Oliver Sartor, MD, is the Laborde Professor of Cancer Research at Tulane School of Medicine in New Orleans. He was a co-principal investigator and senior author on three Phase 3 trials leading to the FDA approval of new drugs for metastatic castration-resistant prostate cancer (mCRPC)

These include the randomized trial with samarium-153 EDTMP in bone-metastatic prostate cancer, the TROPIC trial, which compared cabazitaxel and mitoxantone (both in combination with prednisone), and a trial comparing radium-223 with placebo. Radium-223 was approved in May 2013 for the treatment of mCRPC with symptomatic bone metastases and no visceral disease. 

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In the spirit of Prostate Cancer Awareness Month, we spoke with Dr. Sartor about the recent growth in the armamentarium for treating mCRPC. 

Can you review the recent evolution of pharmacotherapy for patients with mCRPC?

Dr. Sartor: The first agent to prolong survival was docetaxel, which was used in combination with prednisone. That was FDA approved in 2004. When that happened, the world was divided into the pre-docetaxel space and post-docetaxel space, and several of the trials that were subsequently conducted were actually conducted specifically in the post-docetaxel space.

The first of these post-docetaxel trials was the TROPIC trial, which compared cabazitaxel/prednisone with mitoxantrone/prednisone. The trial found that cabazitaxel was better in terms of overall survival. That established cabazitaxel as the first “second-line therapy” post-docetaxel.

The next trial that was specifically performed in the post-docetaxel space was COU-AA-301. That was with abiraterone/prednisone which also had a survival advantage. That led to the approval of abiraterone in 2011. The next trial that was specifically conducted in the post-docetaxel space was the AFFIRM trial with enzalutamide, which was approved in 2012 (also with an overall survival benefit).

One recent trial that was specifically done in the pre-docetaxel space was COU-AA-302, also with abiraterone/prednisone. The drug was approved by the FDA for use pre-docetaxel. Now abiraterone is approved both pre- and post-docetaxel.

Radium-223 was approved in May 2013 for use in patients with symptomatic bone metastases and no known visceral disease regardless of their prior exposure to docetaxel.  In a trial, radium-223 was associated with prolonged survival both in patients who received prior treatment with docetaxel and those who did not.

Sipuleucel-T was FDA approved in 2010 in the context of asymptomatic or minimally symptomatic patients.

Who will be prescribing or administering these medications to men with metastatic castration-resistant prostate cancer?

Dr. Sartor: There are very few urologists in the world who will really be managing these patients all the way through. The chemotherapy agents docetaxel and cabazitaxel will be administered by medical oncologists. 

The oral agents such as abiraterone and enzalutamide may well be commonly prescribed by urologists, or medical oncologists, and either can infuse sipuleucel-T, which is straightforward. 

Radium-223 has to be administered by somebody qualified to handle radiation, which is going to be a nuclear medicine physician or radiation oncologist.

In studies, treatment with these new agents is associated with a median survival benefit of four to five months. But do some patients live substantially longer than others?

Dr. Sartor: Yes, and this is because various parameters such as lactate dehydrogenase (LDH), alkaline phosphatase, hemoglobin, and PSA are prognostic factors that influence survival. Pain also influences survival. If you have no pain, you live longer than if you do have pain. 

In addition, if you have a good performance status, you live longer than if you don’t. If you do not have visceral disease, you have a longer survival than if you do. So if we have a patient with elevated LDH, visceral disease, and poor performance status, that patient is not going to be long lived. 

On the other hand, if they are asymptomatic, have good performance status, and have only bone metastases, it’s clear that patient is going to be living a good while longer.

What about using the drugs in sequence and in combination?

Dr. Sartor: We are currently in the sequencing era. But I don’t think, 10 years from now, we’re going to be in a sequencing era. We’re going to learn how to combine these agents. Right now, combination therapy with the new agents is pretty minimal.

In recent studies in which abiraterone was given after enzalutamide, the responses to abiraterone post-enzalutamide have been very disappointing. Studies also have looked at giving docetaxel after abiraterone, with equivocal results. 

One small trial shows a reasonable response rate, and another small trial shows a diminished response rate. And one trial looking at abiraterone first and then enzalutamide found diminished responses to enzalutamide. 

It appears that there is a fair amount of cross-resistance between abiraterone and enzalutamide. Whichever one you use first, it’s probably going to be pretty active. Whichever one you use second, it’s not going to be that active.