a type II transmembrane glycoprotein that is highly expressed in prostate cancer and is well correlated with tumour aggressiveness, metastatic disease, and recurrence.
Eligibility and clinical decision-making should be based on multidisciplinary discussion.
Eligibility criteria include:
Patients with metastatic, castration-resistant prostate cancers (mCRPC), at least one androgen-receptor-pathway inhibitor and one taxane regimen. An evolution toward taxane-naïve patients is expected soon and approved in the USA (2025).
Medical history report from the (referring) physician containing a summary of all previous treatments.
Adequate anatomical imaging (e.g. computed tomography (CT) and/or magnetic resonance imaging (MRI)), not older than 3 months, preferably less than 2 months.
Baseline 68Ga-PSMA11 or 18F-PSMA PET/CT with uptake in metastatic lesions higher than that of normal organs such as liver uptake (i.e. SUVmax at dominant sites of tumour involvement to be at least 1.5 times the SUVmean of liver)
Life expectancy > 6 months.
ECOG performance status ≤2
Renal impairment (i.e., creatinine clearance <30 mL/min).
Impaired haematological function, i.e., haemoglobin (Hb) <8 mmol/L (12.9 g/dL); platelets <75x109/L; white blood cell count (WBC) <2.5 x109/L.
Severe hepatic impairment, i.e., total bilirubin >3 times upper limit of normal, or albumin <30 g/L with an increased prothrombin time and liver enzymes > 5-fold upper limit of normal (ULN)
Life expectancy less than 6 months
ECOG performance status >2
Commonly, treatment is preceded by a diagnostic assessment using an analogue ligand with a PET radionuclide such as [68Ga]Ga-PSMA-11.
Imaging can be performed essentially as described for [177Lu]Lu-DOTA-TATE; however, as lower amounts of radioactivity are given, there may be a need for prolonged acquisitions. Multiple SPECT/CT scanning is recommended using medium-energy general-purpose collimators and an energy window centred at 208 keV. To achieve optimal dosimetry, planar and SPECT/CT at 4, 24, 48 and 120 h is suggested [2]. Alternative or fewer time points are also suggested.
In general, 177Lu-PSMA small-molecule inhibitors are administered in a fractioned approach of 2–9 GBq per cycle [3–5]. Multicentre phase III trial Vision [6] and multicentre phase II trial TheraP [7]; are using a fractionated approach with a maximum of 6 cycles of 7.4–8.5 GBq 177Lu-PSMA-617[1].
For therapy with 177Lu-PSMA small-molecule inhibitors, dosimetry-driven treatment planning could potentially facilitate implementation and provide major benefits for patients. Absorbed doses to at-risk organs could be significant over the treatment cycles, and prospective absorbed dose measures could prove valuable in determining the acceptable number of cycles. Administrations of tracer amounts of [177Lu]Lu-PSMA-617 and pre-therapeutic dosimetry have been investigated, and the authors of this study concluded that substantial individual variance mandates patient-specific dosimetry [8]. A more practical approach might be to perform treatment planning based on quantitative imaging from the previous treatment cycle or by performing pre-therapeutic diagnostic assessment using a surrogate ligand.
The dose-effect curves, with tolerance limits for normal tissue and the desirable absorbed dose to tumours, will likely need to be empirically determined. The organs with the highest absorbed doses are lacrimal glands and salivary glands.
Experience from other molecular radiotherapies demonstrates that the common assumption of identical tolerance limits for MRT and EBRT can often lead to an under-dosage of radiopharmaceuticals, because the tolerance limits are actually higher. This might be explained by different dose-rates, energies, or the short range of the beta- emissions, which necessitate an investigation of small-scale dosimetry.
In patients with mCRPC with at least one androgen-receptor-pathway inhibitor and one or two taxane regimens, [177Lu]Lu-PSMA-617 plus standard care significantly prolonged both imaging-based progression-free survival (median, 8.7 vs. 3.4 months; hazard ratio for progression or death, 0.40; 99.2% confidence interval [CI], 0.29 to 0.57; P<0.001) and overall survival (median, 15.3 vs. 11.3 months; hazard ratio for death, 0.62; 95% CI, 0.52 to 0.74; P<0.001) compared with standard care alone [6]. In patients with metastatic castration-resistant prostate cancer for whom cabazitaxel was considered, the next appropriate standard treatment PSA responses were more frequent in the [177Lu]Lu-PSMA-617 group than in the cabazitaxel group (65% vs 37% by PSA responses; 66% vs 37% by intention to treat; difference 29% (95% CI 16–42; p<0.0001; and 66% vs 44% by treatment received; difference 23% [9–37]; p=0.0016). Overall survival was similar among those assigned to [177Lu]Lu-PSMA-617 versus those assigned to cabazitaxel (19.1 months [95% CI 16.9 to 21.4] vs 19.6 months [17.4 to 21.8]; difference -0.5 months [95% CI -3.7 to 2.7]; p=0.77) [7].
