What is Pluvicto?
Pluvicto (lutetium Lu 177 vipivotide tetraxetan, also known as Lu-177-PSMA-617) is an FDA-approved radioligand therapeutic agent that delivers targeted radiation to prostate cancer cells expressing prostate-specific membrane antigen (PSMA), indicated for adult patients with PSMA-positive metastatic castration-resistant prostate cancer (mCRPC) who have been treated with androgen receptor pathway inhibition and taxane-based chemotherapy. 1
Mechanism of Action
Pluvicto works by binding to PSMA, a transmembrane protein highly expressed in prostate cancer cells. Once bound, the radionuclide lutetium-177 emits beta-minus radiation that delivers cytotoxic radiation directly to PSMA-expressing cancer cells and the surrounding tumor microenvironment, inducing DNA damage that leads to cell death 1. The physical half-life of lutetium-177 is 6.647 days, with beta radiation having a maximum energy of 0.498 MeV 1.
FDA-Approved Indications
The FDA initially approved Pluvicto in March 2022 for PSMA-positive mCRPC patients who have received:
- At least one androgen receptor pathway inhibitor (ARPI)
- One or two taxane-based chemotherapy regimens 1, 2
The FDA subsequently expanded the indication to include patients with PSMA-positive mCRPC who have progressed after ARPI therapy and are considered appropriate candidates for delaying taxane-based chemotherapy 3. This expansion was based on the PSMAfore trial results.
Dosing and Administration
The recommended dose is 7.4 GBq (200 mCi) administered intravenously every 6 weeks for up to 4-6 cycles, or until disease progression or unacceptable toxicity 1, 2. Treatment requires concurrent androgen deprivation therapy 3.
Patient Selection Criteria
Patients must have:
- At least one PSMA-positive metastatic lesion on imaging
- No dominant PSMA-negative metastatic lesions 3
PSMA-negative lesions are defined as metastatic disease lacking PSMA uptake, including:
- Bone lesions with soft tissue components ≥1.0 cm
- Lymph nodes ≥2.5 cm in short axis
- Solid organ metastases ≥1.0 cm 3
Eligibility can be determined using Ga-68 PSMA-11, F-18 piflufolastat PSMA, or F-18 flotufolastat PSMA PET/CT imaging 3, 4.
Clinical Evidence
VISION Trial (Post-Chemotherapy Setting)
The pivotal VISION trial randomized 831 patients with PSMA-positive mCRPC (2:1 ratio) to receive Pluvicto plus standard care versus standard care alone. All patients had received at least one ARPI and one or two taxane regimens 5.
Key outcomes:
- Median overall survival: 15.3 vs 11.3 months (HR 0.62; 95% CI 0.52-0.74; P<0.001) 3, 5
- Median progression-free survival: 8.7 vs 3.4 months (HR 0.40; 99.2% CI 0.29-0.57; P<0.001) 3, 5
PSMAfore Trial (Pre-Chemotherapy Setting)
This trial evaluated 468 patients with mCRPC who progressed on an ARPI but had not received chemotherapy. Pluvicto was compared to switching to an alternate ARPI 3, 6.
Key outcomes:
- Median radiographic PFS: 11.6 vs 5.6 months (HR 0.49; 95% CI 0.39-0.61) 3
- No overall survival difference at analysis, likely due to 57% crossover from control arm to Pluvicto 3
- Importantly, fewer grade 3-5 toxicities occurred with Pluvicto compared to ARPI switch 3
Current Guideline Recommendations
NCCN 2025 (Category 1): Recommends Pluvicto for patients with PSMA-positive mCRPC who have been treated previously with an ARPI and taxane-based chemotherapy 3.
NCCN 2025 (Emerging indication): Also recommends for patients with prior ARPI therapy who are considered appropriate to delay taxane-based chemotherapy 3.
ASCO 2025: Lists Pluvicto as a treatment option for PSMA-positive patients post-ARPI and docetaxel 6. The panel recognizes potential advantages in the pre-chemotherapy setting but is awaiting additional data and FDA review before formal recommendations 6.
Safety Profile
Most common adverse reactions (≥20%):
- Fatigue
- Dry mouth
- Nausea
- Anemia
- Decreased appetite
- Constipation 2
Most common laboratory abnormalities (≥30%):
- Decreased lymphocytes
- Decreased hemoglobin
- Decreased leukocytes
- Decreased platelets
- Decreased calcium
- Decreased sodium 2
Grade ≥3 adverse events occurred in 52.7% of patients receiving Pluvicto versus 38.0% in controls, particularly anemia, thrombocytopenia, lymphopenia, and fatigue 3, 5. However, quality of life was maintained despite higher toxicity rates 5.
Important Clinical Considerations
Fertility: The cumulative dose may cause temporary or permanent infertility. Male patients with female partners of reproductive potential should use effective contraception during treatment and for 14 weeks after the last dose 1.
Renal function: Patients with mild to moderate renal impairment may be at greater risk of toxicity and require frequent monitoring. The drug has not been studied in severe renal impairment or end-stage renal disease 1.
Multidisciplinary approach: Blood counts, renal, and hepatic function should be checked before each cycle. Radioprotection precautions must be followed per national and local regulations 4.