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 ¹¹¹ In and/or ¹⁷⁷ Lu SPECT (N = 171) or ⁶⁸ Ga-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: ¹⁷⁷ Lu-J591 (n = 137), ¹⁷⁷ Lu-PSMA-617 (n = 44), ⁹⁰ Y-J591 (n = 28), ¹⁷⁷ Lu-J591 + ¹⁷⁷ Lu-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.

Trial registration: ClinicalTrials.gov NCT00003391 NCT00195039 NCT00538668 NCT03545165 NCT03042468 NCT03276572.

FIGURE 1

Planar imaging in two patients with different PSMA uptake. Left panel: Patient 1 (IS 1) following IV administration of ¹⁷⁷Lu-J591. From left to right: (A) anterior, and (B) posterior view showing uptake in right external iliac node. Right panel: Patient 2 (IS 4) following IV administration of ¹⁷⁷Lu-J591. From left to right: (C) anterior, and (D) posterior view showing uptake in the thoracolumbar spine, bilateral ribs, sacrum, and bilateral iliac bones.