Clinical Study of Leuprolide Depot Formulation in the Treatment of Advanced Prostate Cancer

0022-534 7 /90/1431-0068$02.00/0 THE JOURNAL OF UROLOGY Copyright© 1990 by AMERICAN UROLOGICAL ASSOCIATION, INC.

Vol. 143, January

Printed in U.S.A.

CLINICAL STUDY OF LEUPROLIDE DEPOT FORMULATION IN THE TREATMENT OF ADVANCED PROSTATE CANCER ROOHOLLAH SHARIFI,* MARK SOLOWAY*

AND

THE LEUPROLIDE STUDY GROUPt

ABSTRACT

In a phase III, open, multicenter study we evaluated the safety and efficacy of the depot formulation of leuprolide (7.5 mg. injected intramuscularly every 4 weeks) in patients with stage D2 prostate cancer who had not previously received systemic treatment. Serum testosterone, luteinizing hormone and plasma leuprolide levels were monitored during the 24-week study period. Median interval to onset of castrate testosterone levels was 21 days and mean testosterone levels decreased to within the castrate range by week 3 of treatment. After onset of castrate levels there were no escapes (defined as 2 consecutive values of greater than 50 ng./dl.) of testosterone levels during the 24 weeks. Suppression of testosterone did not differ significantly from that observed in patients receiving the daily subcutaneous injection of leuprolide acetate in the first 24 weeks of another study. Objective response (no progression) to treatment occurred in 81 % of 53 evaluable patients and adverse (related and unrelated) events were reported in 45 of the 56 patients. The response rate and incidence of adverse events in this study did not differ significantly from those occurring with the daily formulation. We conclude that the depot formulation of leuprolide is safe and effective in the treatment of advanced prostatic cancer, and that the safety and efficacy of this formulation do not differ significantly from those of the daily subcutaneous formulation. (J. Ural., 143: 68-71, 1990) The mainstay of treatment for metastatic adenocarcinoma of the prostate remains endocrine manipulation by means of orchiectomy or hormonal therapy. 1 • 2 More than 70% of the patients respond to endocrine manipulation but mean survival time remains 1.9 years. 3 Once the disease progresses 6-month survival is less than 50%. Furthermore, the psychological problems associated with orchiectomy and the potential cardiovascular adverse effects of diethylstilbestrol are well known. 4 • 5 Luteinizing hormone-releasing hormone analogues and antiandrogens provide the patient with an alternative form of endocrine treatment. In clinical trials luteinizing hormonereleasing hormone analogues proved to have activities comparable with those of established endocrine therapy, including orchiectomy and oral estrogens, in patients with advanced prostate cancer. The result in terms of tumor responsiveness, interval to disease progression and survival was equivalent to orchiectomy and diethylstilbestrol. 4 •6 - 9 To avoid the necessity for subcutaneous daily injections of leuprolide the depot formulation was developed. Given every 4 weeks, each injection contains 7.5 mg. leuprolide acetate incorporated into a biodegradable copolymer of lactic and glycolic acids. The formulation is supplied as lyophilized microspheres in a 1-dose vial, reconstituted with supplied diluent solution, and is given as an intramuscular injection with a 21 or 22 gauge needle.

We report the results of a prospective study comparing the safety and efficacy of the leuprolide depot formulation with those of our former daily 1 mg. subcutaneous formulation in previously untreated patients with stage D2 cancer of the prostate. The comparison indicates a similar effective and steady depletion of testosterone, with no significant difference in objective clinical response or adverse events. MATERIAL AND METHODS

This phase III, open study was conducted at 9 centers in North America beginning in March 1986. The 56 patients enrolled had histologically confirmed stage D2 carcinoma of the prostate, with 2 or more clinically measurable or evaluable manifestations of prostate cancer (for example lymph node metastases or a prostate lesion), pre-study serum testosterone levels of 150 ng./dl. or more and performance status grade of 2 or less as defined by the Eastern Cooperative Oncology Group Scale (O-normal, I-restricted but ambulatory and able to perform light work, and 2-ambulatory for more than 50% of waking hours and capable of all self care but unable to work). Patients had not received systemic treatment other than local radiation therapy, which was permitted provided that the irradiated site would not be used as an evaluable lesion and that at least 2 evaluable lesions remained. Patients voluntarily signed an informed consent form. Patients were excluded from the study if they had undergone chemotherapy or hormonal manipulation, such as orchiectomy, if they had life-threatening renal, hepatic or cardiovascular disease, or if they had a life expectancy of less than 3 months. The treatment period began with a depot leuprolide injection on day 0. Followup visits were on days 4 and 7, weekly through week 6, every 2 weeks through week 20 and every 4 weeks thereafter. Evaluations and procedures included medical and prostatic cancer history, physical examination, performance status assessment, bone scan, clinical laboratory determinations (hematology, chemistry, acid and alkaline phosphatase, and urinalysis) and determinations of blood levels of testosterone, lutein izing hormone and leuprolide. At the end of 12 weeks and at

