CONTACT:
Michael Blash, Zeneca Pharmaceuticals, 302-886-5465, [email protected]
Elizabeth Miller, InterScience, 202-973-0374, [email protected]
Bob Schwadron, InterScience, 212-468-3616, [email protected]

FOR IMMEDIATE RELEASE

NEW PROSTATE CANCER DATA AT AUA COMPARES EFFICACY AND TOLERABILITY OF HORMONAL THERAPY TREATMENT REGIMENS

SAN DIEGO--June 3, 1998--New data on advanced prostate cancer treatment presented today at the 93rd Annual Meeting of the American Urological Association (AUA) suggest there is similar tolerability, time to disease progression, and survival outcome when either of the two luteinizing hormone-releasing hormone analogue (LHRH-A) agents, goserelin (ZOLADEX(R) (goserelin acetate implant), Zeneca Pharmaceuticals) or leuprolide, is used in Combined Androgen Blockade (CAB) with either of two commonly prescribed antiandrogens, bicalutamide (CASODEX(R) (bicalutamide) Tablets, Zeneca Pharmaceuticals) or flutamide. These were the primary aims of an exploratory analysis of an 813-patient study presented by Dr. Michael F. Sarosdy of the University of Texas Health Science Center at San Antonio.

However, a further exploratory analysis of the same database by Dr. Sarosdy comparing each of the four possible CAB combinations separately suggests that the combination of leuprolide plus flutamide has a poorer survival outcome and is less likely to delay disease progression than any of the other three combinations examined in the trial. Though Dr. Sarosdy states that this analysis should be "interpreted with caution because the trial was not statistically powered" to make such a comparison, he concludes that because patients were randomized prospectively to the therapeutic modalities, "this made it valid to perform such a comparison."

CAB uses the combination of a luteinizing hormone-releasing hormone analogue or LHRH-A with an antiandrogen to obtain maximum suppression of testosterone, the male hormone that can stimulate growth of prostate cancer cells.

Data for both exploratory analyses presented by Dr. Sarosdy at AUA were obtained from a randomized, multicenter trial designed to compare the efficacy and tolerability of bicalutamide and flutamide when each was combined with monthly depot formulations of goserelin or leuprolide, in patients with stage D2 prostate cancer.

Two-Arm Comparison: Similar Effectiveness, Tolerability and Injection Site Reaction

In the two-arm analysis, findings for 540 patients randomly assigned to goserelin plus either antiandrogen and 273 to leuprolide plus either antiandrogen were assessed according to the study protocol. While slightly more deaths and progression events occurred in the leuprolide plus antiandrogen group, the differences were not statistically significant. For patients treated with either goserelin or leuprolide, the most common adverse event was hot flashes, an established effect of any LHRH-A therapy. Side effect data specific to the injection site indicated equally low frequency of reactions, pain, hypersensitivity and injection site masses in both groups. Overall, 27 of these events were reported in 1.8% of patients in the leuprolide plus antiandrogen group, compared with 23 events reported in 2.2% of patients in the goserelin plus antiandrogen group. "This suggests that pain at the injection site is not a basis for differentiating between LHRH-A agents," Dr. Sarosdy obse! rved.

Four-Arm Comparison Suggests Leuprolide Plus Flutamide Least Effective Regimen

Though not an original objective of the study protocol, a separate comparison of each of the four CAB regimens was undertaken to generate new hypotheses. Dr. Sarosdy said, "These data, while exploratory, would suggest there may be a better combination of LHRH-A therapy and antiandrogen than leuprolide plus flutamide."

Of the four possible combinations in this analysis, the highest percentage of deaths and disease progression was recorded in the leuprolide plus flutamide group, while the lowest percentage was seen in the leuprolide plus bicalutamide group.

Survival outcome was significantly better for both leuprolide plus bicalutamide versus leuprolide plus flutamide (P=0.008) and for goserelin plus flutamide versus leuprolide plus flutamide (P=0.047). Survival outcomes were similar for goserelin plus bicalutamide and goserelin plus flutamide (P=0.99).

"Overall, each of the four CAB regimens was well tolerated, but the increased side effects of flutamide, particularly diarrhea, continued to be apparent in this subset analysis, indicating a markedly improved tolerability for bicalutamide," Dr. Sarosdy continued. Hematuria was more common in the bicalutamide groups.

"Future prospective randomized trials designed specifically to compare the effectiveness of each of the four CAB regimens may yield data with even more compelling results," said Dr. Sarosdy.

Study Methods and Design

Throughout the trial, the LHRH-A was administered open-label and the antiandrogen was double-blinded in a two-by-two factorial design. Patients were randomized 2:1 to goserelin (3.6 mg every 28 days) or leuprolide (7.5 mg every 28 days) in an effort to reduce costs. Patients were allocated 1:1 to bicalutamide (50 mg once daily) or flutamide (250 mg three times daily). Time to disease progression and survival were assessed after a median period of 160 weeks of treatment.

Prostate Cancer, ZOLADEX and CASODEX

According to the American Cancer Society, more than 189,500 American men will be diagnosed with prostate cancer in 1998, with 39,200 deaths resulting from the disease. Prostate cancer is the most frequently diagnosed of all malignancies in men -- other than certain skin cancers -- and is second only to lung cancer as a cause of cancer-related deaths in men.

Developed, manufactured, and marketed by Zeneca Pharmaceuticals, ZOLADEX is an effective and well-tolerated initial therapy used for the palliative treatment of advanced prostate cancer. The drug is administered by subcutaneous injection and has been available since 1989 as a monthly implant (3.6 mg), and since 1996 as a three-month implant (10.8 mg). Both formulations have been shown to be as effective as orchiectomy (surgical castration) in controlling the spread of prostate cancer, thus offering men a choice between pharmacologic therapy and radical surgery. In treatment groups, adverse events with ZOLADEX were reported as mild to moderate. Hot flashes are the most frequently reported side effect with ZOLADEX, and unspecified cancer-related pain and lower urinary tract symptoms may also be common.

CASODEX, also from Zeneca Pharmaceuticals, was approved by the Food and Drug Administration in October 1995 for use in combination therapy with an LHRH-A such as ZOLADEX for treatment of advanced metastatic prostate cancer (stage D2). In 1997, CASODEX became the most widely prescribed antiandrogen in the United States (Source: IMS America prescription data). CASODEX 50 mg in combination with an LHRH-A is generally well-tolerated. The most commonly reported adverse events with CASODEX plus LHRH-A are hot flashes, pain, constipation, back pain, pelvic pain, nausea, diarrhea, and infection.

Zeneca Pharmaceuticals is a business unit of Zeneca Inc., based in Wilmington, Del. In the United States, Zeneca Inc. is a $3.4 billion bioscience business with approximately 7,500 employees. Zeneca Inc. is a wholly-owned subsidiary of the U.K.-based Zeneca Group PLC (NYSE:ZEN), a major $8.6 billion international bioscience business engaged in the research, development, manufacture, and marketing of ethical (prescription) pharmaceuticals, agricultural and specialty chemical products, and the supply of health care services.

# # #

NOTE: For full prescribing information for CASODEX(r) (bicalutamide) Tablets and ZOLADEX(r) (goserelin acetate implant), please call 1-800-456-3669, ext. 2231, or access the World Wide Web at www.prostateinfo.com.