When we begin to think about what is novel, it is always in the context of the period or era, and that goes all the way back to 1941 and traditional hormonal therapies and androgen deprivation. Later, chemotherapy was introduced, with some modest survival gains. From there, we moved forward with a whole multiplicity of different therapies, probably the most impactful of which have been the modern androgen axis-targeted agents. First there was abiraterone, followed by apalutamide and darolutamide. So now we have these novel androgen receptor antagonists, and, as good as they are, they are not really the big innovations. 

Beyond the chemotherapy and hormonal axis, we began to explore the immune axis, going back to 2010 in prostate cancer. In 2013, radium-223 was introduced after it was shown to prolong survival. Then, in 2018, we had something a bit different. At that time, we had the understanding that patients could actually have quite a profound response to treatment if the tumors had a mismatch repair deficiency. In particular, pembrolizumab was US Food and Drug Administration (FDA) approved in a tumor agnostic manner, with prostate among the indications. 

More recently, we have been making a lot more progress in metastatic castration-resistant prostate cancer, and this is where some of the more exciting therapies have arisen. First of all, we learned that approximately 20% of patients with advanced prostate cancer may have either somatic or germline mutations having to do with DNA repair. We can now target that with the FDA-approved poly (ADP-ribose) polymerase inhibitors rucaparib and olaparib. 

Now, the latest new kid on the block is not FDA approved, but a positive trial presented at the recent 2021 American Society of Clinical Oncology Annual Meeting shows promise. The VISION trial examined the prostate-specific membrane antigen (PSMA)–targeted radioligand therapy lutetium-177 (¹⁷⁷Lu)–PSMA-617. The study selected patients who were PSMA positive without other significant disease in the viscera. All of these patients had failed traditional androgen deprivation therapy with either abiraterone, enzalutamide, or apalutamide and 1 or 2 taxanes. So, this is a very difficult-to-treat patient population; these are patients who have pretty much run out of treatment options. Patients in this study benefited from ¹⁷⁷Lu-PSMA-617, with overall survival extended to 15.3 months for ¹⁷⁷Lu-PSMA-617 vs 11.3 months with the standard of care alone. In my opinion, this is going to be approved by the FDA, as we have a survival benefit in a prospective randomized trial of 131 patients. 

PSMA positron emission tomography–based imaging has given us much more insight into the extent of disease either before treatment in high-risk patients or at the time of biochemical relapse in men previously treated with surgery or radiation therapy. Many of these patients, it should be noted, were treated by empirical paradigms. I believe that PSMA is giving us much more knowledge about the true extent of disease.

I also think that the data from the VISION trial is very exciting. In this patient population, the median 4-month overall survival is significant. The trial probably does not even reveal or indicate what the full impact of ¹⁷⁷Lu-PSMA-617 will be in prostate cancer in the years to come. Like most things in advanced prostate cancer, what we will see is a migration downward for this form of treatment, similar to what we have seen with enzalutamide and abiraterone. I think that this type of targeted therapy will become more common in earlier stages of disease. 

The idea that we may be able to upregulate PSMA expression in prostate cancer cells by using oral agents is also exciting, and this is currently being studied. If successful, it could take PSMA-based imaging tests and targeted radioligand therapies such as ¹⁷⁷Lu-PSMA-617 to the next level. And that is just one agent—there will be other agents that will follow soon. Given all of these advancements, I am actually quite upbeat about this technology. And I think that we will see it used earlier and more selectively in the future.

Both Dr Sartor and Dr Carroll gave really great overviews and complementary coverage on the key innovations. I would add that we have seen more and more therapies that are getting FDA approval for advanced prostate cancer, typically at the late stages of this disease, in patients who have already been previously treated with a number of prior therapies. And I think that one of the things that we are going to be looking for in the future is combination or layered therapy. It is just not going to be possible to provide patients with the advantages of all of these treatments one at a time. We will need to understand how we can safely layer various treatments together, either concomitantly or using some type of strategy in which the next therapy is started before the last agent is completed.

There is also a concept that is more often associated with other malignancies, including hematologic malignancies, that I would like to see us try to develop a bit more in prostate cancer. And that is the idea of getting patients down to a minimal residual disease state. We talk about PSMA as an imaging biomarker, and now we are exploring things such as circulating tumor DNA, circulating tumor cells, and methylated RNA products. These are all potential markers that might be used to characterize a minimal disease state in prostate cancer. Tools such as these, together with the many emerging treatment options, may allow us to begin to treat patients down to a minimal disease threshold. And as we see newer modalities like radionuclides, PSMA-targeted radionuclides in particular, entering into this space, it is possible that in the future they could be part of a strategy to help us achieve that goal.