The release of positive Phase III results for Sanofi-Aventis' next-generation chemotherapy agent cabazitaxel in hormone-resistant prostate cancer could put a damper on recruitment for clinical trials of other late-stage drug trials in the same indication.

Sanofi presented the first evidence of a survival benefit in HRPC (also called castration-resistant prostate cancer) in patients who failed chemotherapy in the Phase III TROPIC study on March 5 at the American Society of Clinical Oncology's 2010 Genitourinary Cancers Symposium in San Francisco.

The release marks an important achievement for an area in need of clinical advances. Metastatic prostate cancer ultimately becomes resistant to hormone treatment, and Sanofi's older taxoid Taxotere (docetaxel) is the only drug currently cleared by FDA for HRPC. No drugs are cleared for those who progress on Taxotere.

Unmet need is high and the potential for market growth is obvious. About 103,000 people in the U.S. have metastatic prostate cancer and the annual death rate is about 27,000. The target population for HRPC drugs lies somewhere between these two figures and the market value will depend on pricing of emerging therapies, according to Leerink Swann analyst Howard Liang.

Cabazitaxel recently received fast-track designation from FDA, a status that allowed Sanofi to start a rolling submission. During a February earnings call, execs said they hoped to complete the rolling NDA by the end of the first quarter and launch by the end of early 2010 (¹ Also see "Unknown Timing of Lovenox Generics Complicates Sanofi-Aventis' Outlook" - Pink Sheet, 15 February, 2010.). However, after the GU meeting a Sanofi spokesperson gave a first-half filing projection.

The new cabazitaxel results are being viewed as game-changing, as evidenced by comments in a late-afternoon GU symposium session on "future pathways" in prostate cancer on March 5.

"Will this change the standard of care? Yes, it probably will," said William Kevin Kelly, Yale University. Kelly was also part of the data safety monitoring board for the cabazitaxel study. In an e-mail after the meeting he explained: "If the FDA finds that there is an acceptable risk/benefit ratio for cabazitaxel and approves the drug, it may have substantial effect on the treatment practices across the U.S. and may have an impact on outcomes of the ongoing randomized studies."

Several treatments are in development for HRPC, including late-stage compounds from Pfizer, Medivation, Bristol Myers-Squibb and Cougar Biotechnology, now owned by Johnson & Johnson (² 'The Pink Sheet,' March 8, 2010).

But the release of the positive results for cabazitaxel could have the effect of making it difficult to carry through with studies as currently designed.

Cabazitaxel Shows First Survival Benefit

In the TROPIC study, the combination of cabazitaxel with the steroid prednisone in HRPC patients with metastatic disease that had progressed after docetaxel treatment significantly reduced the risk of death by 30 percent compared to the comparator arm of the generic chemotherapy mitoxantone with prednisone. Specifically, median overall survival - the primary endpoint - was 15.1 months in the cabazitaxel arm compared to 12.7 months in the comparator arm.

Lead investigator Oliver Sartor, Tulane Medical School, noted that these are the first data to show a statistical improvement in overall survival in this group of patients. As such, if cabazitaxel is approved, there could be "significant repercussions" for other drugs being tested in second-line treatment, said Sartor.

Such an advance creates a clear choice for appropriate treatment and could make it difficult for sponsors testing other treatments to convince practitioners to enroll their patients in their experimental protocols instead of putting them on a proven product.

In fact, institutional review boards would have to update consent forms with the information about cabazitaxel's availability, once it gains approval, Sartor explained in a follow-up interview.

That means competing programs have a short window of time before cabazitaxel reaches the market to advance their clinical trial programs.

Sanofi is also trying to hasten the process and make cabazitaxel available to patients as soon as possible. The company confirmed via e-mail that it is "exploring options around patient access to cabazitaxel and will provide more details as soon as possible."

Still, full availability in the market could take a while, and accrual of other trials should continue to be brisk until that point, Kelly said. However, once there are alternative treatment options such as cabazitaxel available for second-line treatment for CRPC, accrual may slow down. "This is not uncommon when we see a new drug approved for a new indication," he said.

