Imaging expression of prostate‐specific membrane antigen and response to PSMA‐targeted β‐emitting radionuclide therapies in metastatic castration‐resistant prostate cancer

Abstract

Background Prostate‐specific membrane antigen (PSMA)‐targeted radionuclide therapy (TRT) has demonstrated efficacy and tolerability with a dose–response effect in phase I/II trials in men with metastatic castration‐resistant prostate cancer (mCRPC). The need for positive PSMA imaging before PSMA‐TRT to select patients is largely practiced, but its utility is not proven. Given target heterogeneity, developing a biomarker to identify the optimal patient population remains an unmet need. The aim of this study was to assess PSMA uptake by imaging and response to PSMA‐TRT. Methods We performed an analysis of men with mCRPC enrolled in sequential prospective phase I/II trials of PSMA‐TRT. Each patient had baseline PSMA imaging by planar 111In and/or 177Lu SPECT (N = 171) or 68Ga‐PSMA‐11 PET/CT (N = 44), but the results were not used to include/exclude treatment. Semiquantitative imaging scores (IS) on a 0‐4 scale were assigned based on PSMA uptake in tumors compared to liver uptake. We compared the ≥50% PSA decline response proportions between low (0–1) and high (2–4) PSMA IS using the χ2‐test. We used multivariable logistic regression analysis to understand the relationship between independent and dependent variables, including IS, radionuclide activity (dose) administered, CALGB (Halabi) prognostic risk score, prior taxane use. Results 215 men with progressive mCRPC received PSMA‐TRT as follows: 177Lu‐J591 (n = 137), 177Lu‐PSMA‐617 (n = 44), 90Y‐J591 (n = 28), 177Lu‐J591 + 177Lu‐PSMA‐617 (n = 6). High PSMA expression (IS 2–4) was found in 160 (74.4%) patients and was significantly associated with more frequent ≥ 50% PSA reduction (26.2 vs. 7.3%, p = .006). On multivariate logistic regression analysis, higher IS was associated with a ≥50% decrease in PSA, even after accounting for CALGB (Halabi) prognostic score, the dose administered, and previous taxane use (OR, 4.72; 95% CI, 1.71−16.85; p = .006). Patients with low PSMA expression (N = 55, 24.7%) were less likely to respond. Thirteen of 26 (50%) with no PSMA uptake (IS = 0) had post‐PSMA‐TRT PSA decline with 2 (7.7%) having ≥ 50% PSA declines. Conclusion Collectively, the data provide evidence in favor of the hypothesis that patients with high PSMA uptake and high administered radionuclide dose correlate with a higher chance of response.

Lutetium-177 Labelled PSMA Targeted Therapy in Advanced Prostate Cancer: Current Status and Future Perspectives

“…Each patient must undergo PSMA imaging, for example 68 Gallium (Ga)-PSMA-PET, to prove the presence and to quantify the amount of uptake of PSMA in tumour lesions. Whether the amount of PSMA-tracer uptake has an impact on the following RLT and its efficacy remains unclear to this point [ 19 , 20 , 21 , 22 , 23 ].…”

“…PSMA expression might predict and prognosticate response and outcome [ 19 , 20 , 22 , 23 ]. It seems logical that a higher PSMA expression is linked to a better response to PSMA targeted RLT.…”

Biomarkers in Prostate-Specific Membrane Antigen Theranostics

“…One group has used a five-point imaging score (IS) which was assigned based upon PSMA uptake in tumors compared to liver uptake and scored by two independent radiologists on a 0–4 scale [ 11 , 12 ]. PET images were scored by averaging SUV max of the five lesions with highest uptake and then comparing that value with liver SUV mean .…”

“…Planar single photon imaging was also studied, scoring the three lesions with the highest uptake. Using this assessment in 215 men with progressive mCRPC who were treated with β-emitting radionuclides ( 177 Lu-J591, 177 Lu-PSMA-617, 90 Y-J591, 177 Lu-J591 + 177 Lu-PSMA-617), a high IS of 2–4 was independently associated with ≥50% decrease in PSA, after accounting for CALGB (Halabi) prognostic score, dose administered, and previous taxane use [ 11 ].…”

PSMA Expression Assessed by PET Imaging Is a Required Biomarker for Selecting Patients for Any PSMA-Targeted Therapy

“…Studies reported that the whole-body PSMA PET SUV mean correlated with outcomes of patients treated with 177 Lu-PSMA (7,11,12). In a study conducted at Weill Cornell, fewer than 10% of patients with no or low PSMA expression at baseline had a significant PSA response to PSMA-targeted MRT (13).…”