Dendreon And Provenge's True Median Life-Extension Benefit

Feb. 1.12 | About: Dendreon Corporation (DNDN)

The 2012 Genitourinary ("2012 GU") Cancers Symposium, Novel Mechanisms and Therapies in Multidisciplinary Management, to be held 2-4 February, 2012, includes multiple poster presentations on Dendreon's (NASDAQ:DNDN) Provenge (Sipuleucel-T) that will be of major interest to the medical community in general and practitioners treating prostate cancer in particular. Several presentations addressed two of the overarching issues that have vexed physicians and investors alike when it comes to Dendreon's active immunological treatment for end stage prostate cancer:

1. What is the true median life extension survival conveyed by Provenge?
2. By what means might it be possible to measure and/or predict a patient's response to Provenge (that is, what "biomarkers" can be used to determine whether or not a given patient is responding to the treatment)?

The material below is intended to review several papers to be presented at the symposium and to provide readers with a "road map" to presentations of special interest in matters pertaining to Dendreon's treatment. I would encourage you to read the abstracts and other material that will appear in today's popular and online literature pertaining to Provenge and other treatments for prostate cancer to be discussed at this week's meetings in San Francisco. (Note: if you have problems accessing any of the abstracts cited below, read the press release issued by Dendreon last night, which contains several of the documents as well as related comments that will be of interest.)

Readers will recall that I addressed the first point above - that is, the true median life extension benefit of Provenge - last November in my article entitled Dendreon: New Trial To Examine Understatement Of Provenge Life-Extension Benefits. In it, I noted the following:

Recall that in the case of the pivotal Phase III Provenge trials, the overall survival advantage was a median of 4.1 months (at 50% survival, 25.8 months in the Provenge arm vs. 21.7 months in the placebo arm) ...

"... Some readers may recall that in the pivotal Phase III Provenge trials performed to obtain FDA approval, Frovenge - or APC8015F, as it also is known - was given to more than two-thirds (80%, according to Schiffman) of the placebo arm. As concluded by Gomella, et al.* in a 2011 ASCO poster presentation, "Post-progression treatment with APC8015F may have extended survival of subjects, potentially reducing the magnitude of survival difference observed between sipuleucel-T and controls in randomized controlled trials." Put another way, the life-extension value of Provenge may have been significantly underestimated by the manner in which the trial was designed. (Emphasis added.) (You can view the entire poster here.**)

"By how much was it underestimated? Well, inspection of the figure below (Figure 3 on the poster) shows that the segment of the control arm that did not receive Frovenge had a median survival time of 12.7 months while the segment of the control arm that did receive Frovenge had a median survival time of 23.6 months. This implies that the "true" overall median survival advantage to Provenge should be considerably longer if it is determined in a trial for which the control arm is NOT given Frovenge. In fact, one might reasonably argue, on the basis of these data, that the "true" overall, median survival advantage in treating end stage prostate cancer with Provenge should be something on the order of 12.7 months, or more than one year (25.4-12.7=12.7 months)."

In General Poster Session B of 2012 GU, Chadi Nabhan, MD, director of the division of haematology and medical oncology at Advocate Lutheran General Hospital in Park Ridge, Illinois, will present Abstract #144 entitled: An analysis to quantify the overall survival (OS) benefit of sipuleucel-T accounting for the crossover in the control arm of the IMPACT study. (D7) A read of the abstract reveals the following important Conclusion: "Adjusting for a positive effect of APC8015F (Frovenge) in the control arm resulted in a sipuleucel-T OS treatment benefit in the IMPACT study ranging from 4.1 to 7.8 months. (Emphasis added.) These results support a greater treatment effect of sipuleucel-T than reported in the IMPACT study and should be factored into future studies without APC8015F crossover." This is totally consistent with the results reported previously and at the most, is almost 2 times the median 4.1-month life extension benefit upon which Provenge was approved.

If anything, this argues even more for Provenge becoming the Foundation of Care in the treatment of asymptomatic or minimally symptomatic metastatic castrate resistant (hormone refractory) prostate cancer, with other treatments (e.g., Zytiga and MDV3100) "layered" in on top of it. In the case of Zytiga, this order of treatment has already been recommended by the Journal of Clinical Oncology, which stated: "The practical dilemma of the appropriate sequence of use of the two new noncytotoxic agents (sipuleucel-T and abiraterone) is being addressed by trials that are under development. For now, given the broader window of applicability of abiraterone and the longer time required to develop an immune response with sipuleucel-T, if both agents are to be used, it seems reasonable to administer sipuleucel-T first with Abiraterone after additional disease progression. Biomarkers to help define the optimal use of immunotherapy are needed."

There are two presentations in General Poster Session C of special interest to the Provenge community. These are Abstracts 178 and 181.

Abstract #178: Evaluation of immune activation following neoadjuvant Sipuleucel-T in subjects with localized prostate cancer. (A7), Nadeem A. Sheikh, PhD.