Accepted for publication July 28, 1989. Supported in part by TAP Pharmaceuticals/Abbott Laboratories, North Chicago, Illinois. Read at annual meeting of American Urological Association, Dallas, Texas, May 7-11, 1989. * Requests for reprints: University of Illinois Hospital, 840 S. Wood St., Chicago, Illinois 60612 (R. S.) or Department of Urology, University of Tennessee Center for Health, 956 Court Ave., Box 10, Memphis, Tennessee 38163 (M. S.). t Participants: Roy J. Correa, Jr., The Mason Clinic, Seattle, Washington; Andrew G. Glass, Northwest Permanente, Portland, Oregon; Patrick D. Guinan, Cook County Hospital, Chicago, Illinois; Marc B. Garnick, Dana Farber Cancer Institute, Boston, Massachusetts; L. Michael Glode, University of Colorado, Denver, Colorado; Joseph A. Smith, University of Utah Medical Center, Salt Lake City, Utah, and Barry S. Stein, Rhode Island Hospital, Providence, Rhode Island. 68

69

LEUPROLIDE DEPOT Sr:f'UD'i

12-week intervals thereafter National Prostatic Cancer criteria were used to assess response to treatment and performance status. After each visit radioimmunoassays for serum testosterone and luteinizing hormone levels and plasma leuprolide acetate concentrations were performed. Six patients were assigned to an expanded blood collection schedule. Blood was drawn for testosterone and luteinizing hormone determinations before the study, on days O and 4, and then twice weekly until castrate levels of testosterone were observed in 2 consecutive tests. The schedule then reverted to that of the other patients. At 12-week intervals, patients were assessed for objective responses to treatment, including complete response, partial response, objectively stable (no change) or progression as defined by National Prostatic Cancer Project criteria. The grade mixed response was given if 1 lesion had improved or disappeared but others had progressed. Data were analyzed statistically with standard chi-square and paired Student's t test, when appropriate. P values of 0.05 or less were considered significant. RESULTS

The mean age of 53 evaluable patients was 68 years (range 50 to 93 years). Mean height was 69 inches (range 58 to 76 inches) and mean body weight was 180 pounds (range 101 to 287 pounds). The interval from the first histological diagnosis of prostate cancer to the start of leuprolide treatment ranged from 3 days to more than 6 years. Half of the patients were diagnosed within 2 months before the first injection and more than 75% were diagnosed within the preceding 2 years. The interval fron1 first diagnosis of stage D2 disease to first depot injection ranged from 1 day to more than 1.5 years. Half of the patients had been diagnosed as having stage D2 disease within 2 weeks of the initial injection and none had prior systemic treatment for prostate cancer. A total of 22 patients (42%) had no prior treatment and 21 (40%) had prostate resections only. The remaining patients had radiation, radioactive implants to the prostatic lesions or combinations of resection, implantation and radiation. Ten patients were discontinued from the study before 24 weeks: 3 died (2 of prostate cancer at weeks 11 and 24, and 1 of septicemia at week 24), 4 had disease progression at weeks 8, 15, 24 and 24, 2 were discontinued for early protocol violation at weeks 2 and 7, and 1 had an adverse event (testicular pain) at week 24. Five patients were considered for partial hormonal data exclusion of 4 weeks when the schedule was delayed for 7 days or more. Three patients had serum testosterone levels of 100 to 150 but all had a su:t111;1ent.l} increased response to the initial injection of leupro!ide to indicate the presence of active testicular tissue. Testosterone and luteinizing hormone levels. Figure 1 shows the mean (plus or minus standard testosterone levels caiculated for the 53 evaluable patients. The mean baseline testosterone value before treatment was 370.6 ng./dL (range 111 to 893 ng./dl.). Mean serum testosterone levels initially increased, peaking at 552.7 ng./dL (range 219 to 996 ng./dl.) on day 4 and then decreased ultimately to castrate range (less than 50 ng./dL). Mean levels had decreased to 33.8 ng./dl. by week 3 and to 17.0 ng./dl. by week 4, and then stayed at less than 15 ng./dl. through week 24. This result is similar to the testosterone levels in patients who received the daily subcutaneous injection (fig. 1). Castrate levels of testosterone occurred in all evaluable patients at some time during the study. In 51 patients (96%) castrate testosterone levels occurred within 30 days after the initial depot injection. Of the 2 remaining patients 1 reached castrate testosterone level (38 ng./dl.) 36 days after the initial depot injection but the testosterone value on day 29 was 57 ng./dl., slightly above the castrate range. The other patient had

