Prostate Cancer Paradigm Expanding With Ongoing Research

Przemyslaw W. Twardowski, MD

While there has been some progress with treating prostate cancer, how to prevent the progression of metastatic prostate cancer is still unclear, according to Przemyslaw W. Twardowski, MD.

While agents such as abiraterone acetate (Zytiga) and enzalutamide (Xtandi), LHRH antagonists such as degarelix (Firmagon), and bone-targeted therapies such as radium-223 dichloride (Xofigo) have led to significant advancements in the paradigm, researchers are continuing to evaluate them in an effort to improve outcomes.

“As good as these drugs are that we have right now, unfortunately, none of them provides a curative effect in metastatic advanced disease,” said Twardowski. “Ultimately, over a period of time, they fail. This is when the patients start developing symptoms and developing new metastatic sites. That’s when we know that the cancer is entering into a more ominous phase—the potentially life-threatening phase.”

OncLive: What are some factors that you take into consideration when choosing which androgen-receptor (AR) targeted therapy is best for patients with prostate cancer?

In an interview during the 2017 OncLive^® State of the Science Summit^TM on Genitourinary Cancers, Twardowski, professor of medical oncology at John Wayne Cancer Institute (JWCI), discussed a variety of factors to consider when treating patients with prostate cancer.Twardowski: That’s a great question and not easy to answer because we don't really have any laboratory molecular biomarkers that would guide us. I sometimes joke that, in many ways, for me, in the regular practice setting, the choice between the key second-generation androgen pathway inhibitors, such as abiraterone acetate and enzalutamide, is almost like flipping a coin, essentially. There are very subtle nuanced clinical factors that may influence one agent over the other.

For example, enzalutamide has been associated with more side effects related to neurological abnormalities like very rare incidents of seizures, falls, and perhaps, a little bit more fatigue. In my practice, certainly in patients who are at risk for these side effects or have a history of seizure, falls, or maybe some performance status issues that may predispose them to that, I would potentially consider using the alternative of abiraterone acetate.

On the other hand, in patients who have brittle diabetes, a history of liver problems, or congestive heart failure, they would potentially sway me to use the alternative drug, enzalutamide. As you can see, those are relatively subtle nuanced clinical factors that can influence the decision making, but, honestly, for a majority of patients, they don’t really apply. We really need better ways to select these agents in an academic institution.

How does degarelix fit into the paradigm?

In many cases, we are also influenced by potential availability of subsequent clinical trials, so that may also play a role in consideration. For example, we have clinical trials that particularly look at patients who are failing abiraterone acetate therapy. That may sway us to use that agent versus the other one, but that may not apply, of course, to the community setting that much.That’s also a very good question. Degarelix was approved in 2008 for the treatment of patients with prostate cancer. It is an agent that blocks the production of testosterone in the testicle in a slightly different way that may be more like traditional, older-generation agents. The main difference, without going into details of the pathophysiology of degarelix, is that degarelix causes more rapid suppression of testosterone production in the testicle. It is usually within 1 or 2 days versus 10 to 20 days for these other agents.

Also, the other agents tend to have this paradoxical effect initially that they cause what is called “testosterone surge,” which is the initial increase of testosterone that takes place over a few days. Then, ultimately, testosterone goes down. However, in this initial period, that may be detrimental—especially in patients who have very large-volume metastatic disease symptomatic perhaps at risk of spinal cord compression or urinary retention.

That leads me to the logical conclusion that, in those kinds of patients with high-volume metastatic disease who are at risk of significant deterioration through that initial testosterone surge process, I would potentially favor degarelix. Now, in the long run, it’s a very debatable question whether degarelix provides any long-term advantage over agents like leuprolide or goserelin. It’s slightly less convenient because it only comes in monthly injections versus longer-acting injections. One strategy would be to use degarelix initially in these patients and then switch them to more traditional agents.

If a patient is progressing while on treatment, what factors do you consider when switching their therapy?

There are some studies going on also looking at potential slight differences in the long-term side effect profile, particularly as it relates to risk of cardiovascular disease. There is some theoretical consideration that degarelix may provide some advantage; however, so far, it is not proven. There’s an ongoing randomized study looking specifically at that question. That will be very important to find out.This is obviously a typical scenario, unfortunately, for medical oncologists who deal with patients with advanced prostate cancer. There are many considerations. We obviously have some preconceived notion about what kind of sequence of drugs we're going to be using, but it is very flexible. We have to adapt to the circumstances, so there are many factors.