This study, called NeoACT (NEOadjuvant Active Cellular immunotherapy), was intended to understand the immunologic effects of sipuleucel-T. It was an open-label Phase 2 study undertaken with 42 patients, each with localized prostate cancer and each of whom would subsequently receive a radical prostatectomy (NASDAQ:RP). Prior to that, however, patients received three infusions of sipuleucel-T at approximately two-week intervals, beginning 6-7 weeks prior to their RPs. The researchers concluded that "(N)eoadjuvant sipuleucel-T resulted in robust immune system activation that included antigen presenting cells (APCs), memory and activated mature B cells, and both CD4+ and CD8+ T cells. The patterns observed at the second and third infusions, relative to the first, are consistent with an immunological prime-boost profile."

As Eric Small, MD, University of California, San Francisco Helen Diller Family Comprehensive Cancer Center, noted in Dendreon's press release, "I find these data to be very compelling - this exploratory analysis provides insight into the biological effect of Provenge and immunologic activity across different stages of prostate cancer. These data suggest that Provenge should be studied in earlier stages of disease, when patients have less tumor burden."

Abstract #181: Immune responses in prostate tumor tissue following neoadjuvant sipuleucel-T in patients with localized prostate cancer. (B1), Lawrence Fong, MD.

This paper also discussed results of the NeoACT Phase 2 trial described above. The researchers concluded that "(N)eoadjuvant sipuleucel-T treatment appears to result in an increased frequency of T cells in prostate cancer tissue at the rim between the benign and malignant glands. These data suggest that sipuleucel-T may modulate the presence of lymphocytes at the prostate tumor site. Work is ongoing to more fully characterize the immune response within the prostate tumor tissue and in the peripheral blood."

Lawrence Fong, MD, University of California, San Francisco Helen Diller Family Comprehensive Cancer Center, was quoted by Dendreon in the press release as saying that "This analysis of prostate tissue from patients participating in the Phase 2 NeoACT trial demonstrated increased T-cell activity at the rims of prostate cancer tumors, which provides important support for Provenge's intended mechanism of action."

Also of interest are the following from General Poster Session A:

Abstract #42: Sipuleucel-T product characterization across different disease states of prostate cancer. (C8), Nadeem A. Sheikh , PhD.

This paper provided the results of an exploratory analysis performed on several Provenge clinical trials (IMPACT, ProACT, OpenACT, and NeoACT). The intent was to examine and compare Provenge's characteristics across different disease states. In the study, according to the description in the abstract, "(C)ellular composition and APC activation (CD54 upregulation) were evaluated in all courses of sipuleucel-T, and cumulative CD54 upregulation was calculated for each patient. They concluded: "While cellular composition varied with disease state, manufacture of sipuleucel-T activated APCs in both early and late disease states of prostate cancer, and generated similar T and B cell activation and cytokine production profiles consistent with immunological prime-boost. APC activation tended to be more robust in earlier disease states." (Emphasis added)

Eric Small, MD, commenting on the results (see Dendreon's press release), stated that "These data suggest that Provenge should be studied in earlier stages of disease, when patients have less tumor burden."

Abstract #75: Parametric effect size estimates from sipuleucel-T randomized trials. (D18), Brent A. Blumenstein, PhD.

The researchers asserted that "Median survival differences are frequently used as measures of effect size because they are easily understood." For example, in the case of Provenge, they noted that "The sipuleucel-T D9901 (Small, JCO 2006) and IMPACT (Kantoff, NEJM 2010) trials provide 4.5 and 4.1 month estimated median survival differences, respectively ..." The authors went on to assert that "Other effect size estimates can more fully represent the whole of survival distributions, however, and are less subject to local variations." They concluded that "Statistical modeling illustrates alternative methods of obtaining effect size estimates. For the sipuleucel-T trials there is a suggestion of more effect than obtained from non-parametric or semi-parametric methods." The table below, from the abstract, shows that using the various models examined by Blumenstein, the median survival benefit for Provenge ranged anywhere from the 4.1 months upon which FDA approval was based to 10.3 months.


Estimate type

Median difference (NYSE:M)

Hazard ratio








Modified Weibull










Modified Weibull

Delayed effect conjecture not supported

Click to enlarge

a Applicable after delayed effect.

Technical Analysis

The daily chart, courtesy, shows the stock, having broken through the 50-day moving average, now trading in the area of $13-$15. It closed yesterday at $13.57 in a lackluster market. One reason given was the release of the data for MDV3100, which exhibited a 4.8-month median survival benefit.

The weekly chart shows a significant improvement in relative strength, with the stock jumping off its oversold condition to neutral. The MACD is positive, indicating the "smart money" has returned to the issue. The next level of resistance will be found in the neighborhood of $21.

*L. G. Gomella, C. Nabhan, J. B. Whitmore, M. W. Frohlich, D. J. George; The Kimmel Cancer Center at Jefferson, Philadelphia, PA; Advocate Lutheran General Hospital and Oncology Specialists, S. C., Park Ridge, IL; Dendreon Corporation, Seattle, WA; Duke Cancer Institute, Durham, NC.

**Reproduced with the permission of Dr. L. G. Gomella, personal communication, November 17, 2011

Disclosure: I am long DNDN.

Additional disclosure: I am long DNDN and will not alter my position within 72 hours of the time of publication of this article. Material presented here is for informational purposes only. Consult your financial adviser before making investment decisions. Investing includes risks, including loss of principal.