AR Therapy Early Intervention & The Future of CRPC Treatment

Neeraj Agarwal, MD:A question often arises: If these drugs are already approved for castrate-resistant metastatic prostate cancer, why should we use them early on—whether for the nonmetastatic state or for hormone-sensitive or castration-sensitive prostate cancer? I think we have seen a very consistent theme emerge from multiple trials over the last 60 years. The earlier we use these drugs, the higher the magnitude of improvement in overall survival and progression-free survival. If you use these drugs earlier, does the biology get refactored in a way for which there’s a higher magnitude on survival impact or magnitude of improvement in survival? The answer is likely yes.

As we can see, if you look at enzalutamide in the castrate-resistant prostate cancer setting, in the castrate-resistant metastatic prostate cancer setting, the progression-free survival is in the range of 12 to 14 months. And it may be even less in the real-world setting.

But if you move enzalutamide to the nonmetastatic castrate-resistant prostate cancer setting, we see almost a 22-month improvement in delay of metastasis, which by the way, we don’t want in our patients. So you move this drug, or apalutamide, up front to nonmetastatic CRPC, and certainly you see the magnitude of progression-free survival going up. We are seeing the same thing with hormone-sensitive metastatic prostate cancer.

When we move to frontline use in the castrate-sensitive metastatic prostate cancer setting, we see an even higher magnitude of improvement in overall survival and radiographic progression-free survival. So I think there is no doubt in my mind that these drugs work best when used earlier in the course of disease.

Six years ago, when we saw enzalutamide [and] abiraterone getting approved for castrate-resistant prostate cancer, there was a lot of excitement. Now we have drugs that are not chemotherapy and that have meaningful impacts on survival and quality of life for our patients. But now we are seeing these drugs move up. A few months ago, apalutamide showed a tremendous improvement in overall survival and radiographic progression-free survival in castrate-sensitive metastatic prostate cancer. Enzalutamide did exactly the same thing. So all these drugs are moving upstream, to be used either in hormone-sensitive or castrate-sensitive metastatic prostate cancer, or nonmetastatic castrate-resistant prostate cancer.

This is great news for our patients because these drugs are definitely improving survival in a very meaningful fashion when used earlier in the course of the disease. But that also poses new challenges for us, such as what to do with the patient who was progressing on these up-front intensified therapies. It’s great that they’re living much longer, but unfortunately, none of these drugs is curative. All these patients are going to have disease progression on these newer agents, and now we are dealing with a space of castrate-resistant metastatic prostate cancer with much more limited options, because these drugs are moved to the up-front setting.

We have very limited options right now, in the form of chemotherapy with docetaxel or radium-223, which is a great drug in my view. It is very meaningful and clinically significant. There is a statistically significant improvement in overall survival, but I would say meaningful improvement in delaying skeletal events, fractures, and pain. So these are good drugs, but these are not sufficient for our patients.

Even though we do not have anything approved yet, the field is rapidly evolving. There are multiple phase III clinical trials going on using a new class of drugs known as PARP [poly (ADP-ribose) polymerase] inhibitors. These enzymes are critical for DNA repair in patients who harbor DNA repair defects in their tumors. But also, based on recent data, these drugs may have efficacy in patients who do not have traditional DNA-repaired defects in their tumors. And there are multiple clinical trials going on using these newer agents known as PARP inhibitors, such as talazoparib, in combination with enzalutamide. There is a phase III registration trial. There are other trials going on combining olaparib with abiraterone. Now there are many other drugs. So this is 1 class of drugs.

But then there is another class of drugs, which is already being used in many other settings but has not been able to garner approval in prostate cancer yet: immune checkpoint inhibitors. There are multiple clinical trials going on using immune checkpoint inhibitors, also known as PD-L1 [programmed death-ligand 1] or PD-1 [programmed cell death protein 1] inhibitors, such as nivolumab, pembrolizumab, atezolizumab. These drugs are used either alone or in combination with PARP inhibitors or traditional androgen receptors. These trials are ongoing right now, and we hope to see very exciting results in the next 1 or 2 years.

There are other drugs that are also on the horizon, known as PSMA [prostate-specific membrane antigen]—targeting agents. PSMA is a known target in prostate cancer, and we have not been able to utilize this target in the treatment of our patients. There are multiple agents that are being utilized, that are being tested right now targeting PSMA, either in the form of radionuclide drugs or in the form of immunotherapy targeting PSMA.

I think this is just a beginning, just a start. There are many other drugs already in phase I trials. There are the newer androgen receptor inhibitors. As I said earlier, the androgen receptor remains the driving force, even during castrate-resistant prostate cancer. And newer mutations of the androgen receptor, or newer forms of the androgen receptor known as androgen receptor variants, need to be targeted. And there are drugs that are already being tested in earlier trials targeting these newer forms of more aggressive forms of androgen receptors.

To summarize, there are many different classes of drugs, such as PARP inhibitors, immune checkpoint inhibitors, newer PSMA-targeting agents, and newer androgen receptor inhibitors, in advanced forms of development. We will see them get approved, or at least some of them get approved, in the very near future, and they will likely, again, lead to a dramatic turnaround in the prognosis of our patients.

Transcript edited for clarity.