Repeated PSMA-targeting radioligand therapy of metastatic prostate cancer with 131I-MIP-1095

Abstract

Purpose: Prostate-specific membrane antigen (PSMA)-targeting radioligand therapy (RLT) was introduced in 2011. The first report described the antitumor and side effects of a single dose. The aim of this analysis was to evaluate toxicity and antitumor activity after single and repetitive therapies.

Methods: Thirty-four men with metastatic castration-resistant prostate cancer received PSMA-RLT with 131I-MIP-1095. Twenty-three patients received a second, and three patients a third dose, timed at PSA progression after an initial response to the preceding therapy. The applied doses were separated in three groups: <3.5, 3.5-5.0 and >5.0 GBq. Antitumor and side-effects were analyzed by blood samples and other clinical data. Follow-up was conducted for up to 5 years.

Results: The best therapeutic effect was achieved by the first therapy. A PSA decline of ≥50% was achieved in 70.6% of the patients. The second and third therapies were significantly less effective. There was neither an association between the applied activity and PSA response or the time-to-progression. Hematologic toxicities were less prevalent but presented in a higher percentage of patients with increasing number of therapies. After hematologic toxicities, xerostomia was the second most frequent side effect and presented more often and with higher intensity after the second or third therapy.

Conclusion: The first dose of RLT with 131I-MIP-1095 presented with low side effects and could significantly reduce the tumor burden in a majority of patients. The second and third therapies were less effective and presented with more frequent and more intense side effects, especially hematologic toxicities and xerostomia.

Keywords: Endoradiotherapy; PSMA; Prostate cancer; Prostate-specific membrane antigen.

Conflict of interest statement

Conflicts of interest

Molecular Insight Pharmaceuticals, Inc. (a wholly-owned subsidiary of Progenics Pharmaceuticals), New York City, NY, USA had a role in sponsoring material used in the study. Thomas Armor is a full-time employee of Progenics Pharmaceuticals, Inc. All other authors declare that they have no conflicts of interest.

Ethical approval

All patients published in this manuscript signed a written informed consent form for the purpose of anonymized evaluation and publication of their data. All reported investigations were conducted in accordance with the Helsinki Declaration and with our national regulations (German Medicinal Products Act, AMG §13 2b). This evaluation was approved by the ethics committee of the University of Heidelberg (S-321-2012).

Figures

Fig. 1

Patient no. 2 received three therapies with 131I-MIP-1095. Staging before and after each therapy was conducted with PSMA ligand PET/CT (124I-MIP-1095 and 68Ga-PSMA-11). The first two therapies reduced the tumor burden. However, the third therapy didn’t show a sufficient effect. The last two pictures on the right side show the rapid progress between September and November. The images of the PET scans show the maximum intensity projections, those of the therapies show the geometric mean of the gamma-ray co-emission which enables imaging during therapy

Fig. 2

Best PSA response after the first, second and third therapies with 131I-MIP-1095. As demonstrated by this figure, the second and third therapies were significantly less effective compared to the first therapy. There was no association between the applied activity and the PSA response (first therapy: p = 0.70; second therapy: p = 0.74). Blue bars: patient group 1 (<3.5 GBq applied activity); black bars: patient group 2 (3.5–5.0 GBq applied activity); red bars: patient group 3 (>5 GBq applied activity)

Fig. 3

Average time to PSA progression following 1–3 RLT with 131I-MIP-1095. There was no association between applied radioactivity and the time to progression (first therapy: p = 0.19; second therapy: p = 0.61)

Fig. 4

Clinically relevant hematologic toxicity was observed with regard to platelets and leucocytes. W0-W10: average values of the pretherapeutical state (W0) to 10 weeks after therapy administration (W10)