As Sally Church, PhD noted on Pharma Strategy Blog, the 2012 annual meeting of the American Association for Cancer Research (AACR), recently held in Chicago, showcased many new cancer products in early development.
Cancer new products have a high attrition rate as they move through the development pipeline, so any promising results seen in early stages of development must be viewed with caution.
Results from laboratory studies using cell lines or trials in animals do not always translate into new drugs that work in man, e.g. they may have an unacceptable toxicity, not target the driver mutation, or adaptive resistance may just lead to the cancer bypassing the blocked pathway.
However, scientific meetings such as AACR do provide a window into the possible new drugs of the future. One prostate cancer new product that caught my attention at AACR 2012 as one to watch is AZD3514.
Sarah Loddick from AstraZeneca gave one of the few oral presentations at AACR on this exciting new compound. This was the only AACR session I attended where I was able to access wifi. Some of my live-tweets are captured in the Storify below (click here to access this on Storify):
Unfortunately, Sarah Loddick has not (as of time of writing) shared a copy of the AZD3514 prostate cancer poster that she presented later in the meeting, so I’m unable to write more about the preclinical prostate cancer data.
AZD3514 is a novel selective androgen receptor down-regulator (SARD) and has a different mechanism of action to drugs such as enzalutamide (MDV3100) that functionally inhibit AR signaling by binding to the AR & AR splice variants.
Sarah Loddick concluded at the end of her oral presentation that AZD3514:
- inhibits prostate cancer growth in vitro & in vivo
- has activity against wild-type and mutated AR
- has activity in pre-clinical models that represent castration resistant prostate cancer (CRPC)
- inhibits seminal vesicle growth in rats in the presence of physiological levels of circulating tumor cells.
AZD3514 is in a multi-center phase 1 clinical trial in patients with metastatic CRPC in Europe (NCT01162395) and Japan (NCT01351688). I look forward to seeing the presentation of the results from these trials.
From what I saw at AACR, AZD3514 is a new prostate cancer drug to watch.
Update April 20, 2012
I was delighted to receive an email this morning from Sarah Loddick of AstraZeneca with a copy of the AZD3514 poster that I requested (AACR abstract #3848): “Pre-clinical profile of AZD3514: a small molecule targeting androgen receptor function with a novel mechanism of action and the potential to treat castration resistant prostate cancer.”
I am sensitive to the unpublished status of much of the research presented at AACR, but without giving too much away, some of the key messages from this poster are that AZD3514:
- Binds to the androgen receptor (AR) ligand binding domain & reduces viability of prostate cancer cells in vitro.
- Inhibits AR transcriptional activity within 2h of exposure in LNCaP cells, and reduced both PSA & TMPRSS2 mRNA
- Inhibits AR induced translocation to the nucleus
- Causes AR down-regulation in prostate cells in vitro
- Causes AR down-regulation in rat R3327H prostate tumors
- Has activity in pre-clinical models of CRPC
A drug such as AZD3514 in prostate cancer could potentially be used to overcome resistance to enzalutamide (MDV3100), or alternatively it could be used ahead of enzalutamide if it has the potential to avoid resistance and offer better outcomes. We obviously will have to wait for clinical data to see what it’s true potential is and the data from AACR, while promising, is still only preclinical.
The prostate cancer market is a busy one and companies with AR targeted new products in development will have to offer drugs that are superior to enzalutamide if they wish to have lasting commercial success.
Update June 6, 2013: AstraZeneca terminates development of AZD3514 in Advanced Prostate Cancer
At ASCO 2013 it was announced that the development of AZD3514 in advanced prostate cancer has been terminated. You can read more about what happened in the first-in-human clinical trial in my AZD3514 blog post from ASCO 2013.