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a decrease to 14 ng./dl. at day 67. The testosterone level was 71 ng./dl. at week 3 but he did not report to us at week 4. The second injection was given at week 5 when the testosterone level had increased to 303 ng./dl. Then, 31 days after the second injection the serum testosterone was 14 ng./dl. and remained within castrate range throughout the study. No patient had a prolonged escape (2 consecutive values of greater than 50 ng./dl.) for the duration of the followup (lower 95% confidence limit for percentage of patients free of escape was 95 % ). Four patients had 1 testosterone value of greater than 50 ng./dl. (range 53 to 72 ng./dl.) after onset of castrate levels but never 2 consecutive values of greater than 50 ng./dl. This was true even for patients with progression of disease. Injections were delayed 7 to 12 days in 5 patients. Analysis of testosterone levels revealed that only 1 of the 5 patients had an increase in testosterone levels after an injection was delayed for l week. The testosterone levels in this patient subsequently decreased, and were within castrate range 5 weeks later and throughout followup. Thus, in most patients delay of an injection by up to 12 days did not result in a clinically significant increase in testosterone. However, if an injection was delayed by 2 or more weeks testosterone levels increased significantly. Mean (plus or minus standard error) testosterone levels for the 6 patients on the expanded schedule are shown in figure 2. Although the samples were collected more frequently the levels are essentially the same as those in the other patients (fig. 1). Thus, the response seen in all patients provides an accurate picture of the decrease in testosterone levels after the initial depot The pattern of in mean serum luteinizing hormone levels was similar to the pattern for testosterone After an initial increase from a baseline of 6.6 mIU /ml. (range 2.3 to 23) to 4 mIU/ml.), mean serum luteinizing hormone levels decreased to 4.8 mIU/mL week 2 and remained between 3.8 and 4.1 mIU/ml. for weeks 3 through 24. Of 56 patients 3 were excluded from evaluation (2 for protocol violation at weeks 2 and 7, and 1 for irregular schedule visit). Fifty evaluable patients were available at week 12 and 44 at week 24 for objective response assessment. Table 1 summarizes evaluable objective response data for 12 and 24 weeks. At week 12, 3 patients had progression and were dropped from the study, while 3 had progression and were kept in the study, for a total of 6 patients (12%) with progression. At week 24, 3 patients with progression from week 12, 2 with new progression and 3 with a mixed response at 12 weeks also had progression, for a total of 8 (18.2%) with progression. The best objective response was defined as the most favorable response evaluation at any time during the first 28 weeks. By this time all 53 patients had 1 evaluation. Best objective response for 10 patients was pro-

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70

LEUPROLIDE STUDY GROUP LEUPROLIDE DEPOT FORMULATION KAPLAN-MEIER SURVIVAL CURVE APRIL, 1989

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t Mixed responses not included. Summary of best objective response for evaluable patients in depot study and for evaluable stage D2 patients who received subcutaneous daily injections of leuprolide as first treatment

TABLE 2.

Response* Complete Depot leuprolide Daily leuprolide

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gression in 18.9% and no progression in 81.1 %. In table 2 the best objective response rates are compared to those for the daily subcutaneous injection. The response rates are not statistically different, indicating that the depot formulation of leuprolide is as effective as the daily formulation. A Kaplan-Meier long-term survival curve is shown in figure 4. This survival curve involves all 56 patients and indicates the survival times for the 33 patients who died during the course of the study to

