Urologists Adapt Treatment Paradigm to Incorporate Novel Agents in mCRPC

Raoul S. Concepcion, MD, FACS

Since 2010, the FDA has approved several therapies to treat patients with prostate cancer, including the immunotherapy sipuleucel-T (Provenge), cabazitaxel (Jevtana), and the androgen axis modulators abiraterone acetate (Zytiga) and enzalutamide (Xtandi). Two bone-targeting therapies have also recently emerged—denosumab (Xgeva) and radium-223 (Xofigo). Denosumab was approved for the prevention of skeletal-related events, and radium-223 was approved for the treatment of metastatic castration-resistant prostate cancer (mCRPC) in men with symptomatic bony metastases with limited soft tissue involvement.

With the advent of new therapies approved to treat prostate cancer, what impact does this have on urology?

In an interview during the 2015 Large Urology Group Practice Association (LUGPA) Meeting, Raoul S. Concepcion, MD, FACS, director of Advanced Therapeutics at Urology Associates, PC, discussed novel therapies for treating mCRPC and deciding which patients are appropriate candidates.We have had five or six new agents that have been specifically approved for this very difficult population of patients with mCRPC. The beauty about that is that all of these therapeutics have a survival benefit and the delivery of these therapeutics actually can be done by the urologist. However, it does take a well-motivated urologist or urology group to go ahead and adopt and adapt that treatment paradigm.

Traditionally, urologists have not tended to manage the patients once they failed androgen deprivation therapy because prior to 2010, there was only traditional cytotoxic chemotherapy, which the vast majority of the urologists in the country did not deliver. So those patients always went to medical oncology or worst yet, never got treated.

What is the appropriate sequence of treatment and how do you choose which therapy to initiate with?

With all the new therapeutics, it is incumbent upon the urologist to identify these patients early. If they want to start therapy, which I believe we should as a specialty, then we need to identify these patients early and institute treatment. If, as an individual or as a group, you don’t want to treat because you feel like it’s not within your wheelhouse, then at least identify the patients and then get them to a medical oncologist so that the patient can be treated. It is incumbent, again, upon us. We are taking care of these patients, and it would be unconscionable to not offer these patients some types of therapies.Most of us try to go by guidelines, and the ones that most everyone in the United States tends to utilize are National Comprehensive Cancer Network (NCCN) and American Urological Association (AUA).

How do you decide when to combine therapies, and how do you choose combinations?

For the most part, if you have a patient with asymptomatic mCRPC who has a great performance status and who has a life expectancy greater than 12 months, standard of care should be continuation of androgen deprivation therapy. If they have bony metastases, one should consider bone-targeting therapy like denosumab. Sipuleucel-T is a therapeutic vaccine specifically geared for mCRPC.All the studies have been done, essentially, not in combination with other drugs. They’re all monotherapy trials, single-agent trials, and no one really knows the best combination. Most of the time, we believe that if the patient starts to get symptomatic, there are many factors that come into play. Was there progression on imaging? Does the patient have more bony metastases? Does the patient have visceral metastases, lung, liver, or soft tissue? How rapid is the PSA going up? You have to take all of that into consideration and it’s not just PSA.

If the patient is clinically worsening, if they have more symptomatic bone pain, the urologist might consider the addition of radium-223 but you have to have an understanding that that drug is only going to help with bony metastases because it’s a calcium-mimetic agent. If the patient is symptomatic, you can still use that drug, but you may have to also consider the use of external beam to a particular area if that is truly what’s causing the pain.

How do adverse events associated with these therapies affect treatment plan?

If the patient has progression, more soft tissue disease, worsening bony disease, and the patient is somewhat resistant to traditional cytotoxic chemotherapy, some of the oral agents—abiraterone acetate, an androgen synthesis inhibitor, as well as enzalutamide, an androgen receptor blocker—both can be used.If you have a patient who has some history of neurologic disorders, has had a stroke, has had seizures, or maybe some element of dementia, more than likely enzalutamide is not going to be the appropriate agent because it does have some central nervous system (CNS) effects. Abiraterone may be a better choice for that patient.

Are any there any ongoing clinical trials that look promising?

On the other hand, if you have a patient with congestive heart failure, hepatic dysfunction, out of control blood pressure, or difficult-to-control blood pressure, abiraterone may not be the appropriate choice. I think it’s important for the urologists as they manage these patients to understand these drugs and the mechanism of action. And, more important, they have to understand the adverse effect profiles because one agent may not be the best for a particular patient’s comorbidities and it may actually worsen the patient’s quality of life.There are a tremendous amount of clinical trials going on in every little space of prostate cancer. We have two or three global trials that are looking at the M0 space in those patients with mCRPC who do not have demonstrable radiographic evidence of spread. That’s a very difficult patient to treat because none of the therapies that are currently approved that have a survival benefit in the M1 space are approved in the M0 space. So that’s index patient 1 in the AUA guidelines, and that’s the M0 space in NCCN, and all we can offer them are clinical trials versus observation.

There are a number of new novel molecules that are being looked at in terms of the M1 space. Probably the biggest one is a drug called galeterone. Galeterone is a unique molecule in that it has some properties that are very similar to abiraterone acetate and enzalutamide. But it also has this third property that could lead to degradation of the androgen receptor. The agent is under development by Tokai Pharmaceuticals. It possesses a unique dual mechanism of action, acting as both an androgen receptor antagonist and an inhibitor of CYP17A1, an enzyme required for the biosynthesis of the androgens.