Sartor Discusses Expanded Radium-223 Program, STAMPEDE Data in Prostate Cancer

Oliver Sartor, MD

Two recent trials—the expanded access program (EAP) following the ALSYMPCA trial and the STAMPEDE trial—provided critical insight for prostate cancer treatment, according to Oliver Sartor, MD, medical director of Tulane Cancer Center. However, both trials leave some questions unanswered, he adds.

The EAP, which included 180 patients, was initiated after the positive phase III ALSYMPCA data was released, but prior to the FDA approval for radium-223 for castration-resistant prostate cancer (CRPC) with bone metastases.

Some men in the trial had received abiraterone acetate (Zytiga) and/or enzalutamide (Xtandi) before, during, and following the EAP treatment period, which was not the case in the original ALSYMPCA trial.

Radium-223 was shown to be safe and well tolerated, regardless of prior or concurrent exposure to abiraterone and/or enzalutamide. However, it not yet understood if an earlier setting of abiraterone and/or enzalutamide and radium-223 would be more beneficial, said Sartor.

The STAMPEDE trial, which was the largest randomized prostate cancer clinical trial ever conducted, investigated the addition of docetaxel to standard hormonal therapy in men with newly diagnosed, hormone-naïve advanced prostate cancer.

Study results showed that OS was approximately 77 months for those receiving docetaxel with standard of care, versus 67 months for those receiving standard of care alone (HR, 0.76; 95% CI, 0.63-0.91; P = .003).

This data confirmed outcomes from the phase III CHAARTED trial, which showed that docetaxel in combination with standard hormone therapy extended OS by nearly 14 months.

The results of the STAMPEDE trial are “practice-changing,” said Sartor, but they do raise several questions.

OncLive: What were the most significant takeaways from the expanded access trial?

In an interview with OncLive, Sartor expands on the impact of these two trials and discusses how the results may change the treatment paradigm for prostate cancer going forward.Sartor: In the ALSYMPCA trial, we really did not have any experience with abiraterone and enzalutamide given concomitantly with radium-223. In the expanded access trial, we did. We determined that it is a safe combination.

We also found that if people had been on abiraterone and enzalutamide before they started radium-223, it was safe; however, their ability to get 5 or 6 cycles was greatly diminished. If a patient started using radium-223 in the third-line or forth-line setting, getting in the 6 cycles of radium-223 that has been FDA approved and recommended was not very probable.

We were able to look at what was predictive of survival as well, and we found that those individuals that had 5 or 6 doses of radium-223 had a much longer survival than those who had one to four doses. However, that analysis was confounded because the people that got only 1 to 4 doses typically had a worse prognosis and were more likely to have failed prior therapies.

How will radium-223 impact the treatment of prostate cancer?

Are there any other recent trials that you feel will make a big impact in the treatment of prostate cancer?

One of the lessons learned from this is that we ought not to be thinking about radium-223 in the last line; it should be moved up in the treatment sequence. We can combine it with abiraterone and enzalutamide, and that can be safe. We also know that there are patients that get concomitantly abiraterone and/or enzalutamide as a frontline therapy that do have a very favorable prognosis. However, to better understand that we would need to conduct a randomized trial. A phase III trial that consists of abiraterone frontline with radium-223 or placebo is now accruing. That trial is well underway.For the first time, we have utilization of an alpha particle, which is a completely novel concept in therapeutics. It is the first FDA-approved alpha particle, and that is really an interesting thing to be able to understand. It is a bone-targeted agent, which can prolong survival in the bone-metastatic castration-resistant patient population. It may work for other patients with cancer as well; that has to be explored. It is extremely well tolerated. We have found that, after treating thousands of patients, the safety signals are low. Patients may have a small amount of diarrhea or thrombocytopenia, but it is manageable.The STAMPEDE trial was a game-changer. It really gave us complete confidence in the CHAARTED trial. These are patients with hormone-sensitive metastatic disease at presentation. In the United States, it is only about 5% of the total patient population in prostate cancer, but it is a really important 5%. These patients are unfortunately going to die from this disease. We have been using androgen deprivation therapy (ADT) since 1941, and now we understand that for patients with metastatic disease, docetaxel added to ADT can have a pretty profound impact.

What questions remain regarding the STAMPEDE trial?

Based on the results of this trial, I am going to be using docetaxel upfront with ADT in my patients. This is practice-changing. The study was not only very well-powered, it was very well-conducted and it was integrated extremely efficiently. It is a marvel to watch the STAMPEDE investigators in action; they are the best in the worth at what they are doing right now.There are a number of questions that arise as a result of STAMPEDE. There was some PFS data in the non-metastatic subset. I am personally not willing to change my practice in non-metastatic based on PFS data, I am going to require that the OS data be presented. They did not do stratification between the high-volume and low-volume category that was utilized in the CHAARTED trial, so we don’t have any information on that. It could be that the vast majority of the treatment benefit is in a high-volume subset, but we will never know. In any good trial, there are positives and there are questions but, in this case, I think the positives really outweigh the questions.