This is a relatively typical case one might see in a urology or even a radiation oncology clinic: a 62-year-old man who&rsquo;s physically active. He has got some cardiac risk factors. He&rsquo;s diagnosed with a Gleason-7 prostate cancer, a moderately high PSA. He undergoes radical prostatectomy and he has an extra capsular extension, and that puts him at risk for relapse. And so, with a detectable PSA after radical prostatectomy, and in some cases even without a detectable PSA, men will undergo salvage radiation therapy or adjuvant radiation therapy, depending on whether they have a detectable PSA.

So, this patient did that and also received androgen deprivation therapy with his radiation. Now, the use of androgen deprivation therapy with radiation is a little controversial because we don&rsquo;t have a significant amount of granular data on the duration and the type of it. There are some data that suggested maybe some patients get bicalutamide alone at 150 mg, and very little level 1 data looking at leuprolide, as is done in that case. That said, it&rsquo;s very common to do it and I do it as well, because we know that the use of hormonal therapy with radiation therapy is generally more effective than radiation alone.

Most patients who present with early prostate cancer don&rsquo;t have any symptoms. They are found to either have a prostate nodule when their primary care physical does a digital rectal exam, or they have an elevated PSA. Those who do present with symptoms typically will have lower urinary tract symptoms, difficulty voiding, getting up at night to urinate. Sometimes there can be blood in the urine or the semen, but generally, patients are asymptomatic or do not have symptoms.

This patient&rsquo;s initial testing consisted of a prostate biopsy and a PSA test. We don&rsquo;t know if other things were done. Many patients nowadays are trying to make a decision about what type of treatment to have. Doing scans for metastatic disease is quite common. This patient&rsquo;s at very low risk for metastatic disease so it&rsquo;s not a problem that he did not have a bone scan, for example. There are a series of newer generation genomic tests that can be done in localized prostate cancer that might help determine a patient&rsquo;s risk of recurrence after radical prostatectomy, for example. But those are still in development in some cases, and many urologists are perfectly fine making treatment decisions without the use of those tests.

This is a very typical treatment course. He&rsquo;s a young man with a healthy lifestyle for the most part and he&rsquo;s a surgical candidate. And so, those are patients who could and should be offered surgery and they typically do very, very well. In the hands of an experienced surgeon, many patients will end up with preserved erectile function and preserved urinary continence, although maybe it&rsquo;s not perfect. But I do agree with the radical prostatectomy in this setting. I further agree with the use of hormonal therapy in the context of salvage radiation therapy, which was given to this patient.

Generally, once patients start ADT, I&rsquo;ll see them every 3 months and we&rsquo;ll do a PSA test every 3 months. There&rsquo;s a lot that can happen with a patient on ADT. It&rsquo;s not just about bringing down the PSA. You&rsquo;re taking a man at the age of 62 in this case and you&rsquo;re reducing his testosterone by 90%. Now, most men have relied on testosterone for a variety of life events and life functions, if you will, since puberty. And so, many patients undergo a pretty profound change when this occurs. They can gain weight, they can experience osteoporosis, and they can get diabetes, which is a known risk of androgen deprivation therapy. Their cardiac risk factors may worsen.

This is a patient, for example, in our case who has some cardiac risk factors. So, if he starts to gain weight as a consequence of his androgen deprivation therapy, we may worsen that cardiac risk. There are potential cognitive changes that can occur. There are potential psychological and even psychiatric changes that can occur. So, I believe it&rsquo;s actually, while it seems like a benign treatment for the most part, important to get to know your patients and see what their journey is like on androgen deprivation therapy.

Surprisingly, some patients have almost no problem with it and they breeze through it. And even some patients say they feel better on androgen therapy paradoxically. But there are patients who experience real problems from itdepression, mood swings, those types of things&mdash;and it&rsquo;s important to identify who they are.

Nonmetastatic CRPC: Initial Therapeutic Approach

So, 1 year after starting ADT, this patient&rsquo;s PSA rises to 12. And that&rsquo;s fairly aggressive I would say because 12 is a pretty high number, this quickly, and a year is a relatively short period of time. In our CRPC studies, for example, the median duration the patients have been on ADT before they get CRPC is somewhere between 4 and 6 years. So, this patient probably has an underlying disease forming. Just based on the fact that his PSA went from almost 0 to 12 in a year means he has a rapid PSA doubling time. He underwent a next-generation scanning modality with fluciclovine. He was found to have 1 pelvic node.

So, here&rsquo;s the challenge with this patient. We know that there&rsquo;s likely to be cancer in that 1 pelvic node, but we don&rsquo;t know if all of the cancer is in that 1 pelvic node. And so, the consequence is that he probably does have tumor cells elsewhere. If we were confident that he only had cancer packed into that 1 node, we could argue to do surgery or radiate that node and eliminate it, but the reality is he probably has bone marrow-based disease that isn&rsquo;t quantifiable enough with a scan. And so, he has nonmetastatic castration-resistant prostate cancer, assuming that we check his testosterone is less than 50, which I&rsquo;m sure it is if he has been receiving the leuprolide.

