Bone-Targeted Therapy for Metastatic Prostate Cancer

Daniel J. George, MD:Abiraterone and prednisone essentially have the same label indication as enzalutamide, and that is for men with metastatic castration-resistant prostate cancer, whether it’s symptomatic or not and whether they’ve received docetaxel chemotherapy or not. So, because those drugs share a very common label, they’re frequently compared with each other. The fact is that when we look at the phase III studies that led to their FDA approval, they’re pretty similar in terms of overall survival, progression-free survival, and PSA.

A couple of things that differ between those studies—the enzalutamide studies included patients with visceral disease. So, for our patients with, say, asymptomatic visceral disease, we’ll sometimes favor enzalutamide in that population. Abiraterone was done with prednisone. For some patients, even low doses of prednisone can be difficult to tolerate, particularly for diabetics.

Overall, these drugs have very similar and well-tolerated side effect profiles, but we did see a little bit more incidence of cardiac events, low-grade typically, associated with abiraterone/prednisone than with enzalutamide. For patients who have a cardiac history or a significant problem with diabetes, I tend to favor enzalutamide. Enzalutamide, though, was associated with more falls, particularly in our patients who are 75 or older. So, for many of our older or slightly frail patients, we might consider abiraterone/prednisone. They’re really both good options. I use both drugs in overlapping indications, but those are some of the factors that push me toward using 1 agent over another.

Abiraterone/prednisone is a standard of care for patients with metastatic castration-resistant disease. In this particular case that we presented, the patient had symptoms with some mild migratory pain and fatigue. You could argue those are mild enough symptoms—maybe the abiraterone alone could manage this. But remember, this was a rapid natural history. This patient went from localized disease to a rapid PSA rise to hormone-refractory, or castrate-resistant, disease and widely metastatic bone metastases over a couple of years. I would argue that’s a natural history that’s rapidly progressing, and this is a patient who’s at risk for developing resistance to abiraterone sooner rather than later.

Remember also, this is a case where the patient has limited treatment options following abiraterone, it makes sense to say, “Is there a way to administer additional therapy sooner rather than later?” The advantage of doing that with radium-223 is that it takes a while to administer. It’s a 5-month therapy. It’s 6 monthly injections. So, you’ve got a long course to get through, and you’ve got a patient whose natural history has been progressing in-bone relatively rapidly.

To me, it makes sense to say, “Hey, let’s not wait for this patient to become resistant to abiraterone; let’s move that radium-223 up.” It’s actually on-label as well. If you look at the label associated with radium-223, it’s for symptomatic patients, even minimally symptomatic patients. It’s for patients with bone-dominant metastatic castration-resistant disease, which he has, and it allows standard of care, best supportive care, which you can argue in this case is his LHRH agonist therapy as well as his abiraterone/prednisone. For me, this is on-label, sensible, and a little bit of a proactive and aggressive approach to managing this patient with an otherwise rapid natural history of disease.

Rajan T. Gupta, MD:When this patient presented, I think one of the most interesting things was the presence of imaging findings that were not seen prior—and also the rapid elevation in his PSA up to about 150 ng/mL. The presence of bony metastatic disease, in both the CT scan and the bone scan, and the absence of visceral or lymph node metastatic disease are helpful things, and I think they help to inform us on some of the treatment decisions. That’s my impression of the patient, and it was just the rapid progression of their disease from where they were after their radical prostatectomy—where their PSA decreased to less than 0.1 ng/mL—to the point where they’re at a PSA of almost 150 ng/mL.

The concept of radium-223 is that it allows you to really attack the bone metastases. And I think here, the imaging informs the decision-making as well. We don’t have any visceral metastases, and we don’t have any solid organ metastases, so our disease is really confined to the bone. This makes radium-223 a potentially attractive choice for this patient.

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