First, what were the prior agents that the patients received? For example, there is now quite compelling evidence that if the patient failed one of the second-generation androgen-pathway inhibitors—either abiraterone acetate or enzalutamide—going with the other agent in symptomatic patients is probably not a good idea because the response rate is very low. If I know that somebody already received abiraterone acetate and is developing symptoms, I would not go with enzalutamide and vice versa. That’s one factor.

The other one is the extent of disease. The extent of symptoms and location of the metastasis in somebody, for example, who has exclusively bone metastatic disease that is symptomatic, those patients may respond and benefit from treatment with a radioactive isotope, such as radium-223. That would be certainly a strong consideration.

On the other hand, for patients who have bulky adenopathy, then radium-223 would not provide adequate coverage of these areas because it exclusively targets bone metastasis. Then, I would prefer a chemotherapy agent like docetaxel.

The third potential clinical scenario would apply to the circumstance where patients, for example, developed liver metastasis. This is a relatively rare event in prostate cancer, and may have relatively low prostate-specific antigen level, that would potentially raise some red flags about the development of a neuroendocrine or small cell phenotype of prostate cancer. In those kind of cases, I would strongly consider biopsy of the liver metastases to allow the presence of a neuroendocrine component that, if present, would dictate different chemotherapeutic choices based on platinum-based combinations. Of course, now we are increasingly beginning to look at genomic characteristics of tumors.

What additional research with PARP inhibitors is ongoing that could change clinical practice?

It is not as prominent and widely used yet because we don’t have specific therapies outside of clinical trials for that; however, there is a lot of excitement about DNA-repair mutations. There are potential implications for treatment on clinical trials with PARP inhibitors, such as olaparib (Lynparza) or niraparib (Zejula), from that class. Certainly, if I see that the patient is beginning first- or second-line therapy for metastatic castration-resistant prostate cancer (mCRPC), [I am] beginning to think about a sampling of the tissue for genomic sequencing to look for these rearrangements in the pathways of DNA-repair genes and hypermutated phenotypes that may potentially predict response to PD-1 inhibitors. That’s a rare phenomenon, but, nevertheless, it happens in the few percentage of patients.Definitely. If I were to choose one class of agents [that could change practice] in prostate cancer, it would be PARP inhibitors because there is very solid early phase II data of activity in patients who harbor mutations in the DNA-repair gene pathways. Those are genes like BRCA1/2, ATM, and FANCA. They’re present in about one-quarter of patients with mCRPC. We're seeing robust responses with PARP inhibitors in these patients. If I were to guess, that category will change the practice over the next couple of years in this selected group of patients.

What research are you currently involved in that you would like to share?

Immunotherapy is a bigger question mark. As great as PD-L1 inhibitors have been in many other tumor types, they haven’t really shown a lot of activity in prostate cancer; however, we're certainly not giving up on that area of development. Probably, if that pans out in the future, it will have to be in the context of combination therapies that will somehow change the immune environment of the prostate cancer and make it more susceptible to PD-1 inhibition—but the jury is still out on that.I’m interested in the concept of more aggressive therapy of patients who present with so-called oligometastatic prostate cancer. That refers to this group of patients who we frequently see in the clinic that have maybe 1 or 2 metastatic sites on even the most sophisticated imaging scans.

What is the prevalence of oligometastatic prostate cancer?

We still traditionally treat these patients the same way as when somebody has more extensive disease with hormonal therapy and maybe the addition of a second-generation hormone agent or chemotherapy. Nevertheless, there is a strong interest in more aggressive local therapy for that situation with stereotactic radiosurgery (SRS) and maybe incorporation of other investigational agents like immunotherapy or radium-223. I’ve been working on a clinical trial that will attempt to address that particular scenario.It’s been around for quite a long time in prostate cancer. It’s kind of the subject that’s resurrected periodically. Right now, what’s more exciting about it is that we have better imaging. We are getting a little bit more confident that these small metastases that are detected on these super sensitive imaging tests, such as certain types of PET scans, may select some patients with very low-volume metastatic disease that may benefit. Of course, “may” is a big operative word here for more aggressive local therapy.

We will be looking at the addition of radium-223 in the early setting of the metastatic disease to the bone especially, and then following that with SRS to all these visible areas. We'll look at the signal of activity.