Significance of the ERA 223 Trial in mCRPC

Daniel J. George, MD:There are a couple of things that I took away from the ERA 223 presentation that I think are really key. With patients, we probably haven’t discussed and paid enough attention to the risk of fractures associated with all of our therapies, including drugs like abiraterone and enzalutamide. We see that. In the control arm of the ERA 223 trial, we saw an 11% fracture rate associated with abiraterone. That had never been reported like that before. It certainly wasn’t collected like that in COUGAR-AA-302, which was essentially the same population.

This clearly tells me that this study uncovered something. It was looking for fractures at a higher rate than we’d seen before. Although many of those are asymptomatic fractures, it still matters to me because asymptomatic fractures can lead to more symptomatic fractures down the road.

The second takeaway from ERA 223 was that bone strengthening agents made a big difference in the outcomes of these patients. This really suggests that as we are thinking about the evolution of these patients, even in their hormone-dependent states, hormone-sensitive prostate cancer states, or nonmetastatic disease states, we want to be thinking about conditioning bone for strength. There are a couple of ways to do that. Calcium and vitamin D are great supplements that every one of our patients should be taking from the beginning of hormonal therapy. Exercise is a key way to manage that. Particularly for our patients who are not heavy or bearing a lot of weight at baseline, it’s really important for them to do weight-bearing exercises. Then, use bone strengthening agents to help prevent osteopenia. These are not necessarily pathologic fractures. These are fractures that could happen anywhere in bone.

We know that this is a population of patients who are not going to just get androgen deprivation therapy, but will get drugs like abiraterone and others, and, in many cases, for years. These kinds of complications can happen in those scenarios at a higher rate than we appreciated before.

The third thing with the ERA 223 trial is that radium-223 can add to that complication. We didn’t know that from ALSYMPCA because we treated a more advanced disease population, didn’t look carefully by scans, and these were patients, in the control arm, who had 1 year to live. Fractures were less critical to a patient population that would die of disease complications in a short timeframe.

As we think about using this drug earlier, it’s more important to be aware of this complication and mitigate it. Bone strengthening agents certainly help. They don’t make it go away completely. This is something that we need to include in our conversations with patients, but it shouldn’t deter us from the fact that we want to keep these patients alive for as long as possible. For that overall survival benefit, radium-223 is unique in class. There’s nothing else in our armamentarium like radium-223. If we don’t use it, we’re going to lose that survival benefit that is associated with it. Finding out how to use it safely with the minimum amount of complications associated with it is key. I think bone strengthening agents really help us do that, along with these other lifestyle changes and monitoring.

There are a lot of differences between the United States and Europe. We don’t have to go into these. Culturally, my jackets are much looser fitting than theirs. At the end of the day, there are differences in how we view the relationships between healthcare systems and physicians. In the United States, we value the physician—patient relationship as being the ultimate arbiter of how we should manage these folks.

In Europe, it’s more paternalistic. It’s a bit more health system-driven. That may be cost effective and wise on a national level, but, in the United States, we value the opportunity to be able to individualize our treatment choices. I think that’s really important. The label that we have in the United States is really reflective of the ERA 223 data. It was studied in a situation where we’re not really using radium-223—the upfront use of abiraterone and radium-223. It gives us a warning regarding that usage, and I think that’s important because we don’t want to have off-label usage or usage that is outside of our clinical experience or clinical data.

What it doesn’t do is undermine the ALSYMPCA data, which demonstrated a benefit associated with radium-223, including best supportive care, which included antiandrogens, ketoconazole, and external beam radiation. We know that layering those therapies in addition to radium-223 in the ALSYMPCA study was associated with a survival benefit that was better than those therapies alone. We want to continue to offer our patients the best survival benefits we can, and we’ll want to monitor for these complications, which may have been underappreciated in that context.

Transcript edited for clarity.

mCRPC Treated With Radium-223 Therapy

January 2015

H&P:

• A 71-year old gentleman presented with urinary incontinence
• Past medical history: HBP controlled with lisinopril
• On digital rectal examination prostate was enlarged
• Patient was asymptomatic

Imaging:

• Transrectal ultrasound and biopsy revealed adenocarcinoma of the prostate gland with a Gleason score 9 [4+5] with 9 of 12 cores positive
  • PSA, 10.2 ng/mL
• CT scan was negative for metastases
• He was started on a 3-month depot injection of leuprolide 22.5 mg and treated with 7800 cGy IMRT

April 2016

• Patient returned for 3-month injection; his PSA level increased to 47 ng/mL
  • CT/Bone scans were negative for metastases
• He was started on enzalutamide
  • PSA, 12 ng/mL

October 2016

• 6 months later the patient complained of severe fatigue and lower back pain
  • Imaging with CT and bone scan showed multiple metastases of the spine and pelvis
  • PSA levels increased to 76 ng/mL
  • ALP, 268 U/I
• Radium-223 therapy was initiated in addition to continuing enzalutamide
• After 3 infusions of radium-223
  • PSA declined to 31 ng/mL
  • ALP decreased to 80 U/l
  • CT scan showed no new bone metastases
  • Fatigue decreased, and patient’s physical activity increased