Apalutamide Significantly Delays Metastasis in SPARTAN Trial of Nonmetastatic CRPC

Julie N. Graff, MD, Assistant Professor of Medicine, Division of Hematology and Medical Oncology, Oregon Health & Science University Knight Cancer Institute, discusses the promising results of the SPARTAN clinical trial.

Transcript

My name is Julie Graff. I am a prostate cancer medical oncologist, so I don't do surgery or radiation. I treat people typically who have prostate cancer that can't be cured. I work at the Portland VA, and also at Oregon Health & Science University, and I'm a clinical researcher who's trying to find new treatments for prostate cancer.

Unfortunately, some people get their prostate cancer treated by surgery or radiation and then have it relapse. So there are different ways to have it come back. One is you could get tumors in the bones and lymph nodes that you could see on a scan, but more commonly we see the PSA, or prostate-specific antigen, begin to climb. No other organ in your body makes PSA, so when we see it going up we know there must be some prostate cancer still in the body.

We have a couple of imaging techniques that we do to find out if the cancer has spread and to look for tumors, typically in the bones and lymph nodes. We do CT scans and nuclear medicine bone scans.

There are some scans that are more sensitive, particularly for people who have had their prostate removed or had radiation to the prostate and have the PSA climbing back up again—those are PET scans, and some of the newer ones are looking for PSMA, which is a prostate-specific membrane antigen, so it's very prostate cancer specific.

Instead of catching things that are the size of a sugar cube, as the traditional scans do, it might be able to catch things when they're the size of a grain of rice. But a lot of these cancer patients have cancer that's the size of grains of sand that can't be seen by any imaging technique.

Typically, in the United States at least, when we see that PSA climb, especially if it's climbing rapidly, we start patients on therapies to turn off the testicles, which then lowers the testosterone, which is a fuel for these cancer cells. So, for a while that works really nicely.

Typically we give shots in the abdomen or muscle that send a chemical to the brain that ends up turning off the testicles, and at first the PSA goes down, and then, though, over time, those cells can learn how to live on very little testosterone and they start increasing and in that situation we check the serum testosterone. If it's below 50 ng/dL and the PSA's climbing we call that castration-resistant prostate cancer (CRPC), so if there's nothing on the scans and the PSA is climbing despite having a very low testosterone, that's nonmetastatic CRPC.

For many years we didn't have great options, so we've been, over the years, using what we call a first-generation antigen receptor antagonist. There's actually 3 examples of those—bicalutamide, nilutamide, and flutamide. That can help get the PSA back down, but eventually the PSA comes back up anyway, so they're not a great treatment. They're OK. They can cause the cancer to grow sometimes, which is a drawback. So, sometimes when we stop using them the PSA comes back down and starts going up again.

There are also estrogen patches we used to use in this setting, and ketoconazole. Ketoconazole turns off the adrenal glands; this is an old-fashioned fungal medication that can reduce adrenal gland production of male hormones.

Recently, though, the SPARTAN trial and the PROSPER trial have used second-generation androgen receptor antagonists in the setting where people have nonmetastatic CRPC but nothing on the scans.

For these studies the PSA had to be doubling every 10 months or less, because those are the patients who are at higher risk for developing metastases and then dying of prostate cancer. These trials were looking at this patient population. The SPARTAN study allowed lymph nodes up to 2 cm in the pelvis, but otherwise it was fairly similar to the PROSPER study.

The SPARTAN study showed that apalutamide, which is one of the second-generation androgen receptor antagonists, delayed the time to metastatic disease. In this study patients got pills called apalutamide that they would take daily. We would do imaging studies every 4 months. They were blinded to their PSA, so we didn't check PSA, because there were not any other alternative options that were better if the PSA were climbing. It was a good way to keep the study pretty pure.

Two-thirds of the patients got the apalutamide, and one-third got the placebo. They found that getting the apalutamide delayed the time to metastatic disease or appearance on the scans by about 2 years.

That was the first real data we have that these drugs can be very beneficial in the nonmetastatic setting.

We already knew that for people with tumors that you could see on scans that it did help people live longer, bring down the PSA, and even shrink the tumors, but we didn't know that in this setting it was useful.

The primary end point was metastasis-free survival. We showed definitively that it delayed the time to metastases. Then there were some secondary end points that included overall survival, which is a very clinically important end point, and that has not yet been reached. We probably need more time to follow patients before we get the answer to that.

And then they included also this other one called symptomatic progression-free survival (PFS). So, patients with prostate cancer, especially if it goes to the bones, can have pain and other symptoms like that. In the patients who got apalutamide that was significantly delayed. That is clinically relevant.

We've, since the study came out, shown too that the PSAs declined dramatically, which is not too surprising.

Also, there was an end point in the study called PFS2, which is the time from randomization to time of progression on the second treatment following the study treatment. In other words, when patients got the apalutamide and their cancer began to grow despite that, they were put on another treatment option. Same is true for placebo. The PFS2 is longer in the people who got apalutamide, which could suggest that getting it earlier is better than getting it later. That was interesting.

The safety data were very, very important, too, because they showed that they were similar to the other androgen receptor antagonist that was available at the time, called enzalutamide. However, with apalutamide there were more patients who had thyroid dysfunction and rash, so those are a couple things we're looking for carefully.

We're also very concerned about bone health. We know women who go through menopause lose bone density, and men for whom we severely decrease the testosterone also lose bone density and are at risk of fracture. So that's an important thing to look out for.

In the real world patients are getting apalutamide. They're also getting enzalutamide, per the PROSPER study, which I mentioned was similar to the SPARTAN study.

A lot of times it's important for patients. They're very anxious about the PSA going up, which is understandable. It can be a relief to see it go back down with these treatments.

Now we're using enzalutamide in the metastatic and nonmetastatic state. Apalutamide so far is just approved in the nonmetastatic state, and we've learned from this trial what side effects to look for.

We're looking at these results further. Any well-run clinical trial is rich with data and gives researchers an opportunity to ask important clinical questions. So, one thing I'm interested in is how older people do on this drug. I mean, should we be treating an 80-year-old with this treatment, and does that patient benefit? So I hope to learn results of that and present them soon.

There are multiple studies going on with apalutamide in patients who are newly diagnosed with metastatic prostate cancer (they're not castration-resistant, they're just now being diagnosed). A press release says that the apalutamide was beneficial, but I have not yet seen the data.

Then there are studies looking at apalutamide for people who have aggressive localized prostate cancer and are receiving radiation. There's a lot of interest in how apalutamide and other androgen receptor antagonists perform with immunotherapy because there's some data that enzalutamide helps people respond to pembrolizumab, which is the PD-1 inhibitor.