Initial Treatment Options for mCRPC


Dr Matthew R. Smith reviews initial treatment options for a patient with metastatic castration-resistant prostate cancer (mCRPC).

Matthew R. Smith, MD, PhD: For patients who've received primary androgen deprivation therapy, the standard options as first-line treatment for mCRPC include an androgen receptor pathway inhibitor—drugs like abiraterone acetate or enzalutamide, or docetaxel chemotherapy. There are other approved options including sipuleucel-t. Other agents like radium-223 would typically be used in later lines of therapy. There are approved PARP inhibitors, but those 2 are approved only in specific molecular subsets and in later lines of therapy.

In this case, we have a patient with castration-resistant prostate cancer. He had previously documented metastases by conventional imaging, but interestingly enough, at the time of his progression to CRPC, conventional imaging showed no detectable cancer, and it was really only what remained visible or was visible by PSMA PET, a more sensitive imaging modality. In this case[…]it sort of falls in this gray area of whether he's metastatic or non-metastatic by conventional nomenclature. We certainly know he has distant spread, but it's whether or not it's detectable by conventional imaging. The choice of initial salvage therapy with enzalutamide is very reasonable. He did have a PSA decline, as most patients would, but in this older gentleman with some other medical comorbidities, he did not tolerate therapy well and chose to discontinue treatment because of what he described as profound fatigue and difficulty with ambulation. I certainly would not be enthusiastic about persisting or pursuing continued treatment given those side effects.

He was monitored closely while off treatment for several months, and only when we saw a resolution of those symptoms were we comfortable in retreating him. We made the decision to treat him with darolutamide based on his disease state and prior intolerance of enzalutamide. Darolutamide lacks blood-brain barrier penetration. While there are no head-to-head phase 3 trials between darolutamide and enzalutamide, comparison between the phase 3 studies in non-metastatic CRPC suggests a better tolerability of darolutamide. Further support for that point was made in a French trial (ODENZA) that did a head-to-head comparison looking at patient preference between darolutamide and enzalutamide. In that trial, darolutamide had the edge with more patients preferring darolutamide over enzalutamide.

Thankfully, the patient did tolerate darolutamide well and remains on treatment and his PSA continues to decline on therapy, but we do recognize that mCRPC is not yet an approved indication for darolutamide. This patient kind of falls in this gray area because his PSMA PET was the only basis for visible metastatic disease when we treated him. The other reason that it was reasonable to treat him in this fashion was that he had an intolerance of prior enzalutamide treatment.

Transcript edited for clarity.

Case: A 82-Year-Old Man with Metastatic Castration-Resistant Prostate Cancer

Sept. 2016

Initial presentation

  • A 82-year-old man with nocturia

Clinical workup

  • Abnormal digital rectal exam, PSA 31 ng/mL
  • No family history of prostate cancer
  • Diabetes and hypertension, both of which are managed with medications, neuropathy and uses a cane for long distances
  • Prostate biopsy confirms advanced adenocarcinoma of the prostate and Gleason score of 8 (4 + 4)
  • Bone scans show no detectable spread to bone, abdominal pelvic CT scan shows enlarged pelvic and retroperitoneal nodes consistent with metastatic prostate cancer.
  • His ECOG PS is 1


  • Patient starts continuous ADT in October 2016.
  • PSA levels go down to undetectable levels within 3 months after start of treatment. Levels are checked every 3 months thereafter.
  • Patient undergoes repeat abdominal pelvic CT scan after completing a year of therapy which show resolution of pelvic and retroperitoneal nodes.

April 2018

  • An increase in PSA is seen and PSA levels are 2.7 ng/ml, with PSA doubling time of 6 months
  • Patient undergoes conventional imaging with bone scan and CT that show no detectable prostate cancer.
  • PSMA PET scan shows multiple areas of increased uptake in pelvis and retroperitoneum, consistent with previously identified sites of metastasis.
  • Lab tests are normal and patient has adequate liver, renal and bone marrow function.
  • Patient is treated with enzalutamide (160 mg/day) and PSA levels decline
  • After some time on enzalutamide, patient decides to discontinue treatment due to fatigue and problems with gait.
  • Symptoms resolve on their own after going off treatment for a few months
  • Patient is started on darolutamide and continued ADT (leuprolide depot) and remains on this treatment
  • PSA levels stay undetectable on treatment
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