FDA’s speedy approval of Johnson & Johnson’s Zytiga (abiraterone) on April 28 – two months before the PDUFA date – paves the way for a third new advanced prostate cancer drug to get to market in a year and heralds the coming of even more competition in the valuable space.

An oral androgen biosynthesis inhibitor, abiraterone was cleared for use in combination with prednisone in patients with metastatic castration-resistant prostate cancer (CRPC) after chemotherapy with docetaxel. Castration-resistant prostate cancer is also referred to as hormone-refractory prostate cancer (HRPC).

Up until recently, few therapies were effective in treating castrate-resistant prostate cancer. Almost exactly a year ago, however, on April 29, 2010, Dendreon received FDA's green light for Provenge (sipuleucel-T), a therapeutic vaccine for metastatic CRPC patients who are asymptomatic or minimally symptomatic. For the majority of patients, this means chemotherapy-naïve. On June 17, 2010, Sanofi-Aventis gained approval for the second-generation chemotherapeutic Jevtana (cabazitaxel), for use in a similar indication as Zytiga – with prednisone and after failed chemotherapy.

Zytiga's list price compares favorably to Dendreon’s customized therapeutic vaccine Provenge, which costs $93,000 per course of lifetime treatment, but the drugs target different patient segments.

Zytiga costs $5,000 per bottle, equivalent to a one-month supply, according to J&J. Given median duration of treatment in the pivotal COU-AA-301 trial of eight months, average cost per patient would come to $40,000, but in clinical practice, length of treatment could vary significantly, commented Oliver Sartor, medical director of the Tulane Cancer Center. Sartor, who was the lead investigator on the pivotal cabazitaxel study, also was an investigator on abiraterone trials.

In annual terms, the price for Zytiga would come to roughly $60,000, which is about what some analysts expected. Some, however, thought J&J might go higher, given the price for Provenge and also the high price –$970 million – J&J paid for Cougar Biotechnology to get the abiraterone asset ([A#121609916854]).

For Dendreon, the Zytiga approval means more competition coming soon if the drug is used off-label in minimally symptomatic CRPC.

For Dendreon, the approval means more competition coming soon if abiraterone is used off-label for minimally symptomatic CRPC and/or if it wins approval in this indication down the line. Dendreon’s stock price did not suffer on the news, however.

Labeling As Expected

J&J filed an NDA for abiraterone on Dec. 20, 2010, earning a priority review designation from FDA that set a user fee date of June 20. Zytiga’s early approval was expected by the Street, wrote Deutsche Bank’s Robin Karnauskas in an April 28 note on Dendreon stock.

Sartor commented that he expected the Zytiga approval to come even sooner than April 28, considering that the approval of Jevtana was a stand-out in terms of speed. That review took a mere 11 weeks (Also see "The Lesson Of Jevtana: With A Survival Advantage, All Things Are Possible" - Pink Sheet, 1 March, 2011.).

“I’m surprised it took this long,” said Sartor.

The COU-AA-301 study, which formed the backbone of J&J's NDA filing for Zytiga, included 1,100 patients who had failed one or two chemotherapy regimens, one of which must have been docetaxel. It found that patients taking abiraterone and prednisone had a median survival of 14.8 months, versus 10.9 months for prednisone and placebo.

The label for Zytiga is what was expected, based on the results from the ‘301 trial, in the refractory population, commented Howard Soule, chief scientific officer of the Prostate Cancer Foundation.

Soule acknowledged that there could be interest in using the drug off-label in patients with earlier-stage disease, but that the foundation hopes that use will match clinical results.

Deutsche Bank’s Karnauskas argued that because Zytiga was approved in the refractory (castration-resistant) prostate cancer population, the drug's use will be limited to use after chemo, and therefore is not a threat to Provenge.

“We continue to believe Provenge and Zytiga will be used in sequence, and they are not competitors,” the analyst wrote.

