A VISION of ALSYMPCA

TO THE EDITOR: I just read the 2 editorials written by Hofman (1) and by Czernin and Calais (2) commenting on the use of ¹⁷⁷Lu-PSMA-617 therapy in patients with metastatic castration-resistant prostate cancer (mCRPC), mainly on the results of the VISION trial (3). ¹⁷⁷Lu-PSMA-617 together with ⁶⁸Ga- or ¹⁸F-labeled PSMA ligands are doubtless important theranostic technologies that provide a new perspective on mCRPC treatment, as stated in another recent editorial by Srinivas and Iagaru (4). However, I miss in the VISION trial a comparison with the results of another study performed a few years ago that analyzed the use of ²²³Ra in the treatment of mCRPC patients, the ALSYMPCA trial (5). Although ²²³Ra is used to treat patients with exclusive bone metastases, this group represents most patients with mCRPC. In some studies, the percentage of patients with bone metastatic disease, with or without concomitant lymph node disease but without visceral (lung and liver) disease, represents around 70% of cases (6), and in this group the presence of concomitant lymph node disease does not appear to change the overall survival (this high percentage was also confirmed in the VISION trial, in which 91% of patients had bone metastases, 50% had lymph node metastases, 9% had lung metastases, and 12% had liver metastases) (6). Therefore, ²²³Ra could represent an adequate option to treat most patients with mCRPC. In this sense, it will be useful if the authors of the VISION study, as well as of other future studies on this issue, also present the survival results for the distinct groups of metastatic lesions or, at least, separate the results of the ones with bone metastatic disease without visceral disease from the group with visceral disease. This separation would be useful to indirectly compare the effects of ¹⁷⁷Lu-PSMA-617 with the effects of ²²³Ra in the group without visceral metastases and also to assess the effect of ¹⁷⁷Lu-PSMA-617 in the group of patients with visceral metastases, who certainly are not candidates for ²²³Ra therapy.

In this line of reasoning, it is interesting to note that median survival differences between groups receiving or not receiving the radionuclide therapy are similar in both trials: 4 mo (15.3 mo vs. 11.3 mo for patients receiving or not receiving the therapy, respectively) in VISION and 3.6 mo (14.9 mo vs. 11.3 mo) in ALSYMPCA. Besides, although the authors of the VISION study did not present the results of subgroups with and without visceral metastases, in the supplementary appendix of the study (3) the authors presented the survival results in subgroups with and without liver metastases and showed that there is no statistically significant difference in overall survival in the subgroup with liver metastases. These findings, in my opinion, are worrisome and suggest that the main effect of ¹⁷⁷Lu-PSMA-617 in overall survival could be due to its action on bone metastases and not on visceral metastases.

Therefore, presentation of the survival results by subgroups will be essential to define the patients who would most benefit from ¹⁷⁷Lu-PSMA-617 therapy and to further establish the best theranostic algorithm to treat these patients (e.g., patients with exclusive bone disease would first receive ²²³Ra, and patients with visceral disease would first receive ¹⁷⁷Lu-PSMA-617). Last, it is important to say that ²²³Ra therapy is already a reality in several places around the world whereas ¹⁷⁷Lu-PSMA-617 is a distant vision; thus, to move from ALSYMPCA to VISION, VISION has to show where it is really effective.

• © 2022 by the Society of Nuclear Medicine and Molecular Imaging.

• Revision received September 3, 2021.
• Accepted for publication September 8, 2021.