Residency · Residency · Nuclear Medicine

Lu-177 PSMA Therapy for Metastatic Prostate Cancer

Introduction

Lu-177 PSMA-617 (Pluvicto) is an FDA-approved radioligand therapy for PSMA-positive metastatic castration-resistant prostate cancer (mCRPC). Approved in March 2022 based on the VISION trial, it targets prostate-specific membrane antigen (PSMA), a transmembrane glycoprotein overexpressed on prostate cancer cells. This therapy extends the theranostic paradigm to the most common non-cutaneous cancer in men, using diagnostic PSMA PET/CT to select patients and therapeutic Lu-177 PSMA-617 to treat them.

PSMA Biology

PSMA, also known as glutamate carboxypeptidase II or folate hydrolase I, is a type II transmembrane protein expressed on prostate epithelial cells and markedly overexpressed in prostate cancer. Expression increases with higher Gleason grade, castration resistance, and metastatic disease, making it an ideal target for advanced prostate cancer. PSMA is also expressed in normal tissues including the salivary glands, lacrimal glands, proximal renal tubules, small bowel, and the neovasculature of some non-prostatic tumors. Crucially, PSMA is internalized upon ligand binding, which facilitates intracellular delivery of the radionuclide payload directly into the tumor cell.

Diagnostic PSMA PET Imaging

Approved Tracers

Three PSMA PET tracers are FDA-approved: Ga-68 PSMA-11 (approved 2020, produced by generator or cyclotron), F-18 piflufolastat (DCFPyL, marketed as Pylarify, approved 2021, cyclotron-produced), and F-18 flotufolastat (Posluma, approved 2023).

Role in Therapy Selection

PSMA PET/CT is required before Lu-177 PSMA therapy to confirm PSMA expression. All sites of disease should demonstrate PSMA uptake above liver background. PSMA-negative lesions or those that are FDG-positive but PSMA-negative predict poor response because these tumor cells lack the therapeutic target. The VISION trial required at least one PSMA-positive lesion and no dominant PSMA-negative disease for enrollment.

Patient Selection

FDA-Approved Indication

The approved indication is for adult patients with PSMA-positive mCRPC who have received prior treatment with an androgen receptor pathway inhibitor (ARPI) and taxane-based chemotherapy, with PSMA-positive disease confirmed on diagnostic PSMA PET/CT.

Eligibility Criteria

Patients must have an ECOG performance status of 0 to 2. Adequate bone marrow function requires a white blood cell count of 2,500 or greater, platelets of 100,000 or greater, and hemoglobin of 9 g/dL or greater. Adequate renal function requires an eGFR of 30 mL/min or greater, with a preference for values above 50. Adequate hepatic function is also required, and patients should not have diffuse bone marrow infiltration that would limit hematologic tolerance.

Exclusion Considerations

Dominant PSMA-negative disease, identified as discordant FDG-positive but PSMA-negative lesions, is a contraindication. Severely compromised bone marrow reserve, significant renal impairment, and cord compression or other conditions requiring urgent intervention are additional reasons to exclude patients.

Treatment Protocol

Standard Regimen

The standard regimen is 200 mCi (7.4 GBq) of Lu-177 PSMA-617 per cycle, administered for 6 cycles at 6-week intervals. Each dose is given as an intravenous infusion over approximately 30 minutes. Concurrent androgen deprivation therapy with an LHRH agonist or antagonist is continued throughout treatment.

Key Differences from PRRT (DOTATATE)

Several important differences distinguish PSMA therapy from PRRT. No amino acid co-infusion is required because PSMA-617 has different renal handling than DOTATATE. The protocol calls for 6 cycles rather than 4, administered at 6-week intervals rather than 8-week intervals. Salivary gland toxicity is a more prominent concern than nephrotoxicity, reflecting the high PSMA expression in salivary tissue.

Pre-Treatment Checklist

Before each cycle, the team should confirm PSMA-positive disease on PET/CT (at baseline), verify adequate laboratory values, ensure continued androgen deprivation, counsel the patient on radiation safety precautions, and obtain baseline salivary function assessment if possible.

Efficacy

VISION Trial Results

The VISION trial was a randomized phase III study comparing Lu-177 PSMA-617 plus standard of care to standard of care alone in mCRPC. Median overall survival was 15.3 months versus 11.3 months, with a hazard ratio of 0.62. Median radiographic progression-free survival was 8.7 months versus 3.4 months, with a hazard ratio of 0.40. PSA response, defined as a 50% or greater decline, occurred in 46% versus 7% of patients. The objective response rate in patients with measurable disease was 51% versus 14%.

