Comparison of adverse event rate of prostate-specific membrane antigen (PSMA)-targeted radionuclide therapy (TRT) with antibody or small molecule ligand targeting vector.
Authors: Samuel Francis Ruder, Michael Philip Sun, Charlene Thomas, Ana M. Molina, Jones T. Nauseef, Joseph Osborne, Cora N. Sternberg, David M. Nanus, Neil Harrison Bander, Scott T. Tagawa
Journal: Journal of Clinical Oncology (2024)

161 Background: PSMA-targeted radionuclide therapy (PSMA-TRT) has been established with use of either monoclonal antibodies (mAb) or small molecule ligands (SML) as the targeting vectors for delivery of 177Lu to PSMA-expressing prostate cancer. mAb and SML differ in their molecular weight, pharmacokinetics, and biodistribution which is predicted to result in different adverse effect profiles. Methods: In this study with written informed consent, we compare the adverse effects from individual patients receiving PSMA-TRT for mCRPC using mAb (J591) vs SML (PSMA-617 or PSMA I&amp;T) for delivering 177Lu in prospective clinical trials or registry. All-grade treatment-emergent adverse events (TEAEs) were extracted from trial databases. Adverse effects were graded 0-5. Pearson’s Chi-squared test was used to assess TEAEs and association with treatment type. Multivariable logistic regression was used to compare TEAEs after adjusting for administered radioactivity dose and CALGB (Halabi) prognostic score. Results: 248 patients with mCRPC were treated from March 2001 to February 2023. 166 (67.7%) received mAb (177Lu-J591), 81 received SML [76 (30.6%) 177Lu-PSMA-617, 5 (2%) 177Lu-PSMA-I&amp;T)]. The median age was 70.9 years (44.5 yrs to 93.8 yrs). At the time of trial enrollment, 137 (55.2% [68% SML and 49% mAb]) patients had exposure to chemotherapy, 112 (45.1%) had exposure to androgen-receptor pathway therapy, 193 (77.8%) had bone metastases, 120 (48.3%) LN mets, 42 (16.9%) lung mets, and 20 (8.0%) liver mets. 142 (57.2%) had Halabi score high disease. All-grade hematologic TEAEs were more common with mAb: neutropenia in 122 (74%) patients vs 16 (20%) (p&lt;0.001), anemia in 122 (73%) vs 26 (33%) (P&lt;0.001), and thrombocytopenia in 145 (87%) vs 25 (32%) (p&lt;0.001). Gr &gt;3 neutropenia occurred in 79 (47%) and Gr &gt;3 thrombocytopenia in 98 (59%) receiving mAb. All-grade non-hematologic TEAEs were generally more common with SML: fatigue in 31 (53%) vs 79 (48%) (p=0.5), pain in 32 (54%) vs 73 (44%) (p=0.2), nausea in 21 (36%) vs 34 (20%) (p=0.02) and xerostomia in 36 (61%) vs 1 (0.6%) (p&lt;0.001). After adjusting for administered dose and Halabi score, treatment with 177Lu via SML vector was associated with less neutropenia (OR 0.04, 95% CI 0.02-0.09, p&lt;0.001), anemia (OR 0.11, 95% CI 0.06-0.22, p&lt;0.001), and thrombocytopenia (OR 0.04, 95% CI 0.02-0.09, p&lt;0.001) but more nausea (OR 3.2, 95% CI 1.54-6.72, p=0.002) and xerostomia (NA due to low event rate in mAb). Conclusions: As predicted, PSMA-TRT with mAb vs SML is associated with different toxicity profiles. PSMA-TRT with the mAb 177Lu-J591 is more commonly associated with hematologic toxicities compared to the SML 177Lu-PSMA-617 and 177Lu-PSMA-I&amp;T, which are more commonly associated with non-hematologic toxicities.