Unmet Needs and Key Takeaways in mCRPC


Matthew R. Smith, MD, PhD, discusses areas of unmet needs and clinical pearls for the management of patients with mCRPC.

Matthew R. Smith, MD, PhD: We now have an abundance of treatment options for prostate cancer, but important unmet needs remain. We have 4 approved androgen receptor pathway inhibitors. This is valuable to managing an individual patient because the differences in the safety and tolerability profile of those drugs may help optimize the therapy choices for an individual patient, but it's important to know that patients derive most or all of the benefit from an androgen pathway inhibitor with the first drug.

There's a tremendous cross-resistance between available androgen receptor pathway inhibitors, and the switch from 1 androgen receptor pathway inhibitor to the other, for progression is associated with very low response rates in a short duration of response. That there's this high cross-resistance between androgen receptor pathway inhibitors is notable and represents an area of major unmet need. A number of studies are attempting to address this by either adding an additional targeted therapy to extend the benefit of an androgen receptor pathway inhibitor or using novel approaches to target the androgen receptor pathway and achieve responses after progression despite a conventional or currently available androgen receptor pathway inhibitor.

We continue to make steady progress in the management of metastatic prostate cancer. One of the important recent developments is the positive results of PSMA lutetium [lutetium-177–PSMA-617]in a phase 3 clinical trial in patients with treatment-refractory mCRPC. That study shows improvement in progression-free and overall survival with PSMA lutetium compared with best standard of care in patients with mCRPC and cancer progression, despite prior therapy with an androgen receptor pathway inhibitor as well as docetaxel. We anticipate that the positive results will lead to regulatory approval, and when available, it will be an important option for patients with very advanced disease. There are other PSMA targeted approaches in development that are also interesting. We expect that future development plans will include introduction of PSMA-targeted therapy in earlier lines of metastatic prostate cancer.

This is an exciting time in prostate cancer. We have more options than ever to manage patients with advanced disease. My key advice to my colleagues who care for patients with prostate cancer is to follow the evidence. We have strong evidence that androgen receptor pathway inhibitors, when introduced early, improve clinical outcomes, including progression-free, metastasis-free, and overall survival. Despite that evidence, data from the community suggests that there were low rates of uptake in certain clinical settings. We need to have shared decision-making with patients and consider interventions that have proven benefit, including a wide range of disease states from mCSPC, non-metastatic CRPC, as well as CRPC.

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
Recent Videos
Video 8 - "Clinical Pearls for Optimal Management of mHSPC"
Video 7 - "Multidisciplinary Approach in mHSPC Management "
Video 6 - "Treatment Considerations in High Disease Burden and Comorbidities"
Video 5 - "Pivotal Trials in mHSPC"
Video 4 - "ARASENS Trial- Darolutamide in mHSPC"
Video 3 - "Treatment Intensification in Metastatic Prostate Cancer"
Related Content