Nonmetastatic CRPC: MFS and AR-Targeted Agents

Julie Graff, MD:Metastasis-free survival is the period of time from identification of nonmetastatic castration-resistant prostate cancer, and then the identification of a metastasis on some sort of imaging modality. So, it’s the time between the 2 points.

To date, metastasis-free survival has not made a big impact, simply because we have no data demonstrating that anything improves that endpoint at this time. One of the benefits and hindrances of prostate cancer is that it’s a very slow growing disease. There can be a huge amount of time between the diagnosis of localized disease, PSA recurrence, development of metastases, and death. That’s great for our patients who have years to live.

But when it comes to designing a clinical trial, it makes things complicated. We can’t always wait 20 years for a result. A study looking backwards at a bunch of other clinical trials that were done for localized prostate cancer was conducted, and the study found that the development of metastases predicted death from prostate cancer.

So, we could use the surrogate endpoint now. It’s a much shorter time between treatment of the primary cancer and recurrence of that cancer than it is from treatment of the cancer to death. It’s a very important finding. It doesn’t really apply to this case because we’re looking more at the development of nonmetastatic castration-resistant disease and the time to metastases. So, it’s a very different setting. But it does speak to the fact that perhaps, if we could delay the time to metastases, we could help outcomes.

The future use of next-generation androgen receptor (AR)-targeted agents will likely include being used earlier in the disease. They are also very likely to be used in combination with other therapies. Now, in prostate cancer, we have chemotherapies, immunotherapy, radiation therapy, and these AR-targeted therapies. There’s not a lot of overlap in toxicity between all of these classes. I’m currently doing a study of enzalutamide, which is an AR-targeted therapy, plus pembrolizumab, which is a checkpoint inhibitor immunotherapy, to see if the survival is improved compared to enzalutamide or pembrolizumab alone. I can see these agents being used in combination. I know several ongoing studies where this is being done.

We also need, maybe, third-generation androgen receptor antagonists that can overcome the resistance that the second-generation causes. And so, I think that we will find, or I hope that we will find, AR antagonists that can bind to the different parts of the AR.

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