The development of an effective second-line therapy that improves overall survival also has an impact on research in first-line therapies, Kelly pointed out. The emphasis on looking at combination treatments (such as doublets) with increased toxicity and modest increased clinical activity is not as attractive.

Also, the typical endpoint for a Phase III study in first-line CRPC therapy was overall survival because in the past there was no effective second-line therapy. "Now that we have a therapy [cabazitaxel] that improves the survival in the second-line setting, using overall survival for first-line trials is complicated," he said.

Bristol, Medivation Explain Impact Of Results

At least three other Phase III studies are now recruiting in hormone-resistant prostate cancer following docetaxel treatment: Medivation's MDV3100, Pfizer's Sutent (sunitinib) and Bristol-Myers Squibb's ipilimumab. Cougar has abiraterone in Phase III, but enrollment has already completed, so the trial is unlikely to be affected by the cabazitaxel results.

OncoGeneX has not yet reached Phase III for its OGX-011 in prostate cancer. The firm has five Phase II trials ongoing, and reached an agreement in mid-2008 with FDA on the design of a Phase III registration trial of OGX-011 via the special protocol assessment process.

Roche subsidiary Genentech announced March 12 that a Phase III trial for Avastin in combination with docetaxel and prednisone in HRPC had failed to extend overall survival. The data will be presented at the full ASCO annual meeting in June.

In a March 7 note on Medivation, Leerink Swann's Liang noted that data from ASCO-GU indicate the "prostate cancer field is growing more competitive with cabazitaxel's pending approval." Still, he predicts that Sanofi's new drug may emerge as the new standard for second-line treatment.

Medivation's MDV3100 was licensed in October by Astellas in a deal that included a whopping $110 million upfront payment (³ Also see "Medivation Gets $110M Upfront From Astellas In Prostate Cancer Collaboration" - Pink Sheet, 27 October, 2009.). In response to questions about the impact of the cabazitaxel results on Medivation's Phase III AFFIRM trial, Medivation Chief Medical Officer Lynn Seely said: "Should cabazitaxel be approved, AFFIRM will enroll patients who choose not to take cabazitaxel because of its side effects, as well as patients who have progressed on cabazitaxel."

Bristol said it does not anticipate that its Phase III ipilimumab research will be negatively affected. One Phase III study is testing ipilimumab versus placebo following radiotherapy in subjects with castration- resistant prostate cancer who have received prior therapy with docetaxel. In this setting, for patients with localized metastases, radiotherapy is an accepted standard of care, the company said.

The second Phase III study is comparing the efficacy of ipilimumab vs. placebo in patients with metastatic castration-resistant prostate cancer before they are eligible for chemotherapy treatment. Bristol has not yet started recruiting for the chemotherapy-naïve study.

"It is important to understand that these are different patient populations than what the Sanofi cabazitaxel trial evaluated," the firm said.

Dendreon Provides Update On IMPACT

Meanwhile, Dendreon's Provenge (sipuleucel-T) has a user fee deadline set for early May and so far, no advisory committee meeting has been scheduled, giving investors hope that the application is on track.

Dendreon presented longer-term positive follow-up overall survival data from the IMmunotherapy for Prostate AdenoCarcinoma Treatment (IMPACT) study at the ASCO symposium. Provenge increased three-year survival by 40 percent compared to placebo (32.1 percent versus 23.0 percent). The median survival difference of PROVENGE compared to placebo was maintained at 4.1 months, with a 24.1 percent reduction in the risk of death, the company reported.

"This is yet another knock against the bear argument questioning the strength of the IMPACT results and should be positive for Dendreon shares," JP Morgan's Cory Kasimov said in a March 4 note. "These updated disclosures add to our already high conviction that Provenge will be approved by its May 1 PDUFA."

Kasimov noted that the cabazitaxel results are intriguing but added, "We don't expect this product to be a meaningful competitor to Provenge anytime soon given the vastly different tolerability profiles and different target patient populations."

- Emily Hayes (⁴ e.hayes@elsevier.com)

Will Cabazitaxel Success Derail Other Prostate Cancer Trials?

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