Rapidly Expanding Options in mCRPC


Evan Y. Yu, MD: One thing I discuss is that there are 6 regulatory approved agents in the United States that lead to a survival benefit for patients with metastatic castration-resistant prostate cancer. If you consider that patients who have microsatellite instability can receive pembrolizumab—that does happen in maybe around 5% of men with metastatic castration-resistant prostate cancer—that could add a potential seventh option for select patient populations. Pembrolizumab, as we know, is a PD-1 antibody that leads to many improved outcomes across many disease states. For an unenriched population with prostate cancer, there are ongoing trials in combination and in select populations. So, we still have to see, but certainly for microsatellite instability that drug can be used as well.

I think another exciting area in metastatic castration-resistant prostate cancer is the concept behind finding DNA repair mutations. This includes BRCA1, BRCA2. This patient did undergo germline testing, but you could develop somatic alterations as well. That can happen in around 23% of patients with metastatic castration-resistant prostate cancer. About half of those patients in the studies had germline alterations. But biallelic alterations that are somatically occurring happen as well.

Now, when one has a DNA repair alteration, that might make them exquisitely sensitive to agents like PARP inhibitors. The PROfound trial recently showed an important progression-free survival benefit with the addition of a PARP inhibitor, olaparib, for men who have metastatic castration-resistant prostate cancer and DNA repair deficiency. We’re waiting to see what the FDA says, but that could come out as soon as this is posted. We’ll see. It could be very soon. But I anticipate that’s another treatment option to come.

And obviously there are many other exciting treatments. I think another thing that’s around the corner is novel radiopharmaceuticals—radioligand therapies, theranostics, as one might say—that are targeted towards highly-expressed proteins on prostate cancer like PSMA [prostate-specific membrane antigen].

For instance, lutetium is another radiopharmaceutical tagged to a small molecule that can find PSMA on prostate cancer cells. The randomized phase 3 VISION trial has completed accrual, and we’re waiting for results. Obviously, there are many other exciting areas that are being explored in prostate cancer, and I could go on and on forever, but those are some of the things that I think are right around the corner.

Transcript edited for clarity.

Case: A 66-Year-Old Man with Metastatic Castration-Resistant Prostate Cancer

Initial presentation

  • A 66-year-old man presented with increasing difficulty walking and sleeping on his back due to lower back and hip discomfort
  • PMH: hypertension, medically controlled; no known family history of cancer
  • PE: DRE revealed a nodular prostate; otherwise unremarkable

Clinical workup

  • Biopsy with TRUS showed adenocarcinoma of prostate
    • Stage T2N0M0
    • Grade group 4
    • Expected survival > 5 years
  • Germline testing: MLH1, MSH2, MSH6, PMS2, BRCA1/2, ATM, PALB2 and CHEK2
  • Chest/abdominal/pelvic CT scan showed no evidence distant metastases or lymph node involvement
  • Bone scan was negative
  • PSA 26 ng/mL

Treatment and Follow-Up

  • EBRT for 8 weeks + neoadjuvant concurrent, and adjuvant ADT for 2 years
  • At 6 months post-ADT follow-up; PSA 5.9 ng/mL
  • At 12 months follow-up:
    • Patient reported continued back discomfort, difficulty walking and loss of appetite
    • PSA 16 ng/mL
    • Bone scan showed multiple lesions in the right femur and pelvis
    • Abiraterone + ADT was initiated for 1 year
  • At subsequent follow-up:
    • Patient complained of increased bone pain in right femur
    • PSA 18.6 ng/mL
    • Abiraterone was ceased; ADT continued
    • Treatment with radium-223 dichloride was initiated; 6 infusions completed and well-tolerated at post-infusion follow-up
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