I’ve been following the development of Oncogenex’s custirsen for a while based on various posters presented at meetings such as ASCO and AUA, but with the publication of phase II data in prostate cancer, it seems a good time to discuss the compound in more detail.

According to Oncogenex:

“OGX-011, also known as custirsen sodium, inhibits the production of clusterin, a protein that is associated with treatment resistance in a number of solid tumors, including prostate, breast, non-small cell lung, ovarian, and bladder cancers.”

Essentially, I think of it a chemo-enhancer, although more technically, it seems to help delay the onset of resistance developing by targeting clusterin (CLU).  CLU is a stress-activated cytoprotective chaperone.  It is upregulated by a several cancer drugs and confers resistance when overexpressed.

Low levels of CLU are therefore more desirable and may be useful as a predictive biomarker of response.

Previous data on custirsen from the phase II front-line trial showed an encouraging shift to the right in the survival curves, validating the hypothesis that resistance is delayed:

The current phase II clinical trial received support from both Sanofi and Oncogenex. Results were reported by Saad et al., (2011), who assessed the weekly administration of custirsen in combination with either docetaxel or mitoxantrone in second-line metastatic castrate resistant prostate cancer (CRPC).  Patients had previously been treated with a minimum of 2 cycles of a docetaxel-based chemotherapy regimen and progressed during or within 6 months of discontinuation of docetaxel treatment.

Overall, patients (n=42) were randomized to receive either docetaxel + prednisone + custirsen (DPC) or mitoxantrone + prednisone + custirsen (MPC).

What did the data show?

Given that the preclinical in vitro and in vivo models have demonstrated the potential of custirsen to enhance chemotherapy and reduce docetaxel resistance, I was keen to see how the concept would pan out in humans.  We all know that preclinical evidence is no guarantee of success in clinical trials!  Although the primary goals of the trial were to measure safety and tolerability, the effects on tumour response and disease progression were interesting.

DPC (n=20):

  • Received: median of eight cycles
  • Overall survival:15.8 months
  • TTPP: 10.0 months
  • 10 of 13 (77%) evaluable patients had pain responses
  • Three of 13 (23%) evaluable patients had objective partial responses
  • PSA declines of ≥90%, ≥50%, and ≥30% occurred in 4 (20%), 8 (40%) and 11 (55%) patients, respectively.

MPC (n=22):

  • Received a median of six cycles
  • Overall survival was 11.5 months
  • TTPP was 5.2 months
  • 6 of 13 (46%) evaluable patients had pain responses
  • No objective responses were observed
  • PSA declines of ≥50% and ≥30% occurred in 6 (27%) and 7 (32%) patients, respectively.

Based on experience, we would expect the results with docetaxel chemotherapy to be better than mitoxantrone, since the latter is only palliative at best.

Additionally, custirsen treatment was shown to significantly decrease levels of the target protein, CLU, and low serum CLU levels during treatment demonstrated superior survival.

Two phase III trials in combination with docetaxel are now ongoing in both the first and second line setting in CRPC.  The trials are currently enrolling patients, so results will not be available for a while, ie 2013 at the earliest.

Many of you will remember the video discussion from the American Urological Association meeting earlier this year, where we highlighted the potential for custirsen in combination with an AR antagonist such as MDV3100 from Medivation/Astellas.  For those interested, the initial data from the custirsen/MDV3100 combination is shown in the short vlog.

In the meantime, the results look most encouraging, although there is a-ways to go yet, since phase II data is no guarantee of phase III performance.

{Update: Luke Timmerman from Xconomy posted about the slow recruitment to the phase III trials and the protocol amendment to include Sanofi’s cabazitaxel (Jevtana).

References:

rb2 large gray Custirsen   a new treatment for castrate resistant prostate cancer?Saad, F., Hotte, S., North, S., Eigl, B., Chi, K., Czaykowski, P., Wood, L., Pollack, M., Berry, S., Lattouf, J., Mukherjee, S., Gleave, M., & Winquist, E. (2011). Randomized Phase 2 Trial of Custirsen (OGX-011) with Docetaxel or Mitoxantrone in Patients with Metastatic Castrate-Resistant Prostate Cancer: CUOG Trial P06c Clinical Cancer Research. DOI: 10.1158/1078-0432.CCR-11-0859