Next Generation Androgen Receptor Inhibitors


Dr Matthew Smith discusses next generation androgen receptor inhibitors and data from clinical trials with these agents.

Matthew R. Smith, MD, PhD: In my practice, androgen receptor pathway inhibitors are a mainstay of treatment for patients with non-metastatic and metastatic castration-resistant prostate cancer. This class of drugs has brought approval across a wide spectrum of clinical disease states from metastatic castration-sensitive prostate cancer (mCSPC) and nonmetastatic castration-resistant prostate cancer (nmCRPC).

There are currently 4 approved androgen receptor pathway inhibitors in the United States: 3 anti-androgens—apalutamide, enzalutamide, and darolutamide—and an androgen receptor pathway inhibitor, abiraterone acetate. The efficacy of these agents, while rarely studied head-to-head, appears remarkably similar based on cross-trial comparisons. The choice of agents tends to focus on the expected tolerability in an individual patient. In non-metastatic castration-resistant prostate cancer, for example, there are 3 approved drugs: apalutamide, enzalutamide, and darolutamide. They were approved based on pivotal studies of remarkably similar design and, candidly, efficacy results that are highly overlapping with marked improvements in metastasis-free survival in each of the 3 trials and in overall survival benefit in the final survival analysis for each of those studies.

In contrast to the 2 other drugs, darolutamide does not cross the blood-brain barrier well and may lack some of the CNS side effects associated with the other drugs. Consistent with that nonclinical information, cross-trial comparison between the SPARTAN, PROSPER, and ARAMIS trials suggest that darolutamide lacks some of the CNS [central nervous system] toxicity with what appears to be less fatigue and no risk for falls or fractures. This case illustrates the importance of having choices so a patient who was intolerant of enzalutamide was able to still benefit from an androgen receptor pathway inhibitor by subsequent treatment with darolutamide. He tolerated that treatment well and continued to respond.

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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