Medivation will never get a drug approved dont worry. Remember these are the people that have had 2 failures and they actually believed Russian data and bought their compound. no threat there not bright enough.
This is an interesting find. First, just for clarification, this is a 4 year old article and not an abstract from ASCO G/U.
The premise is that in this particular cell line, which is androgen deprivation refractory, the resistance was actually acquired by a biological pathway triggered by the androgen deprivation therapy itself which then resulted in an upregulation of cMET expression.
Some caveats have to be attached to this. First, is that this is an observation of a single cell ine and the results might not be universally applicable to all cases of CRPC. The abiraterone experience has also demonstrated that CRPC does not equal HRPC. A fairly high percentage of hormone ablation resistance is probably due to the tumor developing the ability to produce its own Androgen rather than finding an alternative growth stimulus. Though this article addresses a possible mechanism for upregulation of cMET, it doesn't address the MOA that would explain Cabo's apparent ability to address bone met activity. The final sentence of the abstract makes a great argument for a frontline Abiraterone +/- Cabo pivotal trial.
The precise molecular mechanisms by which prostate cancer cells progress from androgen-sensitive to androgen-insensitive status still remain largely unclear. The hepatocyte growth factor/scatter factor (HGF/SF) plays a critical role in the regulation of cell growth, cell motility, morphogenesis, and angiogenesis. The aberrant expression of HGF/SF and its receptor, c-Met, often correlates with poor prognosis in a variety of human malignancies, including prostate cancer. Here, we investigate a potential link between androgen signaling and c-Met expression in prostate cancer cells. First, we showed that the androgen receptor (AR) represses the expression of c-Met in a ligand-dependent manner. Using different c-Met promoter/reporter constructs, we identified that Sp1 induces the transcription of c-Met and that AR can repress the Sp1-induced transcription in prostate cancer cells. Moreover, the data from electrophoretic mobility shift assay showed that AR interferes with the interaction between Sp1 and the functional Sp1 binding site within the c-Met promoter. Furthermore, we tested the effect of AR on c-Met expression in an androgen-insensitive prostate cancer cell line, CWR22Rv1. Finally, the repressive role of androgen signaling on c-Met expression was confirmed in prostate cancer xenografts. The above data indicate a dual role of AR in transcriptional regulation. Although the current androgen ablation therapy can repress the expression of growth-promoting genes that are activated by the AR, it may also attenuate the repressive role of AR on c-Met expression. Therefore, the therapeutic strategies to inhibit the activation of the HGF/c-Met pathway may be of benefit when combined with current androgen ablation treatment. [Cancer Res 2007;67(3):967–75]
Here's a paper that might shed some light on this thread:
The Androgen Receptor Negatively Regulates the Expression of c-Met: Implications for a Novel Mechanism of Prostate Cancer Progression
When the androgen receptor does not makes its way into the nucleus, Met is expressed.
<<You mean after MTC, right?>>
Doc, depending on the rate of accrual, MTC and Ovarian IND's could happen simultanously. Ovarian would get a priority review and MTC a standard review. When they did the Ovarian expansion cohort, one of the protocol changes was to stipulate fully refractory status. The originally reported ORR was 35%. They could get a sustantial dropoff in efficacy and still be able to do an accelerated filing. Hopefully they are still seeing something in 20-30% range for ORR. Subpart H filings usually require around n=100 and they only need a 24 week follow up after last patient enrolled. They started last Oct-Nov.
<<While Dr. Sher has worked with both agents, he could comment on relative safety profiles of the two, but I doubt could say too much about activity since they really haven't been tested in the same populations.>>
Doc's right. We are talking about two drugs, Cabo and MDV 3100, with vastly different means of action and their sponsors are targeting different disease segments. Trying to give a pat answer that one is better than the other is almost nonsensical. MDV 3100 and Abiraterone on the other hand are potentially very competitive.
It is EXEL's job now to design and negotiate a first pivotal trial in a CRPC indication that defines a population that will benefit with a protocol and andpoint(s) that will efficiently and reliably showcase Cabo's strengths.
Eventually (perhaps 2012) EXEL will move into a frontline prostate cancer indication in which Cabo will be paired with an Androgen blocker (likely abiraterone) like MDV 3100, and it will be a large long expensive trial with a survival endpoint.
The more crowded the space becomes with approved drugs (like MDV 3100) the longer and more problematic the eventual fronline trial becomes. However, I don't visualize an oncologist ever choosing between Cabo and MDV 3100 for a patient.
<<One thing I would like would be to see the panel give an opinion about an opportune specific population to target with Cabo.>>
I'm guessing the intitial indication will be CRPC with bone pain. ECOG 0 or 1.
I'm still hoping to hear more about the Ovarian expansion cohort. That could actually be the first NDA.
My recollection of the XL184 poster in Novemebr is that there was not a good correlation between disease measures like CT scan measurements and bone scan intensity and PSA. Wiscman's prior post is very informative and makes the point that PSA may be the wrong endpoint for assessing advanced prostate disease and that just makes it harder to compare XL184 with MDV3100. While Dr. Sher has worked with both agents, he could comment on relative safety profiles of the two, but I doubt could say too much about activity since they really haven't been tested in the same populations. One thing I would like would be to see the panel give an opinion about an opportune specific population to target with Cabo.
TKIs and PSA Response
PSA response (PSA decline>50%) has often been used as a marker of
efficacy in prostate cancer trials
• Based on experience with anti-androgens and chemotherapy
• Generally good correlation between PSA declines and tumor response
PSA expression is driven by AR signaling, but AR-independent
regulators of expression have also been described
• Cytokines (IL-6) and soluble factors released by osteoblasts regulate PSA in
Accumulating evidence suggests that PSA response is not an
appropriate measure of anti-tumor activity for TKIs
• Lack of correlation between PSA changes and tumor responses
• Different mechanism of action
Clinical data with TKIs in prostate cancer show disconnects between
PSA and imaging responses
• Phase 2 trials with sorafenib, sunitinib and cediranib show improvements in
imaging despite stable or increasing PSA
− PSA declines on treatment cessation noted
− Authors suggest PSA may not be an appropriate measure of clinical benefit
for this class of agents
It could be but what is the basis for that statement? It is further along for sure, but I'm not aware of any cross over data with patients getting both drugs (seeing how patients who fail one drug do on the other), nor of any comparative data. Since the agents work very differently, I would argue cross trial comparisons are not helpful. I would say the MDVN drug is further along (and have posted so for quite some time), but I don't know how to meaningfully compare the clinical activity of the two drugs based on currently available data. If you have more info, please share.
A potential threat for the following reasons:
1) it appears to be active
2) it is further along in trials than XL184
While it's mechanism of action is different than J&J's abiraterone, it will end up being used prior to XL184 (just by being approved first). It will then be important for XL184 to either have activity in patients who have progressed on this agent or XL184 will need to have superior activity. The latter is likely given the observed activity in soft tissue and bony disease and effects on pain. The former is less clear since I doubt there are a lot of patients treated with XL184 who had previously been treated with MDV3100.
In any case, the initial approach of going forward in a very advanced population to get an early (accelerated) approval is a worthwhile approach, though it would need to be in a new trial rather than the ongoing trial.
The bottom line is that the more crowded the prostate space is, the more important it is for XL184 to have a competitive profile.
We'll have to wait to see the latest later this week.