Castration resistance is a term that replaced the old term, which was hormone-refractory prostate cancer. And the reason why we use this term is to imply that the disease has become resistant in the context of a castrate level of testosterone. Some people think it means we&rsquo;ve done surgical castration, which we have not. It simply refers to the level of testosterone being under 50. And so, that is a term that entered the clinical lexicon, with the FDA approval of abiraterone and the FDA approval of enzalutamide, because those studies, in a way, told us that hormone therapy can work in this setting. Therefore, it made the phrase &ldquo;hormone refractory of prostate cancer&rdquo; seem like a contradiction in a way.

Currently, there are no FDA-approved therapies for nonmetastatic prostate cancer. Typically, patients will maintain their androgen deprivation therapy, whether it be an LHR agonist or antagonist, and may cycle through a variety of secondary hormonal agents, such as bicalutamide, nilutamide and other things, none of which have been shown to be associated with a survival benefit. The arrival of next-generation androgen receptor antagonists will be a welcome addition to the pharmacopeia in this group of patients insofar as it may allow them to be treated with a well-tolerated treatment that will prevent metastasis from forming and preserve their status as nonmetastatic.

For patients with nonmetastatic castration-resistant prostate cancer, I typically look at the pace of change of the PSA. I use PSA doubling time as a marker. In this case with this patient, he has a pelvic lymph node. If his PSA were going up slowly and he just had the 1 pelvic lymph node, we might argue to maybe treat this with radiation. But this patient&rsquo;s PSA is going up very quickly and it&rsquo;s almost exponential. And in that case, I generally think exponential rise is associated with systemic disease, and probably not something that will benefit greatly from local therapy. So, in a situation like this, I would consider treating this patient with a systemic therapy, if I have one, and it typically would be a secondary hormonal therapy.

I think, currently, next-generation AR-targeted agents are considered a standard of care. I refer to enzalutamide, which actually targets the androgen receptor. We have apalutamide, which we&rsquo;re expecting will become available, a very active drug that looked really good in phase I and II trials. Darolutamide similarly looks very good in the phase I and II trials and is in phase III studies.

So, I think the future for the management of this disease will be the selective use of AR-targeted drugs in patients with nonmetastatic disease, based on a risk profile that&rsquo;s likely to be based mostly on their PSA doubling time and other factors that could arise, such as genomic profiles and things like that.

Current and Future Therapies for Nonmetastatic CRPC

ARN-509, now known as apalutamide, is the derivative of bicalutamide that has a much greater potency against the androgen receptor, and, in fact, was specifically designed to target the amplified androgen receptor. As the disease progresses, in about 75% of cases, the androgen receptor will amplify. And so, that&rsquo;s the critical biological link, in a way.

The early phase I and phase II data with apalutamide suggest a very high rate of clinical response in terms of PSA reduction in the castration-resistant prostate cancer setting. Limited efficacy, but some efficacy, in patients who have abiraterone-resistant disease. But probably its greatest efficacy is demonstrated in patients with nonmetastatic castration-resistant prostate cancer, as well as those with metastatic castration-resistant prostate cancer who have not received prior therapy with either abiraterone or enzalutamide.

The SPARTAN trial is a randomized phase III placebo-controlled trial of apalutamide versus placebo in nonmetastatic castration-resistant prostate cancer. The reason that a placebo was used is that there is no standard of care in the nonmetastatic prostate cancer, and at least in the eyes of regulatory authorities, observation or surveillance is the standard of care in that group of patients. So, this is testing whether integrating apalutamide earlier in the clinical course will lead to an improvement in metastasis-free survival as the primary endpoint and overall survival as the secondary endpoint. The study is fully accrued. We expect data relatively recently demonstrating how and what extent apalutamide may affect metastasis-free survival in this group of patients.

The treatment of nonmetastatic castration-resistant prostate cancer really has 2 goals. One is to improve overall survival in the long run, but in doing so, it would be nice to preserve a metastasis-free state. The development of metastasis is really the development of a lethal phenotype of prostate cancer. It&rsquo;s very disconcerting and troublesome for patients. It can lead to pain, it can lead to fractures, and it can lead to all kinds of comorbidity or morbid complications. And so, by preventing those from happening, or delaying that even, we can improve the clinical benefit for our patients. So, the goal of using metastasis-free survival is an intrinsically good goal, I think, in that we are preserving patients in a metastasis-free state.

