Abiraterone + veliparib in treatment of men with mCRPC

Another important set of data that came out of the ASCO session that your sitemaster was unable to attend were the data presented by Dr. Maha Hussain on the use of the PARP inhibitor veliparib.

We already know that the PARP inhibitor olaparib (which is marketed as Lynparza®, but not yet approved for the treatment of prostate cancer) appears to be effective in treating some men with castration-resistant prostate cancer — most particularly those who carry the BRCA1/2 genes. Hussain et al. (see ASCO abstract 5010 and this report on the MedPage Today web site) have now shown that treatment of men with a combination of abiraterone acetate (Zytiga) + prednisone + veliparib (a PARP1 inhibitor) seems to have beneficial effects in subsets of men with metastatic, castration-resistant prostate cancer (mCRPC) along with ETS fusion-positive disease, ETS fusion-negative disease, and/or DNA disease repair gene deficient tumors.

Hussain and her colleagues enrolled men with recurrent mCRPC into a Phase II clinical trial in which they could be treated with either

  • Abiraterone acetate + prednisone (Arm A) or
  • Abiraterone + prednisone + veliparib (Arm B)

The patients were also stratified based on their ETS fusion status. Every patient also was given a metastatic disease tissue biopsy, which allowed the research team to know their ETS fusion status and also whether they had some type of DNA repair gene deficiency (inclusive of a whole bunch of genetic defects like BRCA 1, BRCA 2, ATM, FANCA, PALB2, RAD51B, and RAD51C).

Here is what was found:

  • 185 patients underwent the metastatic biopsy.
  • 153 patients were actually randomized to Arm A (n = 74) or Arm B (n = 79).
    • 135 were white; 12 were black; 6 were “other”.
    • Average (median) age was 68 years.
    • Average (median) PSA level at study entry was 35.4 ng/ml.
  • PSA responses (defined as a drop in PSA level to ≤ 50 percent of the study entry level) was seen in
    • 63 percent of men in Arm A
    • 67 percent of men in Arm B
  • An objective response was seen in
    • 36 percent of men in Arm A
    • 49 percent of men in Arm B
  • Average (median) progression-free survival was
    • 8.5 months for men in Arm A
    • 11.o months for men in Arm B
  • With respect to time on therapy (with each cycle lasting for 28 days)
    • 30 percent of men in Arm A were on therapy for ≥ 12 therapy cycles
    • 16 percent of men in Arm A were on therapy for ≥ 18 cycles
    • 34 percent of men in Arm B were on therapy for ≥ 12 therapy cycles
    • 20 percent of men in Arm B were on therapy for ≥ 18 cycles
  • There were no differences in response by ETS fusion status.
  • There were distinct differences in response by DNA gene repair deficiency status.
    • 18 patients had some type of DNA repair gene deficiency
    • > 80 percent of these patients in each arm had a PSA response (as defined above)
    • Average (median) PFS for patients with no DNA gene repair deficiencies was 7.8 months.
    • Average (median) PFS for patients with some type ofDNA gene repair deficiency was 13.8 months.
  • Hyperglycemia was the most common Grade 3/4 adverse event (in ≥ 5 percent of patients in both arms).

Hussain et al. concluded that, not only was this first-ever metastatic, biomarker-based trial feasible. In addition,

  • The therapeutic trend favored patients in Arm B over Arm A with respect to PSA response rate, overall response rate, duration of treatment, and metastatic progression-free survival.
  • Exploratory analysis suggests that men with DNA repair gene deficiencies did better on Arm B than on Arm A.

This trial appears to confirm the potential value of PARP1 inhibition in the treatment of at least some patients with mCRPC. However, knowing whether the patients are actually responding or not will be a problem since a PSA response was only evident in the subset of men with DNA repair gene deficiencies.

Clearly this is relatively good news for the men very late stage disease (and particularly for those men who have DNA repair gene deficiencies), but  what we still need more than anything else is better drugs that can significantly delay progression to onset of mCRPC in the first place

2 Responses

  1. I believe the correct spelling of this drug is “veliparib”.

  2. Good catch Tom. Thank you. The text above has been adjusted accordingly.

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