the time of data analysis. Median survival time was 686 days (95% confidence interval 629 to 1,053 days) for this patient group. A total of 39 patients with abnormal prostatic evaluations at baseline and who had not received local treatment previously was assessed at weeks 12 and 24. At week 12 none of the levels had returned to normal, 15 patients (38%) had improved by more than 50%, 24 (62%) remained unchanged and none had worsened by more than 25%. By week 24, however, 6 patients (15%) had returned to normal, 12 (31%) had improved, 20 (51%) were similar to baseline and 1 (3%) had worsened. At week 12 no patient had worsening of prostatic involvement but 11 had an objective evaluation of progression or mixed response. At week 24 only 8 patients had progression on objective evaluation, including 1 with worsening ofprostatic involvement. Thus, metastatic disease as documented by bone scan appears to progress in most patients, even as local tumor response improves or remains unchanged. Of 32 patients with an elevated prostatic acid phosphatase level at baseline 29 (90.6%) had a decrease of 25% or more in these markers at week 12, compared to 20 of 26 (76.9%) at week 24. Only 10.6 and 15% of the evaluable patients showed an increase in prostatic acid phosphatase at weeks 12 and 24, respectively. One of 5 with an increase at week 12 and 3 of 6 with an increase at week 24 had progression at these weeks. Of the 31 patients with an abnormal performance status (greater than O) at baseline 42% had improved performance at week 12 and 52% remained stable, for a total of 94% improvement or stable. Six patients (12%) had an objective response evaluation of progression at week 12, while 5 (10%) had a mixed response. At week 24, 8 patients (18.2%) had progression. None of the patients had worsening in performance status at those visits. Thus, even though bone scans and other parameters indicated progression, performance status had not deteriorated. Prostatic mass, prostatic acid phosphatase and performance status also were evaluated as a part of the National Prostatic Cancer Project criteria. Safety. There was no significant change in pulse rate and blood pressure from baseline at weeks 12 to 24. Mean body weight increased significantly (by 3.5 pounds) by week 24 (p <0.05). At weeks 12 and 24 the results of urinalysis, hematology studies and blood chemistry analyses showed significant changes in only 2 patients. Both patients had significant increases in lactic dehydrogenase levels, believed by the investigator to be drug-related. One patient had a baseline lactic dehydrogenase of greater than normal, with progression of disease at weeks 12 and 24. Because lactic dehydrogenase often is elevated in patients with prostate cancer, especially those with progression, the relationship of this elevation to the drug

71

LEUPROLIDE DEPOT STUDY

is questionable. One had a normal baseline lactic dehydrogenase level, a 25% elevation at week 24 that was believed to be drug-related and a 50% elevation at week 84, at which time the disease had progressed. Adverse effects. During the 24 weeks 45 of the 56 patients experienced 1 or more adverse events. (All adverse events were included, regardless of severity or relationship to treatment.) Hot flashes occurred in 32 patients (57% ), and usually were mild and never troublesome. Six patients (10.7%) who had hot flashes also reported sweating. Reactions (other than hot flashes) in 5% or more of the patients included peripheral edema (7), pain (4), constipation (4), dyspnea (4), chest pain (3), impotence (3) and urinary frequency (3). These results do not differ significantly from those noted with the 1 mg. daily injection. One patient discontinued the study at week 24 due to testicular pain but the relationship to the drug was unclear. An exacerbation of symptoms during the first 2 weeks was not seen. Pharmacokinetic results. Plasma leuprolide levels were monitored to determine if there was an accumulation of plasma leuprolide with repeated monthly injections. Figure 5 shows the mean plasma leuprolide acetate concentrations for all 56 patients. The initial rapid increase in leuprolide levels immediately after injection is characteristic of depot formulations containing microspheres. Plasma levels decreased during the initial 2 to 4 weeks and stabilized after week 8. COMMENTS

Median interval to onset of castrate levels of testosterone for the 53 evaluable patients was 21 days. Mean testosterone levels decreased to within castrate range by week 3 of treatmento After onset of castrate levels, there were no escapes (2 consecutive values of more than 50 ng./dl.) of testosterone values in the evaluable patients, provided that they received the monthly injections on time. We did not observe any additional clinical symptoms or exaggeration of previous signs and symptoms after the initial injection of depot leuprolide. This was different from the previous studies ofluteinizing hormone-releasing hormone analogues in which the so-called flare-up phenomenon was seen in less than 10% of the patients. 10- 12 Serum testosterone levels during the first 24 weeks of treatment remained steady and did not differ from those seen in the patients who had received daily subcutaneous injections of leuprolide. Delay of an injection by up to 12 days could conceivably compromise the treatment but in most cases it did not result in a clinically significant increase in testosterone levels. However, a delay of 2 weeks or more significantly increased the testosterone levels. Mean Plasma

