Nonmetastatic CRPC: Other Therapies and Multimodality Approach

Julie Graff, MD:To my knowledge, there are 2 other androgen receptor (AR) antagonists being studied, darolutamide and enzalutamide. Enzalutamide is the one that’s already FDA approved for metastatic castration-resistant prostate cancer. There are also immunotherapies being tested in the biochemically relapsed space.

If next-generation AR antagonists are approved, I would recommend them in nonmetastatic castration-resistant prostate cancer, simply because they delay the time to metastases, which are what give the patient symptoms. I would, of course, have a discussion with my patient. I can see some patients opting to wait on those therapies, but I would recommend it.

If and when I start patients on these AR antagonists, I would look for a) fatigue; b) worsening of any symptom that the patient had on leuprolide acetate alone; c) I’d be very careful about following their bone densities since these may accelerate loss of bone density; d) I’d be looking for any seizures and cognitive dysfunction; and e) falls, I think, are a big deal, especially since prostate cancer patients are elderly and have decreased bone density to begin with.

Multimodality treatment, to me, means including physicians from different specialties, like radiation oncologists and surgeons. I’m not sure that they do play much of a role in nonmetastatic castration-resistant prostate cancer, but you could also look at multimodality as other cancer treatments too, like, perhaps, immunotherapies and chemotherapies. I don’t think that they play much of a role, either, in this situation.

At this point in time, the patient clearly has metastatic disease. That’s defined as seeing a tumor on a scan. I’m glad he’s asymptomatic, and it does shape my choices here. My impression is that he’s now appropriate for any number of therapies. I’m most likely to start with one of the hormone therapies, such as abiraterone or enzalutamide.

The patient has many treatment options at this point. Once a patient develops metastatic castration-resistant prostate cancer, there are 6 treatments that improve survival, including 2 chemotherapy drugs that I’m unlikely to recommend at this time because he doesn’t have symptoms. There’s abiraterone, to do more complete suppression of androgens; enzalutamide, to block the androgen receptor from the binding to testosterone; and sipuleucel-T, which is an immunotherapy appropriate for patients without symptoms. Down the road, we could do radium-223 if, and when, he develops bone pain.

So, this patient has gone through just about every phase of the disease. First, he had localized prostate cancer. He did everything in his power to get cured but, unfortunately, it came back. Then he developed biochemically relapsed prostate cancer. And then castration-resistant nonmetastatic prostate cancer. At the situation of the nonmetastatic castration-resistant prostate cancer, I hope and believe, in the future, we’ll be able to use our second-generation androgen receptor antagonist in that space. And then, at the development of metastatic cancer, we have all of those other treatments that we can use. So, in the future, what will we be doing? I think for nonmetastatic castration-resistant prostate cancer, for the time being, we will be using the hormone therapies, as we discussed. I’m looking forward, though, to newer immunotherapies that might be useful to wipe out the disease while the volume is still low. And, for the metastatic portion of his disease course, I do hope that, in the near future, with combinations or novel agents, we’ll be able to cure some patients.

Transcript edited for clarity.

January 2014

• A 66-year old retired African American male presents with reduced urinary flow and hematuria.
• PMH: High blood pressure. Currently taking enalapril 10 mg.
• FHx: Father lung cancer — age 74.
• Patient walks 3 miles a day.
• PSA 9.8 ng/ml
• Prostate biopsy shows Gleason 7 (4+3) prostate cancer
• Undergoes robotic-assisted laparoscopic prostatectomy (RALP) and pelvic lymph node dissection (PLND)
• Results show:
  • pT3b (focal extracapsular extension and seminal vesicle invasion) — margins negative
  • N1
  • M0
• Post-operative PSA=0.64 ng/ml
• Patient undergoes adjuvant radiation therapy and is started on leuprolide acetate.
• PSA drops to undetectable levels

January 2016

• PSA starts to rise to 0.3 ng/ml
  • Repeated 3 months later — 0.7 ng/ml
  • Bone scan and prostate-specific membrane antigen (PSMA) scan both negative
  • Diagnosis nonmetastatic castration-resistant prostate cancer (CRPC)
  • Patient declines additional therapy at this time

November 2017

• PSA continues to rise over the next 18 months going up to 9.8 ng/ml
• Bone scan shows lesion in the left superior pubic ramus
• Patient is asymptomatic