CRPC: Responding Poorly to AR-Targeted Agents

Nicholas J. Vogelzang, MD, FASCO, FACP:Looking at this case, the patient has an atypical response to hormone therapy. Almost always, the PSA drops when you give an LHR agonist like goserelin, leuprolide, or degarelix. So, the fact that the PSA did not drop suggests that the patient has developed a de novo castrate-resistant state. Perhaps the patient was already castrated, perhaps he had hypogonadism, perhaps his testosterone was below 100. We don’t know that because the testosterone level was not drawn at the time of goserelin administration, but that’s usually the case. If the patient does not respond to leuprolide, goserelin, or degarelix, they probably are already hypogonadal and they developed a de novo, or nearly de novo, castrate-resistant state. So, this patient has an adverse outcome. There is not going to be a good outcome.

The case is somewhat atypical in that he doesn’t get a good response to leuprolide and goserelin. And, moreover, he doesn’t get much of a response to abiraterone. And, again, we don’t know all the details, but the fact that the patient only gets a drop from 30 to 15 on the PSA and then gets cardiac arrhythmia, probably atrial—which is the most common, secondary to salt retention, by abiraterone—it’s appropriate to switch to enzalutamide.

Well, at that point, we now already know that enzalutamide is not going to be a long-term benefit. At ASCO this 2017, there were 2 papers showing that once enzalutamide or abiraterone failed, switching or adding another drug didn’t give you much benefit. In fact, I think it was it was the PLATO trial that showed that the average duration of benefit of the second-line androgen blocker was only 3 months. This patient is spot on; 3-month benefit, not a lot of benefit.

Now, do you need to image at that point? The answer is, yes, it’s reasonable to image. What images do you do? Well, right now, insurance doesn’t usually pay for the fluoride PET. I love to get the fluoride PET; it’s a more sensitive test. But many times, the insurance just says no, and we can sometimes get it under a Cooperative Group research agreement. But still, we usually can’t get the fluoride. So, you do a regular technician bone scan, a CT scan, and tumor markers. And sure enough, based upon all of those factors, PSA is rising, symptom of fatigue is going up, and he’s got new bone metastases on the fluoride and probably on the regular bone scan. And he’s got a CT scan sign of progression.

Why do we do the CT scan? Well, CT scan is done so you don’t miss liver metastases, because fatigue can be a sign of liver metastases. I’m glad he doesn’t have liver metastases, but I wouldn’t be surprised if, down the road, a highly aggressive tumor like this will pop up with liver metastases. Right now, all he has got is fairly limited bone metastatic disease. Therefore, it is highly appropriate to begin radium-223.

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