Zytiga also is being tested in a second Phase III trial, COU-AA-302, in chemotherapy-naïve patients. That study is fully accrued but it’s unclear when the results will become available, though it could be by year-end.

If the results from that trial are positive, Zytiga would be placed more squarely in competition against Provenge for the pre-chemo market.

Ahead of data from the second trial of Zytiga in chemo-naïve patients, off-label use and/or sequencing of drugs will depend on reimbursement policies. In order to gain access for their patients to Provenge, payers sometimes require providers to fill out a checklist for eligibility that mirrors the label and in some cases goes beyond the label.

Because of the costs involved, payers could be similarly "insistent that [abiraterone] is used within the label just as Provenge is,” Sartor said.

Off-label use of oncology drugs is heavily influenced by inclusion on compendia. However, Sartor said, it’s unclear whether sufficient additional data are available beyond that which supported the NDA to support a recommendation in compendia for off-label use.

The current indication does put Zytiga in direct competition with Jevtana. Sartor expects that safety will be a major consideration in deciding whether to use Zytiga or Jevtana after failure with docetaxel chemotherapy.

The Zytiga label has only one contraindication, for women who are pregnant or may become pregnant. The most common adverse reactions, the label notes, include joint swelling or discomfort, edema, muscle discomfort, and diarrhea.

Competition with Jevtana post-chemo is likely to come down to safety.

Cabazitaxel is linked to severe, potentially fatal side effects, which have a very high profile in the FDA labeling, including a boxed warning for neutropenia and severe hypersensitivity (Also see "With Jevtana Approved For Advanced Prostate Cancer, Sanofi Could See Expansion To First-Line Use" - Pink Sheet, 21 June, 2010.). In the TROPIC study supporting approval, cabazitaxel was shown to give a median survival of 15.1 months compared to 12.7 months for the mitoxantrone chemotherapy comparator arm.

According to labeling, every time cabazitaxel is administered, patients must be premedicated 30 minutes prior to treatment with a corticosteroid, an antihistamine and an H2 agonist.

Zytiga’s “superb safety profile” and its relative ease of use means it is likely to be used after docetaxel but ahead of cabazitaxel, Sartor concluded. But patients will progress, and when they do, cabazitaxel will be a very good option. “I don’t think this is an either/or scenario,” he said.

Prostate Cancer Pipeline Still Packed

The approval of three new prostate drugs within a year illustrates a dramatically changing therapeutic space.

Research firm Decision Resources estimates that the market for prostate cancer drugs is expected to increase from $4 billion in 2009 to $5.7 billion in 2014 to $8.7 billion in 2019 across seven major pharmaceutical markets (Also see "Prostate Cancer Market Snapshot: More Than Provenge" - Pink Sheet, 22 November, 2010.).

More than a dozen other drugs are in mid-to-late stage development.

More than a dozen other drugs are in mid-to-late stage development including Medivation/Astellas Pharma’s MDV3100 and Takeda Pharmaceutical’s TAK-700, which, like abiraterone, regulate hormone activity (Also see "A Chock-Full Pipeline For Prostate Cancer Drugs" - Pink Sheet, 22 November, 2010.)

When it comes to competing with abiraterone, new drugs may accentuate the ability to be used without prednisone and/or compete on price.

If abiraterone gets cleared for chemo-naïve patients, and these other drugs become available, the space is going to become very crowded and sequencing of treatments is going to become a major challenge for clinicians, said the Prostate Cancer Foundation’s Soule.

“We believe that unless clinical trials are funded that [show how to] sequence all these drugs appropriately, there will be clinical chaos,” Soule said. The Prostate Cancer Foundation is now gearing up to run a series of workshops with organizations, companies, and clinical trialists to discuss what studies may be needed.

“What the PCF is interested in, as well as the senior clinical leadership in the field, is not just abiraterone and Provenge. We are thinking about everything that is coming down the pike,” he said.

By Emily Hayes

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