Sequencing in mCRPC: When to Utilize Radium 223

Pedro C. Barata, MD, MSc:Radium 223 is 1 of the 6 life-prolonging therapies. It has a unique mechanism of action because so far, it is the only bone-targeted therapy that has been shown to improve survival. And the study that led to its approval is called ALSYMPCA trial, in which patients with metastatic castration-resistant prostate cancer pre- or post-docetaxel—almost half and half for pre- and post-chemotherapy—received radium 223. And basically the group of patients who were treated with this therapy actually had prolonged overall survival compared with a group of patients who did not receive this treatment. So as we were saying, radium 223 is a very special agent with a very specific mechanism of action. Basically it’s an alpha-emitter and it’s a calcimimetic, so it acts in areas of increased uptake in the bones.

When we think of the ideal setting for radium 223, we would argue that it’s probably pre-chemotherapy, post first androgen receptor targeted therapy. And the reason behind that is we have data showing that patients who receive 5 or 6 treatment administrations do better than those who receive up to 4. On the other hand, patients who do not have visceral disease nor lymph nodes larger than 3 cm are those who are going to benefit from radium 223. In other words, if you think of the setting early on, where you have bone-mainly disease, you have a good performance status, and at the same time you are more likely to receive the 6 doses of radium 223. It’s probably the sweet spot for this therapy.

It is interesting how the development of radium 223 has happened in the last few years. The initial approval was based on radium 223 compared with placebo in the 2:1, ALSYMPCA study. But in real life, because it’s a bone-targeted agent, a lot of us start combining it with oral androgen therapies, such as abiraterone and enzalutamide. And so it was not a surprise that we saw those trials being conducted, both with enzalutamide and abiraterone. Now we had recent data from the trial called ERA 223 showing us that the combination of radium 223 and abiraterone is not safe, basically because we saw an incremental risk of fractures and death. And so the approval was changed, and basically the combination of radium 223 and abiraterone is now not recommended.

So far, the phase II trial exploring the combination of radium 223 with enzalutamide has shown to be safe. So no negative signal has been demonstrated. And the phase III trial is ongoing. I’m excited to see the results of that study because it will be important for us to know whether the combination of bone-targeted agent, such as radium 223, and androgen receptor targeted therapy, such as enzalutamide or any other anti-androgen, can improve outcomes compared with radium or enzalutamide alone. I think that question needs to be answered, and fortunately we’ll know the answer once the study reads out.

After radium 223 has been approved, we had a number of expanded access programs. And the data [have] been published from those programs, showing that patients who received 5 or 6 cycles of radium 223 do better than patients who receive up to 4. At the same time, patients who have better performance status also do better than patients with not-so-good performance status. So indirectly, you can say that if you’re going to think of radium 223 as a good treatment option for your patient, you probably want to offer it to him sooner rather than later because you’re less likely to have bone-only disease. You’re more likely to have not-so-good performance status, and you’re probably less likely to offer the full 6 cycles of therapy.

Transcript edited for clarity.

Case: A 69-Year-Old Man With mCRPC Progressing on Therapy

July 2016

H&P:

• A 69-year old gentleman presented with nocturia
• PMH: unremarkable
• DRE, enlarged prostate
• PSA, 50.3 ng/mL
• TRUS and biopsy showed adenocarcinoma of the prostate gland; Gleason score 8 [4+4]
• CT scan showed minimal nodal involvement

Treatment:

• Started on ADT with initial PSA response - 15 ng/ml — August 2016

March 2017

8 months later, patient complained of fatigue and mild back discomfort

• Imaging with CT and bone scan showed two metastatic bone lesions (1 spine, 1 pelvis)
• PSA, 25 ng/mL
• Hb, 9.0 g/dL
• ANC, 1.7

Treatment:Enzalutamide

• Initial PSA response — 10 mg/ml but rising over one year later continued

March 2018

• PSA 30 ng/ml
• CT showed 4 bone metastases (2 spine, 2 pelvis) and diffuse liver lesions

April 2018

• Radium-223 initiated, patient received 6 injections

April 2019

One year later patient presented with increased lower back discomfort causing disruption in daily activity.

• CT showed new lymphadenopathy and diffuse liver lesions
• PSA 45 ng/mL
• Hb, 9.0 g/dL
• ANC, 1.6
• Treatment: Patient started on docetaxel, 6 cycles completed; achieved stable disease (Hb, 14.1 g/dL)