Layering Therapies for mCRPC

Nicholas J. Vogelzang, MD, FASCO, FACP:When would you start radium-223? Radium-223 is probably best given early before chemotherapy. That’s not to say you should not give chemotherapy first, but the tolerance of radium-223 is best in patients before they get chemotherapy. So, I tend to always either give radium right away if I see progression, or if I’ve given docetaxel or a taxane in the hormone-sensitive phase, I will then follow-up with radium fairly quickly. When they show progression, they’re going to get radium.

In this patient, we have a poor response to initial hormone therapy, a toxicity with abiraterone, and then a short response to enzalutamide with symptomatic deterioration. It’s very appropriate to begin radium right there. Now, you could also argue that the patient should get sipuleucel-T. That would also be appropriate. So, I might consider now stopping enzalutamide, giving sipuleucel-T either concurrently with, or immediately following, radium. But we already know this tumor is probably not androgen-driven, or at least not very androgen-driven, so you’re going to get to chemotherapy fairly quickly. So, we get through 4 doses of radium-223. The patient is doing well; the PSA drops, the symptoms improve, the ALK phosphatase drops. All indications are that we’re on the right track.

So, the issue of combining agents is gaining momentum. In the not long ago days, we would always give sequential therapy: one agent, then another, then another, then another. This is reminiscent of the way we used to treat Hodgkin’s disease before MOPP and ABVD. There’s no reason to give sequential single agents. We know they can combine well together. Giving radium with abiraterone, giving radium with enzalutamide, and giving radium with sipuleucel-T are all very easy, appropriate, and fine.

Giving it with chemotherapy is a little more difficult. So, I generally do not put them together. I will either give radium first, followed by chemotherapy, or chemotherapy first, followed by radium. And my preference is to layer the radium in with a less myelosuppressive drug, such as abiraterone, enzalutamide, or sipuleucel-T.

So, here we are now. The patient has already had 4 doses of radium and is doing well. We have strong evidence that you should give 6 doses. Every study—the Expanded Access study, ALSYMPCA, the European Expanded Access Worldwide—showed that it was always better to give 6 doses of radium rather than 4. And if it takes a little bit of effort on the part of the doctor and the part of patient to get 6 cycles, it’s worth the effort. So, try to hold off. In many cases, you will find that as you get to the fourth cycle of radium-223, the PSA will start to rise a little bit.

And there’s a tendency by doctors and patients to say, “Oh, the radium’s not working and I should switch to chemotherapy.” Resist the urge. Stay with radium, finish the 6 cycles. Everything we know about radium means that you have to go to 6. In fact, there are clinical trials looking at 12 doses of radium compared to 6 or even higher doses of radium. So, we are looking at more radium, not less. Dose response is not yet fully defined and, therefore, a minimum of 6 doses of radium is, in my opinion, mandatory.

Transcript edited for clarity.

November 2014

• A 55-year old gentleman presented with nocturia and PSA level of 4.5 ng/mL
• PMH: Insignificant
• DRE revealed an abnormal area of hardness
• Biopsy showed adenocarcinoma of the prostate gland with a Gleason score 6 [3+3], clinical tumor stage T1c                                                                                                                                                                  
• The patient remained on active surveillance

November 2015

• When he returned after 1 year:
  • PSA, 10 ng/mL
  • Repeat biopsy showed Gleason 7 [4+3] with 8 of 12 cores positive
  • CT scan was negative for metastases
  • He remained asymptomatic
• He was started on a 3-month depot injection of goserelin

February 2016

• PSA, 34 ng/mL
• CT scan was negative for metastases
• He was started on abiraterone and prednisone
  • PSA declined to 15 ng/mL and remained stable
  • After 4 months, he developed cardiac arrhythmia attributed to prednisone; he was switched to enzalutamide
  • PSA remained stable

August 2016

• 3 months following therapy switch, the patient complained of severe fatigue
  • CT scan showed enlarged lumbar spine and pelvic bone metastases
  • ¹⁸F-FDG PET showed increased FDG uptake in several areas of the lumbar spine and pelvis
  • PSA, 45 ng/mL
  • ALP, 225 U/I
• Radium-223 therapy was initiated and enzalutamide was continued
• After 4 cycles of radium-223:
  • Fatigue decreased significantly
  • PSA, 25 ng/mL
  • ALP, WNL
  • CT showed no new bone metastases