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Of the 53 evaluable patients 81 % ,-~o .. plus partial response plus no change) to treatment at some time during the 6 months. This response rate does not differ significantly from the 86% rate in patients receiving daily injections. After the initial drug release, leuprolide was released from the depot formulation at a nearly steady rate and drug concen trations were present in blood samples collected throughout the study. When plasma concentrations decreased to below the limit of assay detectability, testosterone levels did not increase correspondingly. Adverse (related and unrelated) events occurred in 80% of the patients. Hot flashes were reported by 57% and this was the main drug-related side effect. It seems that the effects of depot leuprolide on potency are much lower compared to our previous experience with daily injections. 8 This matter must be studied in the future. There was no significant difference in other adverse events in this group and in the group treated with the daily subcutaneous formulations. In conclusion, our results indicate that the depot formulation of leuprolide acetate (7.5 mg. per month) is safe and effective in the treatment of advanced prostatic cancer. This formulation lacks serious side effects, has excellent compliance and can be used as a medical alternative when bilateral orchiectomy (the cardinal therapy) is rejected by the patient. ,,µw

The depot leuprolide acetate suspension was supplied by TAP Pharmaceuticals, North Chicago, Illinois, Radioimmunoassays for serum testosterone and leutinizing hormone levels were performed at Endocrine Sciences Laboratory, Tarzana, California. Radioimmunoassays for plasma leuprolide acetate concentrations were performed at Abbott Laboratories, North Chicago, Illinois. REFERENCES

1. Huggins, C., Stevens, R. E., Jr. and Hodges, C. V.: Studies on prostatic cancer. II. The effects of castration on advanced carcinoma of prostate gland. Arch. Surg., 43: 209, 1941. 20 The Veterans Administration Co-Operative Urological Research Group: Treatment and survival of patients with cancer of prostate. Surg., Gynec. & Obst., 124: 1011, 1967. 3. Walsh, P. C.: Physiological basis for hormonal therapy in carcinoma of the prostate. Urol. Clin. N. Amer., 2: 25, 1975. 4. Bailar, J. C., III and Byar, D. P.: Estrogen treatment for cancer of the prostate. Early results with 3 doses of diethylstilbestrol and placebo. Cancer, 26: 257, 1970. 5. The Leuprolide Study Group: Leuprolide versus diethylstilbestrol for metastatic prostate cancer. New Engl. J. Med., 311: 1281, 1984. 6. Smith, J. A, Jro: Androgen suppression by a gonadotropin releasing hormone analogue in patients with metastatic carcinoma of the prostate. J. Uro!., 131: 1110, 1984. 7. Soloway, M. S.: Newer methods of hormonal therapy for prostate cancer. Urology, suppl. 5, 24: 30, 1984. 8. Sharifi, R., Lee, M., Ojeda, L., Ray, P., Stobnicki, Mo and Guinan, P.: Comparison of leuprolide and diethylstilbestrol for stage D2 adenocarcinoma of prostate. Urology, 26: 117, 1985. 9. Turkes, A. 0., Peeling, W. B. and Griffiths, K.: Management of patients with advanced carcinoma of the prostate: a randomized phase III trial of zoladex against castration by the British Prostate Group. In: Hormonal Therapy of Prostatic Diseases. Edited by M. Motta and M. Serio. Medicom, 1987. 10. Waxman, J. H., Wass, J. A.H., Hendry, W. F., Whitfield, H. N., Besser, G. M., Malpas, J. S. and Oliver, R. T.: Treatment with gonadotrophin releasing hormone analogue in advanced prostatic cancer. Brit. Med. J., 286: 1309, 1983. 11. Labrie, F., Dupont, A., Belanger, A., Lacoursiere, Y., Ragnaud, J. P., Husson, J. M., Gareau, J., Fazekas, A. T., Sandow, J., Monfette, G., Girard, J. G., Emond, J. and Houle, J. G.: New approach in the treatment of prostate cancer: complete instead of partial withdrawal of androgens. Prostate, 4: 579, 1983. 12. Glode, L. M. and Max, D.: Leuprolide (D-leu- 6 Des Gly 10 -Pro 9 -NH et-LHRH) in the therapy of advanced prostatic cancer. Presented at the 13th International Congress of Chemotherapy, Vienna, Austria, August 28-September 2, 1983.