Approaching Systemic Therapy for mCRPC


An expert in prostate cancer comments on selecting the optimal systemic therapy for metastatic castration-resistant prostate cancer (mCRPC) treatment.

Tomasz M. Beer, MD, FACP: The question is about the broad range of options of metastatic castration-resistant prostate cancer in terms of systemic therapy. Here, we have a series of drugs that have been FDA approved based on an overall survival advantage. In terms of drugs that are molecularly unselected, I think about sipuleucel-T immunotherapy, enzalutamide and abiraterone for metastatic disease, docetaxel, cabazitaxel, and radium-223 dichloride. We’ve got 6 agents that are FDA approved for metastatic CRPC [castration-resistant prostate cancer]. We also have pembrolizumab, which has a general approval for microsatellite unstable tumors, and that’s across histologies; it includes prostate cancer. That’s a rare situation in prostate cancer, but 2% or 3% of patients might qualify for that. Then we have olaparib and rucaparib approvals based on mutational status in metastatic CRPC after at least an androgen signaling inhibitor and, in the case of rucaparib, chemotherapy as well.

We have a host of options, and choosing between them ends up being an extraordinarily individualized exercise. The first thing we think about is the patient’s prior treatment history: what have they been exposed to so far, how they fared on that treatment, comorbidities, and which regimens they can tolerate and benefit from. That often narrows the choices. A lot of folks are treated for their initial disease, metastatic disease, with a 2-drug combination. A lot of folks present with nonmetastatic CRPC and end up on a next-generation androgen signaling inhibitor. By the time they get to metastatic CRPC, we may not have the abiraterone and enzalutamide treatment options available. In that context, we would choose a taxane chemotherapy, typically docetaxel first line. We would assess the patient tumor genotype and consider whether they might qualify for PARP inhibitors and, less commonly, pembrolizumab. We would typically use 2 lines of chemotherapy as necessary and radium-223 dichloride for bone-predominant disease in our practice after chemotherapy. That’s the general approach.

The field has seen a positive result out of the VISION phase 3 randomized clinical trial, which examined 177Lu-PSMA-617. It was the first targeted radiopharmaceutical in prostate cancer to produce a high response rate, a progression-free survival advantage, and an overall survival advantage in metastatic CRPC. The study was conducted in patients who had been relatively heavily pretreated and received at least 1 prior next-generation androgen signaling inhibitor and at least 1 taxane chemotherapeutic. It’s not FDA approved, but we’re certainly anticipating the likely possibility of FDA approval of 177Lu-PSMA-617 therapy. I see that as the most likely next addition to our armamentarium in this disease.

Transcript Edited for Clarity

A 62-Year-Old Man with Metastatic Castration-Resistant Prostate Cancer

Jan. 2017

Initial presentation

  • A 62-year-old man is found to have a firm prostate nodule of 1.5 mm on his routine physical exam

Clinical workup

  • PSA 15.5 ng/mL
  • Family history of prostate cancer
  • Hypertension
  • Digital rectal exam and transrectal ultrasound (TRUS) of the prostate confirm advanced adenocarcinoma of the prostate and Gleason score of 7 (3 + 4)
  • MRI shows lack of metastasis and node involvement (cT2bN0M0)
  • His ECOG PS is 1


  • In Feb. 2017, patient was treated with radical prostatectomy (RP) with nerve sparing surgery and there were no complications.
  • PSA levels go down to 0.3 ng/ml post-operatively but rise to 1.5 ng/ml within 3 months.
  • Patient receives local salvage radiation therapy and PSA goes down to 0.1 ng/ml.
  • PSA levels are checked every 3 months.

Nov. 2017

  • PSA doubling time increased between 2 last check-ups and now PSA is 3.5 ng/ml.
  • Patient undergoes CT and bone scans and is found to 1 metastatic bone lesion.
  • Patient is treated with androgen deprivation therapy (ADT), leuprolide, as continuous treatment and PSA levels go down to 0.2 ng/ml.

May 2018

  • PSA levels rise to 5 ng/ml, but patient is asymptomatic and has adequate organ and bone marrow function.
  • Patient meets the inclusion criteria for the ODENZA trial and is enrolled in it.
  • Patient is treated with darolutamide(1200 mg/day) for 12 weeks, followed by enzalutamide (160 mg/day) for 12 weeks, in addition to continuing on ADT
  • Patient is currently in the extension phase of the study and is being treated with darolutamide.
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