MCSPC: Treatment After Progression on AR-Targeted Therapy

Charles Ryan, MD: This patient has reached a critical point. He is resistant to second-generation AR-targeted drugs, and he’s also essentially resistant to docetaxel chemotherapy. Or let’s just say that he has disease progression despite docetaxel chemotherapy.

There are a few options of FDA-approved drugs for patients with CRPC [castration-resistant prostate cancer] that we have not talked about. We’ve not talked about radium 223 dichloride, and we’ve not talked about sipuleucel-T. One might wonder if those are reasonable options for this patient. My approach, and my opinion, based on the data, is that this is not a patient who would be appropriate for either of these treatments.

I do use sipuleucel-T, but I don’t use it in the majority of my patients, and I don’t use it in patients who have symptomatic CRPC, and I don’t use it in patients with rapidly progressing visceral metastases. The reason for that is sipuleucel-T probably exerts some effect on survival and disease progression when it’s given earlier in the clinical course, perhaps as a lower volume of disease.

If I were going to use sipuleucel-T in this patient, I might go back in time to when his PSA [prostate-specific antigen] level was 10 ng/mL and he was beginning to progress after the docetaxel. In that setting he’s likely to do just fine from a symptom perspective for a long time.

Recall that sipuleucel-T does not induce a remission. It does not take PSA down, except in a minority of patients. And it’s not really known to reverse symptoms or shrink tumors. It simply slows the progression of the disease. That may be of significant benefit for some patients, and when we looked at in a phase 3 study across a whole population of prostate cancer patients, we demonstrated that actually it does exert a survival benefit. That’s important, but at this point with the liver metastases, the new boney lesions, and the rising PSA, this is not really a situation where sipuleucel-T is going to be the answer.

Similarly, radium 223 dichloride is a treatment that is really designed for bone disease and is really approved for patients with symptomatic boney disease.

He is not at this point complaining of a significant amount of new pain, but we are seeing new boney lesions develop, and he’s also got the liver metastases. Radium 223 dichloride is a bone-targeted therapy that is not going to have any effect on those liver metastases, and those liver metastases may be the biological process that is most likely to lead lethality for this patient.

We really need to address those liver metastases, and we can’t do that with radium 223 dichloride, and we’re not going to see much benefit from sipuleucel-T, because that window closed about a year ago for this patient.

That leaves us with second-line chemotherapy, and this is a patient with docetaxel resistance who now may benefit from cabazitaxel. Cabazitaxel is a therapy that has regulatory approval for exactly this indication: for patients who have already received docetaxel chemotherapy who are developing disease progression.

Let’s go back and think about some of the cases here and why we might want to choose docetaxel in this setting. What are the factors we want to consider for this patient in terms of his adverse-effect profile, quality of life, etc.

This patient, if we’ve been doing the math correctly, is now 3 years on from the time of diagnosis of prostate cancer. He’s probably about 70 years old. We don’t have any additional history about a cardiac history of stroke or diabetes or anything like that that has taken hold of him that might impact our choice of subsequent therapy. I think that’s good. It leaves a blank slate for us in terms of talking about the adverse effects of treatment.

Here we are in the setting of abiraterone resistance, and based on our case, he’s still on the abiraterone but he’s developing disease progression. The 1 question is, “Should we add chemotherapy to the abiraterone, and is that of really any benefit?” The truth is, there is some emerging benefit that the combination is feasible. There was a study called “abi-cabazy,” where cabazitaxel and abiraterone were completed. And there’s some ongoing work looking at docetaxel-abiraterone combinations.

It’s fair to say that that remains an interesting question, but I wouldn’t say that we have level 1 evidence at this time to say that both therapies should be continued. For the time being, I consider this to be abiraterone-resistant disease, and not 1 where I still need that suppression of the androgen production from the abiraterone. I hope I’m proven wrong in that maybe combination approaches can be demonstrated to be superior to a single agent. But in this setting we’re most likely well served by simply discontinuing the abiraterone, continuing the prednisone, and adding in cabazitaxel.

Transcript edited for clarity.

Case: A 67-Year-Old Male with Metastatic Castrate-Sensitive Prostate Cancer

Initial presentation

  • A 67-year-old active man presented with intermittent back pain and loss of appetite
  • PMH: unremarkable
  • FH: the patient’s father suffered a myocardial infarction at age 69; paternal grandmother had dementia; no known family history of cancer
  • PE: DRE revealed asymmetric enlarged prostate; PE otherwise unremarkable

Clinical workup

  • Core needle biopsy with TRUS showed adenocarcinoma of prostate
    • Stage T2N0M1b
    • Grade group 3
  • Bone scan reveal 3 spinal lesions (T10, L2, L3) and 1 near the left iliac crest
  • Abdominal and pelvic CT scan showed no other organ metastases
  • PSA 24.9 ng/mL

Treatment and Follow-Up

  • The patient was counselled on treatment options; he expressed concern regarding long-term AR exposure
  • DOCE + ADT was initiated, 6 cycles were well-tolerated; PSA 6.2 ng/mL
  • 2-year follow-up PSA 10.8 ng/mL; continued treatment regimen
    • 5 months later he reported increasing back pain and difficulty walking
    • PSA 21.4 ng/mL
    • PSADT 5.1 months
    • No new bone lesions on imaging
  • Abiraterone 1000 mg PO qDay + prednisone 5 mg PO q12hr was initiated
  • 1 year later PSA 30.2 ng/mL
    • Abdominal/pelvic CT showed multiple new small liver lesions, 1 new vertebral lesion and 1 new appendicular lesion
  • Treatment with cabazitaxel 20 mg/m2 IV q3W + prednisone 10 mg PO qDay was initiated
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