TheraP Trial

The TheraP trial was a randomized phase II study comparing Lu-177 PSMA-617 to cabazitaxel chemotherapy. Lu-177 PSMA achieved a superior PSA response rate of 66% compared to 37% with cabazitaxel, with fewer grade 3 to 4 adverse events. This trial used a dual-tracer selection strategy, requiring disease to be both PSMA-positive and FDG-concordant, which may have enriched for patients most likely to benefit.

Toxicity and Management

Hematologic Toxicity

Anemia is the most common hematologic toxicity, occurring at any grade in approximately 50% of patients and at grade 3 to 4 in approximately 13%. Thrombocytopenia occurs at any grade in approximately 35% and at grade 3 to 4 in approximately 8%. Lymphopenia is common but usually not dose-limiting. Neutropenia is less frequent. Complete blood count should be monitored every 2 weeks between cycles.

Salivary Gland Toxicity (Xerostomia)

Because PSMA is highly expressed in salivary glands, dry mouth occurs in approximately 40% of patients. The xerostomia is usually mild at grade 1 to 2 but may be persistent. Strategies for mitigation include salivary gland cooling, sialagogues, and hydration. Prior external beam radiation therapy to the salivary glands should be avoided if possible before PSMA therapy to preserve baseline function.

Renal Toxicity

Renal toxicity is less significant with PSMA therapy than with DOTATATE due to different pharmacokinetics, though renal function should be monitored before each cycle. PSMA expression in proximal renal tubules leads to some renal uptake of the therapeutic agent.

Other Adverse Effects

Fatigue is common, occurring in approximately 40% of patients. Nausea is usually mild. A bone pain flare may occur after initial treatment and may actually suggest therapeutic response. Myelodysplastic syndrome is rare but has been reported in less than 1% of patients.

Dosimetry

Empiric fixed dosing at 200 mCi per cycle is the current standard. Post-therapy SPECT/CT at 24 and 72 hours can estimate organ and tumor absorbed doses. Critical organ thresholds include approximately 35 to 40 Gy for the salivary glands, 23 to 28 Gy BED for the kidneys, and approximately 2 Gy for the bone marrow. Personalized dosimetry may allow optimization of treatment in the future.

Radiation Safety

Patients typically meet NRC release criteria after Lu-177 therapy and can be treated as outpatients. Standard precautions for bodily fluids are observed for 1 week post-treatment. Patients should avoid close contact with children and pregnant women for 7 days.

Emerging Developments

The PSMAfore trial demonstrated benefit of Lu-177 PSMA-617 in earlier lines of therapy, before chemotherapy. Alpha-emitter PSMA therapy with Ac-225 PSMA-617 is being investigated for Lu-177-resistant disease. Combination strategies pairing Lu-177 PSMA with ARPI or PARP inhibitors are under study. Tandem alpha/beta therapy using Ac-225 and Lu-177 together is an innovative approach. I-131-labeled PSMA agents are being explored as alternative therapeutic isotopes.

Clinical Pearls

PSMA PET/CT is mandatory before Lu-177 PSMA therapy. All significant disease must be PSMA-positive, and dominant PSMA-negative disease is a contraindication because those tumor cells lack the target and will not respond.

Xerostomia from salivary gland irradiation is the most distinctive toxicity of PSMA-targeted therapy and is not seen with DOTATATE therapy. Strategies for salivary gland protection remain an active area of investigation.

The VISION trial established Lu-177 PSMA-617 as a new standard of care for mCRPC after ARPI and taxane therapy, with significant improvements in both overall survival and radiographic progression-free survival.

References

1. Sartor O, et al. Lutetium-177-PSMA-617 for Metastatic Castration-Resistant Prostate Cancer (VISION). New England Journal of Medicine. 2021;385(12):1091-1103.
2. Hofman MS, et al. TheraP: Lu-177-PSMA-617 vs Cabazitaxel in mCRPC. Lancet. 2021;397(10276):797-804.
3. Defined SNMMI/EANM Practice Guideline for PSMA Radioligand Therapy. Journal of Nuclear Medicine. 2023;64(1):e1-e14.
4. Defined Safety and Dosimetry of Lu-177 PSMA-617. European Journal of Nuclear Medicine and Molecular Imaging. 2022;49:3546-3560.

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