Case Review: Rationale and Methods in mCRPC - Episode 4

Pragmatic Considerations for Early Radium-223 in mCRPC

Evan Y. Yu, MD

Evan Y. Yu, MD: In my mind, if I was taking care of this patient, the 2 drugs that I really would have considered would be docetaxel or radium-223. I think that the decision there comes down to many pragmatic factors. I can give docetaxel to somebody who is either asymptomatic or symptomatic. I prefer to give it to someone who is symptomatic and has metastatic castration-resistant prostate cancer. This patient was symptomatic, so it would have been reasonable to offer this therapy.

Radium-223 must be given to a patient who is symptomatic. When I think about the timing of these agents, it’s very clear that if you give radium-223 earlier—it’s 6 doses once every 4 weeks—you’re more apt to get all 6 doses into the patient. There are some data that shows that is associated with better survival outcomes. It’s hard to know whether that’s driven by those 6 doses, getting them all in, or whether that’s driven by the patient having a better prognosis. But it’s very clear that those who get 5 or 6 doses in seem to do better than those who get fewer doses in.

Now, that being said, there are a lot of practical considerations. If you give radium-223, you have to get insurance preauthorization. There are rules in regard to what the absolute neutrophil count, hemoglobin count, and platelet count should be. You can’t have visceral metastases. And for those practical reasons, patients’ counts are usually better earlier in the disease course. That’s because they haven’t yet received cytotoxic agents that might cause chronic myelosuppression. It’s also because prostate cancer can infiltrate the bone marrow. If it takes up space in the bone marrow, some patients can be suppressed due to disease involvement in the bone marrow.

That’s one of the challenges. For an agent that requires insurance preauthorization and has clear requirements and limits, you can’t have visceral disease, you have to have certain counts, it makes sense, pragmatic sense, to give it earlier rather than later. If I give it later after docetaxel, they’ve already had chemotherapy and that could be associated with myelosuppression. Well, the visceral disease tends to develop later in the disease course and that might prohibit use of radium-223. You know they might have marrow involvement that would lead to counts being inhibited.

There are no data that definitively shows that radium-223 should be given before docetaxel and that leads to a better survival benefit. But if you live by the theory that my goal is to help my patients live as long as possible with the best quality of life as possible, and to use as many of the treatment options as I can that prolong survival, then I have to think about just pragmatically taking all of these considerations into account. That’s why I like to use the radium-223 rather than docetaxel in this patient in that situation.

Additionally, the toxicities are low for radium-223. It could cause some myelosuppression. Since it’s degraded and excreted from the body rather than metabolized by the liver or kidney, it can go into the small bowel and can cause some diarrhea. But generally speaking, the toxicities are less than what is seen with docetaxel. In real-life practice, I haven’t seen more toxicities than what one would see when reviewing the randomized phase 3 ALSYMPCA trial that was published back in 2013. There have been some subsequent publications that show long-term safety to not be a concern as well either. Some people worry about giving radiopharmaceuticals and the long-term risk of developing a leukemia or a myelodysplastic syndrome, but we really haven’t seen significant challenges with that.

One thing I’d like to emphasize, that I mentioned earlier, is that it makes a lot of sense when a patient progresses on 1 line of therapy to not keep pressing down on that same pressure point.

For instance, if a patient progresses on abiraterone and you give enzalutamide, the results are not ideal. And, vice versa—abiraterone after enzalutamide. That’s because they’re all working via that androgen axis.

I mentioned that changing mechanism of action makes a lot of sense. This is a unique mechanism of action, as radium-223 sits on the same column of the periodic table as calcium. Therefore, if you think about it, calcium incorporates into bone. Prostate cancer, being a bone-predominant disease, causes osteoblast metastases, where there’s a lot of bone turnover. Calcium can sit in those areas. Likewise, radium can incorporate into those areas. It basically is an alpha-emitting radiopharmaceutical and has very potent kill. It can induce double-strand DNA breaks in the cancer without a lot of spread. So it doesn’t have as much myelosuppression as some of the older radiopharmaceuticals, like samarium-153 or strontium-89. So again, it brings a unique mechanism of action that fits with the biology of prostate cancer.

Transcript edited for clarity.


Case: A 66-Year-Old Man with Metastatic Castration-Resistant Prostate Cancer

Initial presentation

  • A 66-year-old man presented with increasing difficulty walking and sleeping on his back due to lower back and hip discomfort
  • PMH: hypertension, medically controlled; no known family history of cancer
  • PE: DRE revealed a nodular prostate; otherwise unremarkable

Clinical workup

  • Biopsy with TRUS showed adenocarcinoma of prostate
    • Stage T2N0M0
    • Grade group 4
    • Expected survival > 5 years
  • Germline testing: MLH1, MSH2, MSH6, PMS2, BRCA1/2, ATM, PALB2 and CHEK2
  • Chest/abdominal/pelvic CT scan showed no evidence distant metastases or lymph node involvement
  • Bone scan was negative
  • PSA 26 ng/mL

Treatment and Follow-Up

  • EBRT for 8 weeks + neoadjuvant concurrent, and adjuvant ADT for 2 years
  • At 6 months post-ADT follow-up; PSA 5.9 ng/mL
  • At 12 months follow-up:
    • Patient reported continued back discomfort, difficulty walking and loss of appetite
    • PSA 16 ng/mL
    • Bone scan showed multiple lesions in the right femur and pelvis
    • Abiraterone + ADT was initiated for 1 year
  • At subsequent follow-up:
    • Patient complained of increased bone pain in right femur
    • PSA 18.6 ng/mL
    • Abiraterone was ceased; ADT continued
    • Treatment with radium-223 dichloride was initiated; 6 infusions completed and well-tolerated at post-infusion follow-up