Progression of Metastatic Prostate Cancer Defined

Jorge Garcia, MD:Regarding hormone-sensitive disease, I think there is a misconception as to what that really means. I think most of us defineadvanced prostate cancerinto castration-naïve, which are patients who actually have not received suppression of testosterone yet. Testosterone suppression is the backbone of treatment for men with prostate cancer since DHT, dihydrotestosterone, is the primary activator of the androgen receptor. Socastration-naïvemeans to me that you have not yet received testosterone suppressive therapy.Castration-sensitive, or what you’re describing as hormone-sensitive, would imply to me the lack of testosterone is leading to an improvement in outcome, meaning you are responding to a lack of testosterone, however you get that—either using LHRH [luteinizing hormone-releasing hormone] agonists, antagonists, or even if you decide to do a surgical orchiectomy. The goal of the game is medical castration for us. And the third one, which iscastration resistant, is when you develop progressive disease either by a rising PSA [prostate-specific antigen level], clinical symptoms, or radiographic progression—any of those 3 in the context of a low testosterone level, which for us in the field is a testosterone level of less than 50.

There are misconceptions around how one becomes castration-resistant or how one develops that state. I think there are many hypotheses regarding how men will do so biologically. But clinically, we do know that as long as you are suppressed—meaning that your testosterone level is under 50, which is what we call castrated levels of testosterone—your PSA level cannot rise. If you are on an active therapy while you’re suppressed, there is no possibility for you to have a rising PSA level if you are in fact castration sensitive, which means that you’re responding to treatment. So if at any given time your PSA level rises or you develop radiographic changes—meaning progressive disease on the scans, or if you develop new symptoms that are consistent and concerning for symptomatic progression—that defines a patient as castration resistant.

You do not need, however, the 3 of them. You don’t need symptoms, x-ray findings, and serological progression to meet that definition. Any of those 3, in the context of a suppressed testosterone level, will definecastration resistant. I think that’s important for the viewers to understand. It’s any of those 3. Now obviously, how you progress will define how we sequence you through treatment. If you have an asymptomatic patient with a rising PSA level on testosterone suppression, and they got ADT [androgen deprivation therapy]—abiraterone or ADT-chemotherapy, that sequence of treatments may be different from the patient who will become symptomatically or radiographically explosive in disease, if you will.

The natural history of prostate cancer is traditional in the sense that we know most people will first progress by PSA level. There is a lead-time bias between that PSA level that is going up and when the scans change. And once you have the scan findings, there is a gap in time between scan findings and symptomatic disease. That’s a very structured natural history that we all understand. So it’s very uncommon for us to see patients developing symptoms before PSA level rises and/or developing scan findings before their PSA level rises. There are a pocket of patients who do that, but the vast majority of patients, in the context of castration-sensitive progressing to castration resistant, will do so primarily by virtue of their PSA level.

Transcript edited for clarity.

Case: Met HSPCa Progressing to mCRPC

June 2016

H&P

• A 64-year old gentleman referred to a medical oncologist with lower back pain
• Initial work-up included:
  • PSA of 79.5 ng/ml
  • WBS showing 3 bone metastasis — 1 Right pelvic area and 2 in lumbar spine
  • CT Chest/Abdomen and Pelvis showed no pelvic lymph nodes and no evidence of visceral disease
  • TRUS/Bx revealed adenocarcinoma of the prostate gland with a Gleason score of 9 [5+4]
• PMH: HTN, Hyperlipidemia - both controlled on oral medications and a family history of colon cancer
• His KPS is 90% and the remaining of his blood work is unremarkable

Pt was started on ADT with LHRH agonist-based therapy and abiraterone + prednisone. He also was placed on monthly zoledronic acid.

• During therapy minimal AEs that included G1 fatigue, hot flashes and muscle aches
• Nadir PSA at 6 months was 0.9 ng/mL

August 2017

• Despite a Testosterone level < 50 ng/dL, patients PSA began to rise
  • PSA August 1.56 ng/mL
  • PSA November 4.4 ng/mL
  • Patient remain completely asymptomatic

February 2018

• Patient is complaining of new back pain (L spine radiating to right hip area) for which he takes over the counter NSAIDs
• PSA now is 6.5ng/mL
• Repeat WBS and CT C/A/P demonstrated 2 new lesions in L spine. No epidural disease or fractures and no evidence of visceral disease.
• Patient is diagnosed as minimally symptomatic Metastatic castration-resistant and abiraterone + prednisone was discontinued.
• Radium 223 therapy was initiated — 6 cycles were completed with improvement of bone pain and minimal AEs that included G1 fatigue and G1 anemia.
  • PSA during therapy ranged from 6.5 to 8.9ng/mL

September 2018

• Patient now is experiencing anorexia, fatigue and progressive abdominal pain
• WBS showed stable disease however CT C/A/P now showed progressive liver metastases
• PSA is now 10.7 ng/ml
• Hemoglobin is 10 g/dL, ANC is 3900 and Platelets are 331,000
• Normal Liver function tests (ALT/AST, Alk Phos, TBili) and LDH of 565

Patients is started on Docetaxel-based chemotherapy (75mg/m2 on 21-day cycles)

Patient completes 6 cycles of therapy with expected AEs including G1 fatigue, G1 alopecia and G1 peripheral neuropathy. His scans at the completion of chemotherapy showed SD with tumor burden reduction in liver lesions and SD in bones. His Hemoglobin level at the completion of chemotherapy is 12.1 g/dL and his ANC and platelets are also within normal limits.