mCRPC: Sequencing Therapy

Jorge Garcia, MD:If you have a man with prostate cancer who has advanced disease, then again, as I alluded to before, we have to define based on the volume of disease. If you have high-volume de novo metastatic disease, the standard of care, in my opinion, is suppression of testosterone. You may use docetaxel, 6 cycles, 75 mg/m², on a 21-day cycle basis times 6 cycles. You stop, and the patient continues with testosterone suppression. Or you can do testosterone suppression—again, however you achieve that—and the oral agent, abiraterone acetate. That will continue until you either develop serological, clinical, or radiographic progression, or if you have drug intolerance.

Now, if you become castration resistant, then the next step for you is to define what you have seen before so we can define what sequence you get next. The existing treatment for castration-resistant disease may include oral therapy. Again, that depends on how you’re progressing. In the context of M0 CRPC [non-metastatic castration-resistant prostate cancer], which are men who do not have any evidence of metastases in the scans but who have a rising PSA [prostate-specific antigen level] in the absence of testosterone production, the standard of care now in the United States includes either enzalutamide, which is a novel oral AR [androgen receptor] inhibitor, or apalutamide, which is an oral AR inhibitor just recently approved in the United States. There is an agent called darolutamide, which is an agent that actually has not yet been FDA approved. However, we have existing phase III data that I’m sure that the regulatory agencies within the United States are looking at to define whether that agent will get a label in the M0 space.

Now, if you have M1 disease, which is metastatic castration-resistant prostate cancer, and you have not seen any chemotherapy and/or oral therapy such as abiraterone, then your option will be to get either oral therapy with abiraterone acetate, enzalutamide, or you can get immunotherapy. There’s an immunotherapy called sipuleucel-T, which is an autologous cell product. Or you can get radionucleotide-based therapy. Or you can get systemic chemotherapy. The standard frontline chemotherapy for men with castration-resistant disease with metastasis is docetaxel. We have a second-line agent called cabazitaxel.

So you can see we now have 6 or 7 life-prolonging agents for men with metastatic castration-resistant prostate cancer. The sequence and the right patient phenotype are completely unknown right now because we don’t have comparative data against all treatments. We only know that all these agents have the ability to make people live longer and are very effective in the context of their disease, but it’s hard to understand which is the ideal sequence for all-comers. Therefore, we personalize those treatments based on patients’ biology, patients’ prior response to therapy, and how they’re progressing—whether it’s biochemically, clinically, or radiographically. Those things are very important for one when making that decision as to what the best treatment for that patient is when they become castration resistant.

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.