ONCAlert | 2017 San Antonio Breast Cancer Symposium
Prostate Cancer Case Studies

Safety and Efficacy of Bone-Targeted Therapy for mCRPC

Targeted Oncology
Published Online:Sep 22, 2017
In this case-based interview, oncologist Dan George, MD, discusses the management of a patient who develops prostate cancer bone metastases. Radiologist Rajan Gupta, MD, and radiation oncologist Glen Gejerman, MD, share viewpoints on the use of imaging and bone-targeted therapy for this patient.

mCRPC Treated with Concomitant ADT and Radium-223 Therapy

Daniel J. George, MD: Radium-223 is a different kind of drug. It is given primarily in our nuclear medicine department or by a radiation oncologist. It’s a radioactive therapy. I don’t have a nuclear regulatory license to give it. But for many of my patients, I’m going to refer them to my colleagues in nuclear medicine and radiation oncology to administer it.

There are a few key things to know about that. One, because it’s radioactive, it has to be handled in a certain facility that can manage it. Two, we have to follow appropriate safety guidelines around it. But it’s important for patients to realize that this doesn’t carry with it the same kind of external radiation exposure risk that other forms of radiation might. The reason for that is because this is an alpha particle, and radioactive alpha particles have very, very limited penetrates. They are literally stopped by a piece of paper, and in your own body, in your own bones where it’s going to deposit and release its radiation, there’s essentially no risk of radiation exposure to anybody around you. That’s really important for people to know.

Certainly, it’s cleared from your body. When it’s cleared from your body, it’s primarily cleared through your feces, but just normal hygiene can take care of any of those particular risks. So, by and large, this is very safe to administer. It needs to be administered in a properly licensed facility by credentialed and licensed physicians, but it’s been very well tolerated in the patient population, and it really doesn’t expose them to risk outside of their intravenous injection.

In the ALSYMPCA study, which was a pivotal trial that led to radium-223’s approval, patients were treated with either radium-223 or placebo, and the population of patients included symptomatic patients who had refused chemotherapy, were chemotherapy-ineligible, or had previously been treated with chemotherapy. In those populations at the time the study was done, patients were allowed to have best supportive care.

However, abiraterone and enzalutamide were not widely available as best supportive care at the time. So, patients got other secondary hormonal therapies—things like flutamide or bicalutamide, or ketoconazole. Those patients still tolerated radium-223 well and were able to demonstrate a survival benefit over placebo with a hazard ratio of about 0.7—so about a 30% improvement in the risk of death associated with treatment with radium-223 times 6 doses.

In my mind, although abiraterone and enzalutamide were not available at the time, similar mechanism drugs were allowed. In our own experience, we’ve been able to see good tolerance and disease control associated with that combination.

Radium-223 has essentially 2 sets of side effects. One is the marrow side effects, so causing cytopenias—things like anemia, thrombocytopenia, neutropenia, and lymphopenia. By and large, these are rare and transient, the most common one being the anemia associated with it. But the later we use radium, particularly after chemotherapy and in patients with large tumor burdens or who have undergone a lot of external beam radiation to other bony sites, the more cytopenias we see. So in my experience, we’ve been able to see fewer cytopenias when we’ve done therapy early. The other set of side effects we see is GI side effects—things like some diarrhea and upset stomach. And that’s partly because the drug is cleared through the GI tract.

Now, when we start to combine this drug with hormonal therapies like abiraterone or enzalutamide, we can start to see a little bit more fatigue associated with the drug, and that’s probably a mechanism due to both some of the cytopenia changes as well as the fact that our hormonal therapies result in fatigue. So, we do see a little bit of overlapping toxicity there.

I would say, since fatigue is not a major symptom associated with radium, most of that has been attributable to our hormonal therapy, and it’s something that has been very well managed. For the most part, there hasn’t been a dose-limiting toxicity when we’ve administered these agents early. Where we see them becoming more dose-limiting and difficult is in our later-staged, heavily pretreated patients with a high tumor burden.

It’s really important to recognize that the benefits associated with radium are with serial dosing. A single dose is unlikely to replicate the same survival benefit that we see in the ALSYMPCA study versus a patient who’s able to tolerate all 6 doses. So, for us, it’s really important when thinking about a course of radium to think about it in terms of being able to get through that 5- or 6-month period of time, when they would get exposed to radium and live long enough to benefit from that.

And so, now we’re looking at patient populations earlier. When you do that, radium starts to overlap with other therapies that are indicated in that space. One of the really great things that we found in our experience with radium is that it has been able to be well tolerated with other agents. There’s no drug-drug interaction risks with radium. It’s not metabolized through the liver. It doesn’t affect liver enzymes that metabolize other drugs. It’s not a problem in our patients who have slight renal impairment, because most of the clearance is through the GI tract.

For us, the big advantages of using radium have been its ability to combine well with other agents and our ability to use it earlier in the disease state. The hardest thing is finding the right patients because of the label that’s associated with symptomatic bone metastatic disease. And in my mind, symptomatic doesn’t mean severe symptoms. It can mean mild symptoms and recognizing that there’s more to symptomatic disease than just bone pain.

Other symptoms, like fatigue, loss of appetite, weight loss, or decreased functional status and mobility—and even things like lethargy and weakness and some neuropathies—can also be associated with this disease. So, recognizing that symptomatic metastatic castrate-resistant prostate cancer is a broad label, not a very narrow label, is really important to recognize where this drug can be used in our armamentarium.

Transcript edited for clarity.

December 2012

  • A 65-year old gentleman presented to a urologist with urinary incontinence
  • Digital rectal examination was unremarkable
  • Serum prostate-specific antigen (PSA) level of 10.8 ng/mL
  • Transrectal ultrasound and biopsy revealed adenocarcinoma of the prostate gland with Gleason score 7(3 + 4)
  • Bone scan and CT showed no evidence of metastasis
  • The patient opted for radical prostatectomy; pathology confirmed Gleason 7 prostate cancer with evidence of extracapsular extension and negative nodes; pT3aN0
  • Immediately following surgery, his PSA level was undetectable (<0.1 ng/mL)

December 2014

  • Two years later the patient developed disease progression
    • PSA level increased rapidly to 15 ng/mL
    • He was asymptomatic
  • He was referred to an oncologist by his urologist
  • Bone scan and CT were negative
  • He was started on androgen deprivation therapy and had an initial response of PSA decline to 0.5 ng/mL

December 2015

  • Over the next year, his PSA level increased to 35 ng/mL
  • Repeat imaging studies were done:
    • Bone scan showed multiple boney metastases in the spine, pelvis, ribs, and femur
    • CT scan showed no visceral or nodal disease
  • Within 3 months his PSA level rose to 145 ng/dL and he began complaining of fatigue and pain
  • He was started on abiraterone and prednisone
  • Additionally, he opted for therapy with radium-223
  • After 3 infusions of radium-223 his PSA declined to <10 ng/dL; ALP remained stable
  • After 6 cycles of treatment, CT and bone scan confirmed stable disease with no new metastases
  • The combination was generally well tolerated; the patient experienced grade 2 anemia and fatigue
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