Clinical Pearls & Morning Reports
Prostate-specific membrane antigen (PSMA) is a transmembrane glutamate carboxypeptidase that is highly expressed on prostate cancer cells. Sartor et al. conducted a phase 3 trial that evaluated lutetium-177 (177Lu)–PSMA-617 plus protocol-permitted standard care as compared with standard care alone (control group) in a specific population of previously treated patients with metastatic castration-resistant prostate cancer who were selected for PSMA positivity on the basis of PSMA positron-emission tomographic imaging. Read the NEJM Original Article here.
Q: What is 177Lu-PSMA-617?
A: Radioligand therapies such as 177Lu-PSMA-617 can target prostate cancer cells while sparing most normal tissues in patients who have been selected with the use of imaging to confirm radionuclide binding. 177Lu-PSMA-617 delivers beta-particle radiation selectively to PSMA-positive cells and the surrounding microenvironment. This radioligand therapy has been associated with encouraging biochemical and radiographic response rates, reduced pain, and low toxicity in multiple early-phase studies involving patients with progression of metastatic castration-resistant prostate cancer after standard therapy.
Q: What are the implications of high PSMA expression in metastatic castration-resistant prostate cancer?
A: High PSMA expression is an independent biomarker of poor prognosis throughout the course of prostate cancer and across anatomical sites. Metastatic lesions are PSMA-positive in most patients with metastatic castration-resistant prostate cancer, and high expression has been independently associated with reduced survival.
A: The PSMA-targeted radioligand 177Lu-PSMA-617 prolonged overall survival and delayed imaging-based progression when added to standard care in patients with PSMA-expressing metastatic castration-resistant prostate cancer. Among the 581 patients in the analysis set, the median imaging-based progression-free survival was 8.7 months in the 177Lu-PSMA-617 group, as compared with 3.4 months in the control group (hazard ratio for progression or death, 0.40; 99.2% confidence interval [CI], 0.29 to 0.57; P<0.001 [significance level, 0.008]). The median overall survival among all 831 patients who had undergone randomization was 15.3 months in the 177Lu-PSMA-617 group, as compared with 11.3 months in the control group (hazard ratio for death, 0.62; 95% CI, 0.52 to 0.74; P<0.001 [significance level, 0.05]).
A: Among the 248 patients who had measurable target lesions according to RECIST, version 1.1, on independent central review at baseline, a complete response was noted in 17 of 184 patients (9.2%) in the 177Lu-PSMA-617 group and in none of the 64 patients in the control group. A partial response was noted in 77 patients (41.8%) in the 177Lu-PSMA-617 group and in 2 (3%) in the control group. Fatigue, dry mouth, and nausea were the most common adverse events in the 177Lu-PSMA-617 group, and these adverse events were nearly all of grade 1 or 2.