ESMO 2021: Discussion on the PRINCE Trial of 177Lu-PSMA-617 in Combination With Pembrolizumab for Metastatic Castration-Resistant Prostate Cancer

( Following the presentation from Dr. Sandu of the preliminary results of the PRINCE trial of 177Lu-PSMA-617 in Combination with Pembrolizumab for Metastatic Castration-Resistant Prostate Cancer (mCRPC), Dr. Mateo provided an invited discussion to contextualize these results in the Proffered Paper session of the European Society for Medical Oncology (ESMO) Annual Congress focusing on prostate cancer genitourinary tumors.


Dr. Mateo began by discussing the principles underlying drug combination studies. We may expect that the combined effect can be additive or potentially synergistic. Synergy occurs where there is biological cooperating, prevention or reversion of resistance, an induced increase sensitivity, or a synthetic lethal interaction. In the context of the PRINCE trial, we anticipate a synergistic effect in which the Lu-PSMA-617 may increase the neoantigen load and thus, increase the efficacy of immune checkpoint inhibition using pembrolizumab. Both TheraP and VISION have demonstrated the single agent activity of Lu-PSMA-617 whereas pembrolizumab has shown relatively limited single agent activity in advanced prostate cancer with PSA50 response rates of 6% and RESIST objective response rates of 5% among nearly 200 patients.


Thus, the hypothesis tested in PRINCE is that the radiation delivered to the tumor from use of Lu-PSMA-617 can potentially induce immunogenic cell death that may be enhanced by immune checkpoint inhibition. Assuming this basic premise is valid, a number of further questions arise including:

- how much tumor cell damage/death is required and over what duration?
- how do we measure this effect?
 - does this effect apply to all tumors equally?
- and, what improved anti-tumor effect should we anticipate?

Given that one of the included agents in the combination has single-agent activity, Dr. Mateo emphasized that we will need randomized to truly elucidate the efficacy of the combination regime and prove the biologic interaction of the combination.

Dr. Mateo emphasized the importance of the serial biopsies and blood specimens performed in the context of the PRINCE trial, as these samples will all for future study that will help to address many of the above questions.

Dr. Mateo further emphasized that patient selection in the context of the PRINCE trial depended on both PSMA-PET/CT and FDG-PET/CT, in keeping with the methodology of TheraP but differing from that of VISION. In terms of the efficacy co-primary endpoint, a PSA50 response was seen in 73% of patients and an objective response rate per RECIST v1.1 was 78%. He emphasized that this 73% PSA50 response rate was similar to the 66% rate observed in the Lu-PSMA-617 monotherapy arm of the TheraP trial and higher to the rate reported in VISION.

Further, rates of primary resistance appeared to be similar between PRINCE, TheraP and VISION. This is in keeping with the hypothesis that the efficacy of the combination approach depends on the initial Lu-PSMA-617 radiation induced tumor cell death.


Dr. Mateo further highlighted that the follow-up in this trial is, to date, short. Thus, the right side of the PFS curve remains to be defined. He suggested that a number of potential outcomes are possible – including those similar to Lu-PSMA-617 monotherapy. However, he was hopeful the potentially we may see a small right tail with long term responses or potentially even a general delay in progression with the addition of pembrolizumab. He emphasized that, while the true efficacy will need to be demonstrated by a randomized trial, these clues can help support (or not support) such a study.

Dr. Mateo further highlighted a number of other treatment combinations in this disease space including work from Dr. Aggarwal with the use of 117-Lu-PSMA and pembrolizumab (though their approach used a single dose of Lu-PSMA), from Dr. Fong with Radium-223 and atezolizumab, and from Dr. Kwan with stereotactic body radiotherapy and avelumab. Comparisons of these trials may help understand the importance of radiotherapy dosing and immunotherapy action in this disease space.

In conclusion, Dr. Mateo highlighted that there are preliminary results, they provide a proof of concept that may (or may not) support further exploration of this approach based on ongoing follow-up.

Presented by: Joaquin Mateo, MD, Ph.D., Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain


Related Content: ESMO 2021: PRINCE: Interim Analysis of the Phase Ib Study of 177Lu-PSMA-617 in Combination With Pembrolizumab for Metastatic Castration Resistant Prostate Cancer