The ERA 223/PEACE III Trials & the Future of mCRPC Treatment

Nicholas J. Vogelzang, MD, FASCO, FACP:The ERA 223 trial was an 800-or-so-patient trial. It was reported by Matthew Smith, MD, at the European Society of Medical Oncology [ESMO] 2018 Annual Meeting. Unfortunately, I was not able to go to Europe, but I’ve seen the slides and shared the data with some of my friends. The paper apparently is on press or about to be published. And the top-line result is that there was no survival advantage for adding abiraterone [Zytiga] to radium-223 [dichloride; Xofigo]. The median survival was essentially the same. There was, however, a signal that more patients had fractures when given abiraterone simultaneously with prednisone [Deltasone] and radium-223. That signal of fracture was reduced in patients who were given bone-hardening agents such as denosumab [Xgeva] or zoledronic acid [Reclast].

It still showed a higher differential fracture rate in the patients given the abiraterone and radium-223. I believe that it was relatively minor, but it nonetheless led the European Medicines Agency. It recommended Health Canada against giving abiraterone and radium-223.

To me it’s not a game changer. In this particular patient, I’ve already given abiraterone, and he’s progressed on it; now I want to control the bone metastases. A bigger question is whether there are other agents that could enhance the radium-223. As I mentioned earlier, sipuleucel-T [Provenge] is something that I would definitely give. There is a study under way called PEACE III, in which patients are going to be randomized to radium-223 with or without enzalutamide [Xtandi]. That would be interesting because, as I mentioned earlier, the option for this patient would be enzalutamide. It should go very well with radium, and for certain patients it would be fine to administer. There’s no reason not to do it. Some of us will give in this particular situation enzalutamide and radium, even though we don’t have clinical trial data yet to support that position.

What I would remind everyone of is that radium-223 is not a pain drug. It is not given for control of pain. It’s given to improve survival. That is the reason the FDA approved the drug. The FDA looked at the ALSYMPCA trial, the randomized trial of radium-223 versus placebo, and concluded that survival was prolonged by the use of radium-223 when given 6 doses. Radium-223 also met a series of secondary endpoints, including reduction in the use of opioids, reduction in the rate of hospitalizations, reduction in the rate of symptomatic skeletal events, or SSEs. Overall improvement in quality of life when measured in a variety of ways was positive.

I’m surprised when more of my colleagues do not use radium-223. It has a survival advantage and a variety of other important advantages, one of which is the control of fractures and control of pain. And we as physicians don’t always do a great job controlling pain and fractures. But you have to give the drug to get that benefit. And if you don’t give the drug, you don’t get the benefit.

The challenge to us as physicians caring for patients with prostate cancer is that there are an increasing number of options. As I mentioned, integrating these options, including chemotherapy and radium, is a challenge. For example, we have a study under way called DORA, which is run by Michael Morse, MD, from Memorial Sloan Kettering Cancer Center. There will be a number of sites: The Netherlands will be joining the trial, and it will be a randomized trial of chemotherapy with docetaxel versus chemotherapy with a lower dose of radium-223 every 6 weeks, and chemotherapy at a slightly lower dose of 60 mg per square meter instead of 75 mg per square meter. That study is just about to open. It will give us, again, an idea as to whether you can put these agents together. We already know that sipuleucel-T and radium-223 can be given together. We now have the ERA 223, suggesting that abiraterone and radium-223 are not necessarily beneficial together and not particularly harmful except with regard to the fracture rate. We’re waiting on piece 3 to see whether the enzalutamide and radium-223 will improve overall survival.

Transcript edited for clarity.

Hormone Sensitive mPC progressing to mCRPC

March 2015

H&P:

• A 76-year old gentleman presented to his urologist with nocturia and lower back pain
• PMH: unremarkable
• Digital rectal examination revealed an abnormal area of hardness

Imaging:

• Transrectal ultrasound and biopsy revealed adenocarcinoma of the prostate gland with a Gleason score 8 [4+4] with 9 of 12 cores positive
  • PSA, 85.3 ng/mL
  • Testosterone, 300 ng/dL
• CT scan showed multiple metastases of the spine
• He was started on abiraterone + prednisone + goserelin
• PSA and testosterone level continued to decline over the next 2 years to PSA, 0.1 ng/ml; testosterone <3 ng/dL.

March 2018

• After 3 years of therapy patient reported increasing fatigue
• PSA and testosterone levels began to rise
  • PSA increased from 0.5 ng/ml to 1.0 ng/ml; 2.0 ng/mg to 4.8 ng/ml at 2-3 month intervals
  • Testosterone, <3 ng/dL
  • CT scan shows several new bone metastasis; others improved
• Patient is diagnosed as castration resistant and abiraterone + prednisone was discontinued
• Radium-223 therapy was initiated