Clinicians should use PSMA PET to select patients for treatment with lutetium-177 (177Lu)–PSMA-617 radioligand therapy and contrast-enhanced computed tomography (CT) to follow patients while on treatment, according to new consensus-based guidelines developed by an expert panel and published in the Journal of Nuclear Medicine.
The treatment is approved for use in men with metastatic castration-resistant prostate cancer (mCRPC) who have disease progression following at least 1 taxane-based chemotherapy and at least 1 line of androgen receptor pathway inhibitors (ARPIs).
In the phase 3 VISION trial, 177Lu-PSMA-617 significantly improved overall survival (15.3 vs 11.3 months) and radiographic progression-free survival (8.7 vs 3.4 months) compared with the best standard of care in patients with mCRPC previously treated with ARPI and chemotherapy. The TheraP and RESIST-PC trials indicated that treatment in this setting can improve PSA response.
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Patient Selection
Thomas A. Hope, MD, of the University of California, San Francisco, and other members of an expert panel agreed that the VISION criteria – PSMA tracer uptake in all lesions greater than in the liver – should be used to select eligible patients for 177Lu-PSMA-617 therapy. The tracers 68Ga-PSMA-11 and 18F-DCFPyL are preferred, and PSMA PET should be performed within 3 months of therapy initiation. Contrast-enhanced CT or MRI should also be performed to identify potential PSMA-negative disease, especially in patients with liver disease. External-beam radiation therapy can treat low-volume PSMA-negative disease.
The panel gauged the appropriate use of 177Lu-PSMA-617 on a scale of 1 to 9 (low to high) in various prostate cancer clinical settings based on a review of prospective trial data. With a score of 9, the panel agreed that it is highly appropriate to use 177Lu-PSMA-617 to treat men with mCRPC after taxane-based chemotherapy and ARPI. Prior chemotherapy during mCSPC fulfills this criterion, per the panel. Using 177Lu-PSMA-617 after docetaxel and before cabazitaxel in mCRPC is a viable option, they noted.
Renal toxicity has been reported in patients treated with PSMA radioligand therapy. The panel recommended that 177Lu-PSMA-617 candidates have a baseline estimated glomerular filtration rate greater than 30 mL/min/1.73 m2. Patients with lower baseline renal function or dialysis should be referred to a multidisciplinary tumor board. The panel recommended no dose reduction, but monitoring of bone marrow.
Based on consensus, the panel agreed that the baseline requirements for marrow function were a hemoglobin level of at least 8 g/dL, a white blood cell count of at least 2.0 × 109/L, or an absolute neutrophil count of at least 1.0 × 109/L and a platelet count of at least 75 × 109/L. It may be safe to treat patients who have diffuse marrow disease.
The panel noted some outstanding clinical uncertainties in this setting.There is currently no evidence for or against using ARPI with PSMA radioligand therapy. The committee agreed that patients previously treated with radium 223 are candidates for PSMA radioligand therapy. However, the optimal setting for using radium 223 remains unclear.
With a score of 3, the panel judged that it is rarely appropriate to use 177Lu-PSMA-617 to treat mCRPC after ARPI but before chemotherapy based on current evidence. Three phase 3 trials are currently evaluating PSMA radioligand therapy in this clinical setting: PSMAfore (NCT04689828), SPLASH (NCT04647526), and ECLIPSE (NCT05204927).
The panel also deemed it inappropriate (score=2) to use the radioligand therapy to treat patients with metastatic castration-sensitive prostate cancer (mCSPC). The phase 3 PSMAddition trial (NCT04720157) and phase 2 UpFrontPSMA trial (NCT04343885) are currently investigating 177Lu-PSMA-617 for mCSPC.
Other trials are investigating 177Lu-PSMA-617 in combination with immunotherapy (NCT03658447, NCT03805594, and NCT05150236), ARPIs (NCT04419402), or DNA damage repair pathway inhibitors (NCT03874884).
Toxicities
Treatment-related marrow toxicity can be managed in several ways, according to the committee. First, clinicians can delay subsequent therapy to allow marrow function to recover. Second, they can administer platelet or red blood cell transfusions during therapy. Third, with hematology consultation, they can consider using marrow-stimulating agents such as thrombopoietin for platelets, filgrastim and pegfilgrastim for white blood cells, and erythropoietin for red blood cells.
Clinicians should order a complete blood count and metabolic panel at least every 6 weeks and more frequently in patients with lower marrow counts. They should check lab values 2-3 weeks before the next scheduled therapy to determine whether it should proceed.
There is no agreement on the best way to minimize salivary gland toxicity. The panel did not think prophylaxis for nausea and vomiting is necessary.
Monitoring
On treatment, patients should be followed using contrast-enhanced CT. Posttreatment γ-imaging (either planar imaging or SPECT) should be considered, according to the panel. Using PSMA PET is currently not recommended to evaluate therapy response.
Stopping Treatment
It remains unclear how to decide when to stop treatment, according to the panel. Clinicians should consider imaging-based progression, PSA progression, and clinical decline. They should administer 2 cycles of 177Lu-PSMA-617 before assessing response.
If PSA is rising with worsening clinical symptoms or progression on imaging, it may be time to stop therapy, Dr Hope and colleagues stated. If PSA is rising with minimal radiographic progression, it is reasonable to continue treatment. New liver lesions on imaging warrants therapy cessation.
Focal pain can be treated with external-beam radiation therapy without stopping therapy.
Disclosure: Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures.
Reference
Hope TA, Antonarakis ES, Bodei L, et al. SNMMI consensus statement on patient selection and appropriate use of 177Lu-PSMA-617 radionuclide therapy. J Nucl Med. 2023 Sep;64(9):1417-1423. doi:10.2967/jnumed