One of the criticisms continually leveled at Dendreon (DNDN), in articles on Seeking Alpha and elsewhere, in comments to these articles, and in my personal mail, is that the company is doing little if anything to expand Provenge's label to earlier stages of prostate cancer. After all, there is good reason to believe the earlier Provenge is taken onboard, the better are the life extension benefits. This was demonstrated most recently at the ASCO conference that took place June 1-5, 2012 in Chicago, Illinois. Here's the pertinent abstract for what has become to be known as the 'quartile study:'
"Overall Survival Benefit with Sipuleucel-T by Baseline PSA; An Exploratory Analysis from the Phase 3 IMPACT Trial," abstract #4684. General Poster Session, Genitourinary Cancer from 8:00 a.m. to 12:00 p.m. CT on Sunday, June 3, 2012.
What is so important about this presentation -- and the actual abstract may be found here -- is that when you break the data from the 512-patient study into subsets based on Baseline PSA, the results, in the words of the investigators, G. Chodak, et al., "…support a consistent overall survival, or OS, benefit with sipuleucel-T across PSA quartiles." I discussed this and other papers Dendreon presented at ASCO here.
When you look at the trends in the data, the lower the Baseline PSA, the greater is the magnitude of the life extension benefit. In the case of a patient with a Baseline PSA less than or equal to 22.1, the median life extension benefit is a stunning 13.0 months. Put another way, those men with less advanced disease may benefit more from treatment with sipuleucel-T. Unfortunately, the study was not sufficiently powered as to provide anything more than trend data. (That is, it is not possible to show statistically significant results.)
PSA of 22.1 or less
PSA of 22.1-50.1
PSA of 50.1-134
PSA of 134 and up
Table courtesy of the authors.
The Provenge label is strict. Specifically, Provenge is intended for the treatment of asymptomatic or minimally symptomatic metastatic castrate resistant (hormone refractory) prostate cancer. As such, it currently cannot be prescribed for earlier stages of the disease.
However -- and this is critical -- the CMS draft decision has pointedly not forbidden the off-label use of Provenge. It stated: "Thus we are hopeful that unlabeled uses in the near future will take place only in the context of bona fide clinical studies. We may, if this turns out to be an overly optimistic viewpoint, reconsider this NCD to ensure that Medicare coverage is restricted to uses that are supported by robust evidence."
Given this opening, how might the company respond? The study, known as PROTECT (PROVENGE Treatment and Early Cancer Treatment) or P-11, is a double-blind, placebo-controlled Phase 3 trial designed to evaluate Provenge in men with non-metastatic androgen-dependent prostate cancer. It is measuring PSA progression and the onset of metastatic disease. At the time of biochemical progression, men become eligible for one booster of either Provenge or placebo. The study is being conducted at 19 institutions in the United States and has enrolled over 170 men.
This is a prospective, double blind, controlled, randomized trial of immunotherapy with prostatic acid phosphatase (PAP)-loaded autologous antigen presenting cells ((APCs)), in subjects with non-metastatic prostate cancer. Subjects qualifying for this study are men who have previously undergone a prostatectomy and whose only sign of disease recurrence is a rise in serum prostate specific antigen (PSA).
The primary objectives are to compare the time to biochemical failure (BF, PSA greater than or equal to 3 ng/mL) between sipuleucel-T (treatment group) and placebo (control group), and to study the safety of sipuleucel-T. The secondary objectives are to compare time to distant failure (DF, distant metastatic disease), PSA doubling time (PSADT), and survival between the 2 treatment groups.
Following short-term open-label treatment with a luteinizing hormone-releasing hormone-analogue ((LHRH-a)), subjects are randomized to blinded treatment assignments of either sipuleucel-T or placebo in a 2:1 ratio. Following randomization, subjects will undergo 3 leukapheresis procedures on alternate weeks (Weeks 0, 2, and 4). Approximately three days following each leukapheresis procedure, subjects will receive an infusion of either sipuleucel-T or placebo.
Subjects will complete a checklist at specified times during the study. This checklist is designed to compare androgen suppression-related side effects during periods with and without androgen suppression. Subjects will be evaluated periodically for safety and efficacy endpoints.
At the time BF is confirmed, subjects will be eligible for a booster infusion. The booster process will consist of 1 leukapheresis procedure followed by 1 infusion of the same treatment assignment, sipuleucel-T or placebo, allocated at randomization.
Subjects will continue to be observed until DF is confirmed by bone scan or computed tomography (CT) scan, or other imaging modalities as clinically indicated. After confirmed DF, subjects will be followed for safety and survival for the remainder of their lives. The total time on study for each subject is estimated to be approximately 10 to 13 years.
Note the last sentence: The total time on study for each subject is estimated to be approximately 10 to 13 years.
