ODAC Wants More Data on Expanded Casodex Indication

BETHESDA, Maryland—Astra-Zeneca failed to gain backing from the FDA’s Oncologic Drugs Advisory Committee (ODAC) for its effort to expand the indication for Casodex (150 mg bicalutamide) in the treatment of prostate cancer. ODAC members found that the data presented were too premature to recommend that the FDA approve the company’s supplementary new drug application. They suggested, instead, that the agency delay a decision until longer-term data about the drug’s efficacy become available.

AstraZeneca is seeking approval of Casodex 150 mg as an adjuvant therapy to radical prostatectomy and radiotherapy of curative intent in patients with locally advanced nonmetastatic prostate cancer who have a high risk for disease recurrence and as immediate treatment of localized nonmetastatic prostate cancer in patients for whom therapy of curative intent is not indicated.

Casodex in a 50-mg dosage is currently approved in the United States in combination with a luteinizing hormone-releasing hormone (LHRH) analogue for the treatment of stage D2 metastatic prostate cancer. In its 150-mg form, the drug is approved for treating early-stage prostate cancer in more than 40 countries, including Canada. The availability of Casodex and its off-label use in the United States clearly weighed on the minds of ODAC members.

"This drug is going to be used because it is available; we know the drug is going to be imported from Canada," said George H. Ohye, the committee’s nonvoting industry representative. He suggested that FDA grant Casodex 150 mg accelerated approval, which would require the sponsor to conduct phase IV postmarketing trials to further confirm the drug’s safety and effectiveness.

To support its application, Astra-Zeneca presented data from three prospective, randomized, double-blind, placebo-controlled multicenter trials, known as the Early Prostate Cancer (EPC) trial program, carried out in 23 countries with a total population of 8,113 patients. The three studies are as follows:

• Trial 23, a 2-year study of 3,292 patients treated in North America, primarily in the United States: 80% received radical prostatectomy and 20% radiation therapy.

• Trial 24, a worldwide study of 3,603 patients but conducted mostly in Europe: 46% received radical prostatectomy, 19% radiation therapy, and 35% watchful waiting.

• Trial 25, which consisted of 1,218 patients enrolled in Scandinavia: 13% received radical prostatectomy, 6% radiation therapy, and 80% watchful waiting.

Both Trial 24 and 25 were extended to 5 years from the originally intended 2 years and are still in progress. The EPC studies had two major endpoints: time to progression, the choice of AstraZeneca, and survival, which the FDA preferred.

Casodex 150 mg reduced the clinical progression of prostate cancer at 3 years by 42% overall, as determined by bone scans, said William A. See, MD, professor and chief of urologic surgery, Medical College of Wisconsin, who presented efficacy data from the three trials on behalf of AstraZeneca.

"We see a 61% reduction in the risk of objective disease progression for high-risk radiotherapy patients, a 47% reduction in high-risk radical prostatectomy patients, and a 35% reduction in patients who historically would have been managed by so-called watchful waiting," Dr. See said. "With additional follow-up, now out to 4.2 years, the data confirm these observations."

Two adverse events proved common in Casodex-treated patients in the three trials and in far greater numbers than in the placebo group—breast pain (73% vs 8%) and gynecomastia (68% vs 8%). Other adverse events, including asthenia, impotence, hot flashes, and incontinence, were similar in the two groups and occurred in 11% or less in both treated and untreated patients.

"I would conclude that the risk-benefit ratio is clearly favorable in patients who are at high risk of recurrence or progression," said Mark S. Soloway, MD, professor and chairman of urology, University of Miami School of Medicine, who also spoke for the company. "Right now, there is only one systemic treatment option for them, and that is surgical or medical castration."

However, FDA medical reviewer Scott Monroe, MD, noted that 1,116 (27.7%) of the 4,052 Casodex-treated patients and 369 (9.2%) of the 4,061 placebo patients withdrew from the three studies, primarily because of breast pain and gynecomastia in the treatment group.

Gleason Scores

Dr. Monroe also challenged the value of the Gleason scores presented by the sponsor. Gleason scores were extrapolated in trials 24 and 25 rather than derived from pathology slides. "We remain concerned by the lack of valid Gleason scores, which has made it impossible for us to fully characterize those patients enrolled in the non-US trials," Dr. Monroe said.

Moreover, there was discordance between the Gleason scores and disease progression in the EPC studies. "There is less tumor differentiation, at least as assessed by the pathologists in the various trials, in the US study," Dr. Monroe said. "Yet we can see that the incidence of disease progression, as assessed by positive bone scan, was much higher in the US trial. And this is certainly problematic for us."

He also cited several other unresolved problems with the trials’ efficacy data:

• Only 15.6% or 9.3% of patients had disease progression by sponsor or FDA preferred analyses, respectively, across trials 24 and 25.

• Long-term benefit of treatment remains unclear in the absence of survival and meaningful quality-of-life data.

• Post hoc subset analyses by Astra-Zeneca were inconclusive or nonsup-portive.

Daniel Shames, MD, director of the FDA’s Division of Reproductive and Urologic Drug Products, noted that FDA had issued AstraZeneca a not-approvable letter. In it, the agency asked for more mature data; that the company obtain pathology slides to determine the actual Gleason scores of patients in trials 24 and 25; and that the company choose a well-defined subgroup of successful patients and perform a well-controlled prospective trial of Casodex 150 mg.

Although ODAC members strongly agreed that long-term data were needed, several of them found promise in some of the EPC trial data. "These are very interesting results, but follow-up is a big issue," said Steven L. George, PhD, professor of biostatistics, Duke University.

In the end, the committee voted 13 to 3 that the studies were not sufficiently mature to conclude that patients treated in the three studies will derive clinically significant long-term benefit. It then split on an 8-to-8 vote over whether data from trials 24 and 25 could be extrapolated to define a group of watchful-waiting patients that would benefit from treatment with the 150 dose of Casodex.