Re: Lack of (strong) (PFS) response in OGX-011 P2 in mCRPC
I asked the question to IR and got the following very informative answer. which I will post as a reply.
What's the company's explanation while Phase 2 OGX-011 trial showed nearly statistical significant OS benefit, it failed to show a (strong) PFS or response benefit? I remember this being discussed 3 years ago but has there been any new information or a new line of reasoning in the last 3 years?
“Starting with response rates- classically in oncology we are trained to look at response rates in terms of tumor shrinkage. Response rates are designed to capture treatment sensitive patients whose tumor volume is decreasing as a result of treatment. Since clusterin overexpression is directly related to resistance, one would not expect to see a difference between the two arms (docetaxel vs. docetaxel plus custirsen) because these patients had not yet acquired resistance to treatment.
In our Phase 2, we had essentially the same number of PRs as docetaxel alone, as expected based on the MOA of custirsen. Importantly, we are looking for the lack of disease progression, as opposed to shrinkage, which was demonstrated as more patients on the custirsen arm had stable disease (77% vs 50%) and fewer patients on the custirsen arm had progressive disease (4% vs 17%).
Further, in prostate cancer, only about half of patients have measurable disease, so RECIST RR criteria are of limited value. Prostate cancer typically metastasis to the bone and there are no good means to assess change in bone disease. Scans are good to assess M0 (no bone mets) to M1 or greater (with bone mets). But, once patients have bone disease, scans cannot assess bone lesion shrinkage.
For PFS- Per protocol in the Phase 2 study, we did not treat patients to progression. Treatment was discontinued at 10 cycles or 6.92 months. Looking at the PFS curve, the two arms begin to come together shortly after therapy is stopped, which also corresponds with the natural history of time to progression in prostate cancer and the TTP that was seen with docetaxel alone in this study (6.6months). We can hypothesize that if you stop treatment at the time of natural progression, you are not going to have an effect on PFS, whereas if you treat to progression, you perhaps would see a difference.”
Director, Investor Relations
Thanks for posting the response. It's refreshing to receive such substantive information from an IR department. I think Susan provided a reasonable explanation for the OS benefit absent tumor response. We can't completely discount the possibility that the P2 results were an aberration, but from a purely statistical standpoint, it's unlikely. The additional risks of a long position in OGXI seem to be the recent PPS decline on heavy volume as well as the possibility of confounding data. Each day that passes without a futility stoppage reduces the likelihood the recent stock action was related to a leak. So, all things considered, where do you handicap Synergy's odds as of today?
Thanks for posting that Summer. Their explanation regarding how it's hard to measure tumor shrinkage once prostate cancer metastasizes to the bone shows that they're not being inconsistent when they tout tumor response as one of the favorable outcomes in the P2 trial of prednisone +/- 427. In the 427 trial, the patients did not yet have metastatic disease.
With regard to the last paragraph of Susan Specht's email, I vaguely recall Cormack saying at one of the CCs that one of the few differences in the protocol between the P2 and P3 trials for 011 is that in the P3 trial they will not be discontinuing treatment at 10 cycles if the patient had not yet progressed.