Treatment Options Upon Progression on ADT


Prostate cancer expert Dr Smith elaborates on treatment options for patients with metastatic castration-resistant prostate cancer (mCRPC) who have progressed on systemic therapy.

Matthew R. Smith, MD, PhD: For most patients in our practice, the second drug after androgen deprivation therapy is an androgen receptor pathway inhibitor, and that would be true in either metastatic castration-sensitive prostate cancer, non-metastatic CRPC, or in mCRPC. With progression on an androgen receptor pathway inhibitor, we have choices. The disease state we're now talking about would be patients with mCRPC and disease progression despite prior androgen receptor pathway inhibitors. Among available approved options, our standard approach would be to use docetaxel. That's not a decision we would take lightly. An important point to make here is that we wouldn't switch systemic treatments in this setting based on PSA progression alone. We would continue the androgen receptor pathway inhibitor until radiographic and/or clinical progression.

There are now newer options for at least molecular subsets of patients in this disease state, including olaparib, based on the results of the pivotal PROfound (NCT02987543) study. The study included patients with mCRPC and disease progression on an androgen receptor pathway inhibitor and patients could also have received prior docetaxel, and about half of the patients did receive that. PROfound also included patients with a germline or somatic mutation in a DNA repair gene, and it showed an improvement in progression-free and overall survival in favor of olaparib, at least in the BRCA1 and BRCA2 primary cohorts. This is important information and a strong rationale to do tumor genetic testing and germline genetic testing in patients. We typically offer germline genetic testing for all of our patients at diagnosis with metastatic prostate cancer and then do tumor genetic testing typically after they develop mCRPC and progression after first-line 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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