My counseling with patients in this setting is the use of therapy centers around what I call the 3 Ps: preventing metastasis, preserving good function and good quality of life, and prolonging life. And if we&rsquo;re able to achieve all 3 of those Ps, if you will, with 1 therapy, it will represent a significant new benefit on a significant new addition to the pharmacopeia for castration-resistant prostate cancer.

The approval of apalutamide will make available the treatment in a space where there was no treatment previously. There&rsquo;s really no better way to put it than that. It will also bring into the clinic a second AR-targeted drug that may have improved safety profile over the prior one, enzalutamide. I think it&rsquo;s important that we study that question. I don&rsquo;t know that it will necessarily improve the sequencing of these drugs because I suspect that clinicians will want to choose either apalutamide or enzalutamide and won&rsquo;t do one then the other. But that question actually remains to be explored, I think. And it&rsquo;s the addition of a new concept in that it&rsquo;s looking at an earlier intervention in castration-resistant disease, and it&rsquo;s moving the therapies progressively earlier and earlier. I think that one of the general trends we see is that as we successfully move therapies earlier and earlier, we actually see greater benefit from those therapies compared to not giving them.

Impact of ARN-509 on Nonmetastatic CRPC Treatment

Nonmetastatic CRPC is being evaluated with a number of different therapies right now. There&rsquo;s apalutamide, an orally available AR antagonist. Darolutamide is another orally available AR antagonist. Abiraterone had been studied in this setting in phase II studies, and enzalutamide has been studied in this setting as well. So, those are the androgen receptor hormonal therapies that are being evaluated. There are a number of other smaller studies looking at different concepts, immunotherapies and things like that, in this setting, but none of them are quite to mainstream clinic yet.

The monitoring of patients with castration-resistant prostate cancer is undergoing a bit of an evolution because we&rsquo;re seeing new generation imaging modalities come to the clinic. So, more specifically, we are very excited about things like the Gallium-68 PSMA-targeted peptides, which help us to lead to targeted imaging of prostate cancer. There are other approaches, fluciclovine and others like that, that are available in many clinics around the country. And so, this is part of the process of evaluating nonmetastatic castration-resistant prostate cancer.

Nonmetastatic castration-resistant prostate cancer exists to some degree because of the failing of our old imaging modalities. And so, the bone scans that we&rsquo;ve used for decades are relatively weak and such, but they&rsquo;re still used. CAT scans are still used. And I would actually add that one of the things I&rsquo;ve noticed is that patients in a variety of clinic settings may have pelvic imaging done, may have bone imaging done, but actually many patients harbor lung metastases. And so, the imaging of a patient who&rsquo;s felt to have nonmetastatic disease should also include a lung CT, at least one, at least at baseline.

I&rsquo;m not sure it&rsquo;s important exactly to know what the training discipline is of the physician treating the patient as long as they understand what they&rsquo;re doing and they have experience doing it. In my clinical practice, I give all the hormonal therapy. I don&rsquo;t really have any competition from urologists in terms of treating CRPC because in my community, that&rsquo;s not what they do. The urologists are well educated on the side effects of therapy and how to monitor them, and on what&rsquo;s available as a therapy for patients. In other words, anybody who&rsquo;s treating a patient needs to know what the alternate treatments that are available and what they&rsquo;re going to do if this patient&rsquo;s treatment fails.

I think that any clinician who is treating castration-resistant prostate cancer now needs to understand the genomic revolution that we&rsquo;re undergoing. They need to know what the genomic findings, if they obtain them from a patient, mean or the fact that they need to think about obtaining genomic findings from their patients because it will alter therapy in the future. And so, whether that patient has an oncologist or a urologist, I don&rsquo;t really care. What&rsquo;s important is the level of experience and the level of knowledge, and I&rsquo;d also say the level of curiosity about the disease. Because this is a fascinating, nuanced and complex disease. And we are going to discover even new personal ways to treat it or new ways to research it, if we&rsquo;re not asking questions and integrating new therapies and modalities into our clinical practice.

Patients with castration-resistant prostate cancer are enjoying the best survival they ever have. They have a number of treatment options available to them. And in addition to seeing new therapies enter the clinic, we&rsquo;re seeing the established therapies demonstrate benefits earlier and earlier in the clinical course, which is going to allow us to give therapies in the context of patients who aren&rsquo;t quite as ill and don&rsquo;t have quite a high degree of tumor morbidity. And so, I think what this will translate into, over time, is a prolongation of the time in which patients are experiencing a preserved quality of life. They&rsquo;re preventing complications and they&rsquo;re going to live longer, and it&rsquo;s very gratifying to be part of that movement.

Therapeutic Approach for Nonmetastatic Prostate Cancer

Nonmetastatic CRPC: Initial Therapeutic Approach

Current and Future Therapies for Nonmetastatic CRPC

Impact of ARN-509 on Nonmetastatic CRPC Treatment

Nonmetastatic CRPC: Other Therapies and Coordinating Care