Therapeutic Approach for Nonmetastatic Prostate Cancer - Episode 2

Current and Future Therapies for Nonmetastatic CRPC

December 26, 2017

Charles Ryan, MD:So, 1 year after starting ADT, this patient’s PSA rises to 12. And that’s fairly aggressive I would say because 12 is a pretty high number, this quickly, and a year is a relatively short period of time. In our CRPC studies, for example, the median duration the patients have been on ADT before they get CRPC is somewhere between 4 and 6 years. So, this patient probably has an underlying disease forming. Just based on the fact that his PSA went from almost 0 to 12 in a year means he has a rapid PSA doubling time. He underwent a next-generation scanning modality with fluciclovine. He was found to have 1 pelvic node.

So, here’s the challenge with this patient. We know that there’s likely to be cancer in that 1 pelvic node, but we don’t know if all of the cancer is in that 1 pelvic node. And so, the consequence is that he probably does have tumor cells elsewhere. If we were confident that he only had cancer packed into that 1 node, we could argue to do surgery or radiate that node and eliminate it, but the reality is he probably has bone marrow-based disease that isn’t quantifiable enough with a scan. And so, he has nonmetastatic castration-resistant prostate cancer, assuming that we check his testosterone is less than 50, which I’m sure it is if he has been receiving the leuprolide.

Castration resistance is a term that replaced the old term, which was hormone-refractory prostate cancer. And the reason why we use this term is to imply that the disease has become resistant in the context of a castrate level of testosterone. Some people think it means we’ve done surgical castration, which we have not. It simply refers to the level of testosterone being under 50. And so, that is a term that entered the clinical lexicon, with the FDA approval of abiraterone and the FDA approval of enzalutamide, because those studies, in a way, told us that hormone therapy can work in this setting. Therefore, it made the phrase “hormone refractory of prostate cancer” seem like a contradiction in a way.

Currently, there are no FDA-approved therapies for nonmetastatic prostate cancer. Typically, patients will maintain their androgen deprivation therapy, whether it be an LHR agonist or antagonist, and may cycle through a variety of secondary hormonal agents, such as bicalutamide, nilutamide and other things, none of which have been shown to be associated with a survival benefit. The arrival of next-generation androgen receptor antagonists will be a welcome addition to the pharmacopeia in this group of patients insofar as it may allow them to be treated with a well-tolerated treatment that will prevent metastasis from forming and preserve their status as nonmetastatic.

For patients with nonmetastatic castration-resistant prostate cancer, I typically look at the pace of change of the PSA. I use PSA doubling time as a marker. In this case with this patient, he has a pelvic lymph node. If his PSA were going up slowly and he just had the 1 pelvic lymph node, we might argue to maybe treat this with radiation. But this patient’s PSA is going up very quickly and it’s almost exponential. And in that case, I generally think exponential rise is associated with systemic disease, and probably not something that will benefit greatly from local therapy. So, in a situation like this, I would consider treating this patient with a systemic therapy, if I have one, and it typically would be a secondary hormonal therapy.

I think, currently, next-generation AR-targeted agents are considered a standard of care. I refer to enzalutamide, which actually targets the androgen receptor. We have apalutamide, which we’re expecting will become available, a very active drug that looked really good in phase I and II trials. Darolutamide similarly looks very good in the phase I and II trials and is in phase III studies.

So, I think the future for the management of this disease will be the selective use of AR-targeted drugs in patients with nonmetastatic disease, based on a risk profile that’s likely to be based mostly on their PSA doubling time and other factors that could arise, such as genomic profiles and things like that.

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