Newer strategies to interfere with androgen receptor (AR) signaling hold promise even in later-stage prostate cancer that is unresponsive to hormonal deprivation, since sustained AR signaling is relatively common in that setting. The combination of AR-targeted agents with poly (ADP-ribose) polymerase (PARP) inhibitors is quite interesting, as PARP inhibitors seem to combine well with AR-targeted agents. Proteins in the PARP family are associated with the regulation of gene expression in prostate cancer, in addition to their role in DNA repair, so there is a preclinical basis for combining them. Combination studies do show a signal that suggests the possibility of synergy. Still, we will need to learn more about which patient groups benefit from combination therapy vs sequential therapy. This is something that is currently unclear based on the available data. 

Combinations consisting of AR-targeted agents plus PARP inhibitors could also be very interesting in earlier-stage disease before castration resistance develops. There is an ongoing phase 2 trial here at City of Hope that is assessing the use of talazoparib with androgen deprivation therapy and abiraterone in patients with castration-sensitive prostate cancer (NCT04734730). 

PARP inhibition with radiation is another very interesting combination because of the double-hit mechanism, whereby DNA damage is induced with the radiation and then the PARP inhibitor blocks its repair. It will be interesting to see combinations such as radium-223 plus PARP inhibition and lutetium Lu 177 vipivotide tetraxetan plus PARP inhibition.

Regarding cotargeting strategies that incorporate immunotherapy, I do believe that there is some truth to the concept that ineffective DNA damage repair may result in more neoantigens, which might make a tumor more visible to the immune system. Of course, the combination of radiation and immunotherapy has long been of interest; for instance, there have been trials assessing stereotactic body radiotherapy with immunotherapy. 

Targeted radioligand therapy with lutetium Lu 177 vipivotide tetraxetan delivers the radiation in a different way. It appears to heat up the tumor immune microenvironment, which may facilitate the development of a more robust antitumor immune response. Aggarwal and colleagues at the University of California, San Francisco have been running a trial with a priming dose of lutetium Lu 177 vipivotide tetraxetan plus pembrolizumab in patients with metastatic castration-resistant prostate cancer. I look forward to those results and to data from other similar studies.

We also know that tumors can lose prostate-specific membrane antigen (PSMA) expression, potentially through a variety of mechanisms. Thankfully, we have the opportunity to target PSMA in the majority of our patients with prostate cancer, as PSMA is still typically an active target when castration resistance emerges. However, where you do lose PSMA expression is in the transformation from prostate adenocarcinoma to neuroendocrine prostate cancer. For those patients with neuroendocrine prostate cancer, which no longer expresses the established targets such as PSMA, other cotargeting strategies are potentially of interest and are being explored. Some examples include carcinoembryonic antigen–related cell adhesion molecule 5 (CEACAM5, also known simply as CEA) and the Notch ligand DLL3. Clinical trials that are seeking to define optimal targets for T-cell redirection using chimeric antigen receptors and bispecific antibodies are underway.