Frontline Treatment Options for mCRPC


Dr Tomasz M. Beer comments on approaching first-line therapy for a patient with metastatic castration-resistant prostate cancer (mCRPC).

Tomasz M. Beer, MD, FACP: For initial treatment of metastatic disease when it’s diagnosed, I’d be happy to expand on that. Historically, we have used conventional hormonal therapy, and the classic approach is a month of oral first-generation androgen signaling inhibitor like bicalutamide and conventional ADT [androgen deprivation therapy] with injectable, typically leuprolide. There are other choices as well, of course. Over the last nearly decade, we’ve seen the emergence of clear evidence that intensifying that initial regimen yields better progression-free survival and overall survival, and we now have evidence for doing that with a combination of leuprolide or equivalent with docetaxel, abiraterone, enzalutamide, and apalutamide.

How 1 chooses between those options ends up being an individualized decision. For low-volume patients such as this patient, we don’t have clear evidence supporting docetaxel. We have some evidence, and 1 could parse the data, but the original CHAARTED study did not reveal an advantage in low-volume patients for the additional docetaxel. The subsequent STAMPEDE study suggested that the benefit was there; it’s a debated point. But many practitioners will choose a 2-drug hormonal combination for low-volume patients. For high-volume patients, any of the 4 options are reasonable, and they haven’t been compared head-to-head directly, so it’s difficult to make a strong case for 1 particular choice.

A major component of our decision involves patients’ comorbidities and patient preferences. There are differences among these treatments in adverse effects and cost. It ends up being an individualized discussion, and there’s not 1 single answer for every patient.

The big question in the field is would a triple combination work even better. At ESMO [European Society for Medical Oncology Congress] in September 2021, we saw the presentation of the longer-term follow-up of the PEACE1 study, where Dr Karim Fizazi reported that a randomization between conventional ADT plus docetaxel, with or without abiraterone, showed a benefit in terms of radiographic progression-free survival and also overall survival, arguing that perhaps a triplet is the future. The benefit was clearly seen in higher-risk, higher-volume patients, the data are not as mature in the lower-volume patients, and we have to digest and understand and think about those data. But at least for the highest-risk patients, we’re going to start thinking about triplet combinations.

We do have an upcoming triplet trial, and that’s a trial examining ADT plus docetaxel plus darolutamide. Distinct from the trials of enzalutamide and apalutamide, this study is evaluating a triplet. It will be very interesting to see if it yields results that are in line with what we saw in PEACE1.

In this case, I might have taken a somewhat different approach at 2 points. One is when we saw a rapidly rising PSA after surgery. That would be a place where deploying high-sensitivity imaging such as PSMA [prostate-specific membrane antigen], PET [positron emission tomography]/CT, and Axumin PET/CT would have been something that we would consider. That might have led to a different decision regarding salvage radiation. Second, salvage radiation is typically given with a course of hormonal therapy. Several randomized studies have shown superior results with that combination. Finally, at the moment when the patient was diagnosed with metastatic disease, the standard of care is to use a doublet therapy. I would have considered prescribing leuprolide plus either abiraterone, enzalutamide, or apalutamide, and any of those combinations would have been supported by the data.

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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