The Role of Molecular Testing in mCRPC


Prostate cancer expert, Matthew R. Smith, MD, PhD, shares his thoughts about importance of testing in treatment of metastatic castration-resistant prostate cancer (mCRPC).

Matthew R. Smith, MD, PhD: The patient had reported no family history of prostate cancer, but that's a relatively insensitive predictor of having an inherited alteration in a cancer susceptibility gene. The lack of a family history would not discourage me from recommending both germline and tumor genetic testing in this patient. We offer germline genetic testing to all patients with recurrent or de novo metastatic disease and specific younger individuals with high-risk localized disease for the purpose of looking for either DNA repair defects or mismatch repair. Identification of either of those alterations could inform subsequent treatment decisions. For patients who do not have germline alterations or did not have prior germline testing, we'd also recommend tumor genetic testing. We typically recommend that at progression, despite first-line treatment for mCRPC because that's the first point at which that information would currently be actionable. For patients who have an identified pathogenic mutation in a DNA repair gene, whether germline or somatic, they may be candidates for a PARP inhibitor either after an androgen receptor pathway inhibitor or after an androgen receptor inhibitor and docetaxel. The prevalence of those mutations is approximately 10% of mismatch repair alterations. MSI [microsatellite instability]high is less common at about 1% to 3%. In the rare patient who has those alterations, we would consider treatment with pembrolizumab.

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
Related Videos
Experts on prostate cancer
Expert on prostate cancer
Experts on prostate cancer
Expert on prostate cancer
Experts on prostate cancer
Experts on prostate cancer
Experts on prostate cancer
Related Content