In multicentre phase II trial EnzaP in patients with metastatic castration-resistant prostate cancer not previously treated with docetaxel or androgen-receptor-pathway inhibitors, median PSA progression-free survival was 13.0 months (95% CI 11.0–17.0) in the enzalutamide plus [177Lu]Lu-PSMA-617 group and 7.8 months (95% CI 4.3–11.0) in the enzalutamide group (hazard ratio 0.43, 95% CI 0.29–0.63, p<0.0001). Multicentre phase III trial PSMAfore, in taxane-naive patients with metastatic castration-resistant prostate cancer who had progressed once on a previous ARPI, median radiographic progression-free survival was 9.30 months (95% CI 6.77-not estimable) in the 177Lu-PSMA-617 group versus 5.55 months (4.04–5.95) in the ARPI change group (hazard ratio [HR] 0.41 [95% CI 0.29–0.56]; p<0.0001) [7].
More recently, 177-Lu-PSMA treatment showed positive results in a phase III randomized (PSMAFORE) controlled trial in taxane-naive patients with prostate-specific membrane antigen (PSMA)-positive metastatic castration-resistant prostate cancer who had progressed once on a previous ARPI. Patients were randomized to intravenous 177Lu-PSMA-617 at a dosage of 7·4 GBq (200 mCi) ± 10% once every 6 weeks for six cycles, or to a change of ARPI (to abiraterone or enzalutamide, administered orally on a continuous basis per product labelling). In the updated analysis at the time of the third data cut-off (median time from randomization to third data cut-off: 24·11 months [IQR 20·24–27·40]), median radiographic progression-free survival was 11·60 months (95% CI 9·30–14·19) in the 177Lu-PSMA-617 group versus 5·59 months (4·21–5·95) in the ARPI change group (HR 0·49 [95% CI 0·39–0·61]) [9]. On the basis of these results the FDA approved 177-Lu-PSMA-617 in this setting in the United States.
Absorbed doses to normal tissue were shown not to differ significantly between therapy cycles, but it still remains to be investigated whether Gy/GBq values from the first cycle can be used directly for treatment planning of subsequent cycles [8]. Prospective imaging with positron-emitting surrogate markers could deviate from the actual biodistribution.
Further possibilities for development include combination treatments.
Investigations of iodine-131 and yttrium-90-based ligands have also been performed, but the current focus is on lutetium-177-radiolabelled ligands and especially on small-molecule inhibitors. The VISION regimen is effective and currently standard, but the outcome of the many clinical trials currently in progress will likely change this standard regimen.
In studies of SPECT/CT-based dosimetry for [177Lu]Lu-PSMA-617, the salivary/parotid glands (1.2–1.4 Gy/GBq) and kidneys (0.6–1.0 Gy/GBq) were the organs which received the highest mean absorbed doses [8,10]. Mean absorbed doses to red marrow were reported as being between 12 and 48 mGy/GBq. The lacrimal glands might also represent a dose-limiting organ [11]. For [177Lu]Lu-PSMA I&T, similar absorbed doses are observed: 1.3 Gy/GBq for parotid glands, 0.8 Gy/GBq for kidneys, and 14 mGy/GBq for red marrow [4]. In the Vision trial, fatigue, dry mouth, and nausea were the most common adverse events in the [177Lu]Lu-617 group, and these adverse events were nearly all of grade 1 or 2. In the TheraP trial, grade 3-4 adverse events occurred in 32 (33%) of 98 men in the [177Lu]Lu-PSMA-617 group versus 45 (53%) of 85 men in the cabazitaxel group. Thrombocytopenia (11%) and pain (11%) were the most common grade 3-4 adverse events in the [177Lu]Lu-PSMA-617 group. Fatigue, dry mouth, and nausea were also the most common grade 1-2 adverse events.
[177Lu]Lu-PSMA-617 (Pluvicto or lutetium-177 vipivotide tetraxetan) was approved by the EMA in December 2022 and the FDA in March 2023 for clinical use in patients with mCRPC with at least one androgen-receptor-pathway inhibitor (ARPI) and one taxane. For use in taxane-naïve patients [177Lu]Lu-PSMA-617 was approved in the US in March 2025.
[177Lu]Lu-labelled PSMA ligands remain investigational.