Preliminary results were released in 2006:
Preliminary Study Results:
· Biochemical Endpoints: As specified in the protocol, an analysis of PSA doubling time (PSADT) calculated from 90 days following randomization until biochemical progression or the initiation of systemic therapy demonstrated that patients randomized to receive PROVENGE had a 35 percent increase in their PSADT compared to patients randomized to receive placebo (p-value = 0.046). To adjust for potential variations in the rate of testosterone recovery following hormonal therapy, the PSADT was also calculated after a patient's testosterone returned to baseline levels. This analysis demonstrated that patients randomized to receive PROVENGE had a 49 percent increase in their PSADT compared to patients randomized to receive placebo (p-value = 0.038). In addition, although not statistically significant, there was a positive trend in the overall delay in the time to reach a PSA level of 3.0 ng/ml for patients in the PROVENGE arm compared to patients in the placebo arm.
· Clinical Endpoints: There was a delay of approximately 27 percent (HR = 0.73) in the time to distant metastasis for patients randomized to receive PROVENGE compared to patients randomized to receive placebo. Because only 16 percent of patients in the study had a distant failure event at the time of this analysis, it is not yet powered to evaluate statistical significance. Per protocol, patients will continue to be followed for the clinical endpoints of distant failure and overall survival.
The most recent update we have from Dendreon on this trail can be found in the 10K that the corporation filed with the SEC in March, 2012. Here's an excerpt:
"Clinical Trial - P-11. In November 2006, we disclosed preliminary results from our ongoing PROTECT (PROVENGE Treatment and Early Cancer Treatment) ("P-11"), Phase 3 clinical trial in patients with androgen-dependent (hormone sensitive) prostate cancer. The study was designed to explore the biologic activity of sipuleucel-T in patients with recurrent prostate cancer prior to the development of metastatic disease. Among the preliminary findings, the study showed a median time to biochemical failure ("BF") of 18.0 months for subjects in the sipuleucel-T group compared to 15.4 months for subjects in the control group (HR=0.936; p = 0.737). When the analysis was restricted to patients with confirmed BF, the HR for BF was 0.797 in favor of sipuleucel-T (p = 0.278). In addition, the study showed a 35% increase in PSA Doubling Time ("PSADT") for patients randomized to sipuleucel-T compared to control (125 vs 93 days; p = 0.046, F-test) based on an analysis of PSADT calculated from 90 days following randomization to BF or the initiation of systemic therapy. PSADT calculated after testosterone recovery to baseline levels demonstrated a 48% increase in PSADT for the sipuleucel-T arm (155 vs 105 days; p=0.038). PSADT is currently considered to be one of the best predictors of clinical outcome in patients with PSA recurrence following primary therapy. This study is closed to enrollment; however, patients continue to be followed for the clinical secondary endpoints of distant failure and overall survival."
If the time to distant metastasis (TTDM) endpoint of the PROTECT trial indeed achieves statistical significance, that will provide solid evidence that Provenge is effective at stopping the disease in its track when patients are treated early, while their immune systems still are strong and not yet compromised by cancer.
Importantly, the PROTECT/P-11 study, according to my sources, will by NOT by itself be sufficient for label expansion into earlier-stage patients. But it should, if successful, provide the basis for the study necessary to yield evidence of Provenge working in ADPC and lead CMS to allow what is now off-label use of Provenge in this indication. Such a study, for example, might use circulating tumor cell (CTC) technology (here and here) such as that developed by J&J's (JNJ) subsidiary Veridex as a predictive surrogate endpoint for prostate cancer (if the FDA were to approve), significantly shortening the time required to conduct prostate cancer trials.
The US market for Provenge can easily triple or grow even more if Provenge were approved for early stage disease.
The daily chart, courtesy StockChart.com, is below. The stock apparently was pinned around $5 for options expiration. The stock is oversold. The Relative Strength is recovering and the MACD has turned positive.
The weekly data yield little of significance. The stock is just above oversold levels, and the MACD is neutral.
Additional disclosure: I am long DNDN and will not alter my position within 72 hours of the time of publication of this article. I am not a registered investment advisor and do not provide specific investment advice. The information contained herein is for informational purposes only. Nothing in this article should be taken as a solicitation to purchase or sell securities. Before buying or selling any stock you should do your own research and reach your own conclusion. It is up to investors to make the correct decision after necessary research. Investing includes risks, including loss of principal. I am long DNDN and will not alter my position within 72 hours of the time of publication of this article. I am not a registered investment advisor and do not provide specific investment advice. The information contained herein is for informational purposes only. Nothing in this article should be taken as a solicitation to purchase or sell securities. Before buying or selling any stock you should do your own research and reach your own conclusion. It is up to investors to make the correct decision after necessary research. Investing includes risks, including loss of principal.