At the ESMO Congress 2021, we saw a number of studies in progress involving immune checkpoint inhibitors (ICIs). Pembrolizumab is the base, or starting point, for many of these trials in metastatic castration-resistant prostate (mCRPC), and we are looking to see whether there is some evidence of synergy with additional agents, while also examining key patient subsets. PD-L1 and CTLA-4 are probably the best-known ICIs, but others that are being studied include TIGIT and TIM3 inhibitors. The KEYNOTE-365 trial is now up to cohorts G and H, in which pembrolizumab is being paired with a TIGIT inhibitor (abstract 641TiP). When combining ICIs, toxicity is always a concern, but I do think that you see enhanced responses when you block multiple checkpoints and not just 1 checkpoint. We are likely to see more ICI combinations being studied. The combination of cabozantinib with atezolizumab in the COSMIC-021 study continues to generate interesting data, so there may be more to come on that front as well (abstract LBA24). 

These trials point to the fact that we are trying to better understand the immunobiology of advanced prostate cancer so that we can improve our ability to target immune mechanisms and enhance responses. For some time, there has been interest in the possibility that radiation therapy, whether external beam or targeted radioligand, might be associated with neoantigen formation and better responses to ICIs. But, when we seek a rational combination of therapeutic agents acting on different pathways within the tumor, we are looking to avoid overlapping toxicities in the patient. Both radiation and chemotherapy, for instance, may be myelosuppressive; however, there is no such overlap with targeted radioligand therapy and ICI therapy or with targeted radioligand therapy and androgen receptor (AR)–targeted therapy.

Several of the trials in progress shared at the ESMO Congress 2021 built on the VISION trial, which demonstrated a significant survival benefit for lutetium-177–prostate-specific membrane antigen–617 (177Lu-PSMA-617) plus standard of care in the third-line treatment of mCRPC. Information on the randomized phase 3 PSMAddition study (abstract 647TiP), which is investigating targeted radioligand therapy in metastatic hormone-sensitive prostate cancer, and the randomized phase 3 PSMAfore study (abstract 648TiP), which is looking at taxane-naive patients with progressive mCRPC and confirmed PSMA expression, was presented at the meeting. We always start trials of new therapies in second- or third-line mCRPC. Once we show evidence of benefit there, it certainly makes sense to examine these agents in the metastatic hormone-sensitive prostate cancer setting, and that is what the PSMAddition trial is looking at. The randomization will be 1:1 between ¹⁷⁷Lu-PSMA-617 vs standard of care, which will generally be an AR-targeted therapy, with the primary end point of radiographic progression-free survival. The PSMAfore trial is basically the same as VISION, but it includes patients who have not received taxanes and will have received first-line AR-targeted therapy. Patients in the PSMAfore study will be randomized to receive ¹⁷⁷Lu-PSMA-617 vs the alternate AR-targeted therapy. So, the question is: Do you need to have received chemotherapy before you get PSMA therapy?

Many patients do not want chemotherapy or may not be candidates for chemotherapy. However, I think that chemotherapy generally gets a bad rap, and it still has a lot of value. In most situations, I see patients responding very nicely to chemotherapy. That said, I think that PSMA-targeted therapy is a really big advance. The idea is that ¹⁷⁷Lu-PSMA-617 may have comparable efficacy to chemotherapy, and it could potentially have superior efficacy to chemotherapy if you consider comparable patients. And that is different from radium, for example, or drugs such as olaparib, which work well in very small subsets of patients. So, I believe that we are starting to think of ¹⁷⁷Lu-PSMA-617 as a type of “chemo-equivalent” but with higher efficacy potentially better tolerability, and perhaps a comparable speed to benefit, which is important.