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Leuprolide acetate (30-mg depot every four months) in the treatment of advanced prostate cancer
ADULT U R O L O G Y
ELSEVIER
LEUPROLIDE ACETATE (30-mg DEPOT EVERY FOUR MONTHS) IN THE TREATMENT OF ADVANCED PROSTATE CANCER ROOHOLLAH SHARIFI, L. DEAN KNOLL, JOSEPH SMITH, AND EUGENE KRAMOLOWSKY
ABSTRACT Objectives. An unblinded, multicenter study to evaluate the efficacy and safety of a long-acting depot formulation of leuprolide (30 rng injected intramuscularly every 16 weeks) was carried out in 49 patients with Stage D2 prostate cancer. Methods. Clinical evaluations were performed every 16 weeks, and serum testosterone levels were monitored biweekly or weekly for 32 weeks. Results. The mean serum testosterone level for the 45 evaluable patients fell to the castrate range (50 ng/clL or less) by week 3 after the initial depot injection and remained at that level throughout the initial 32-week treatment period. The median time to the onset of castrate levels was 22 clays (range 9 to 43). Onset of castrate levels of testosterone was achieved within 4 weeks of the initial depot injection in 96% of patients. One patient (2%) experienced a transient "escape" (testosterone levels greater than 50 ng/dL on two consecutive determinations). Delay of an injection by up to 3 weeks did not have an effect on testosterone suppression. Objective tumor response (no progression) occurred in 90% of patients at week 16 and in 80% at week 32. Prostate-specific antigen and prostatic acid phosphatase decreased by 50% or more at week 32 in 97% and 76% of patients, respectively. Assessment of local disease status and overall performance status showed improvement or stability in most patients. The most common adverse events were hot flashes (45%), back pain (16%), and arthralgia (14%). Conclusions. The 30-rag depot formulation of leuprolide, which acts in a manner similar to the 7.5- and 22.5-mg depot formulations (given monthly and every 3 months, respectively) is effective in lowering serum testosterone to castrate levels in all patients and demonstrates a favorable response in 80% of the patients with advanced prostate cancer for the 32-week observation period. The drug was well tolerated in all patients. UROLOGY51: 271-276, 1998. © 1998, Elsevier Science Inc. All rights reserved.
L
euprolide acetate, a nonapeptide analogue of gonadotropin-releasing hormone (GnRH) with up to 100 times the potency of endogenous GnRH, has been used to treat a wide range of clinical conditions responsive to changes in the sex-steroid hormone milieu. In the treatment of prostate cancer, leuprolide offers an alternative to orchiectomy or estrogens. It desensitizes the pituitary to native GnRH stimulaSupported by a grantfrom TAP Holdings Inc. From the Department of Urology, University of Illinois Medical Center, Chicago, Illinois; Center for Urological Treatment and Research, Nashville, Tennessee, Department of Urology, Vanderbilt University, Nashville, Tennessee; and The Virginia Urology Center, Richmond, Virginia Reprint requests:Roohollah Sharifi, M.D., Department of Urology. M/C 958, University of Illinois at Chicago, 840 South Wood Street, Chicago, IL 60612-7322 Submitted: April 15, 1997, accepted (with revisions):August 6, 1997 © 1998, ELSEVIERSCIENCE INC, ALL RIGHTSRESERVED
tion, thereby resulting in decreased pituitary gonadotropin release and subsequent suppression of gonadal testosterone production.1 Androgen suppression can result in stabilization, slowing, or regression of tumor (primary and metastatic) proliferation, and it usually results in a reduction of pain caused by metastatic skeletal lesions. First released for the palliative treatment of advanced prostate cancer in 1985, leuprolide was given as a daily 1-mg subcutaneous formulation. To avoid the necessity for daily injections, a depot formulation containing 7.5 mg of leuprolide for monthly intramuscular injection was developed and released in 1989. Subsequently, an extendedrelease depot formulation containing 22.5 mg of leuprolide was developed for intramuscular injection every 3 months. All three formulations result in suppression of serum testosterone to the castrate 0090-4295/98/$19.00 PII S0090-4295(97)00500-1
271
range within 2 to 4 weeks. Favorable objective response rates are not significantly different at 86%, 82%, and 80%, respectively.2,3 A 30-mg formulation of leuprolide has been developed to be administered as an intramuscular injection every 4 months. The efficacy and safety of this formulation of leuprolide were evaluated in an unblinded, multicenter study of patients with Stage D2 prostate cancer. Serum testosterone and luteinizing hormone (LH) levels were assessed to monitor the attainment of the castrate level, to identify the duration of testosterone suppression, and to determine whether there was a transient increase in serum testosterone associated with the reinjection of leuprolide acetate, and whether serum testosterone levels greater than 50 ng/dL (the castrate level) were reached during the study. Results obtained during the first 32 weeks of treatment are presented. MATERIAL
AND METHODS
A total of 49 patients were enrolled in this unblinded, multicenter study conducted at 17 centers. All patients had histologically confirmed adenocarcinoma of the prostate in Stage D2 as defined by the presence of bone, soft tissue, or lymphatic metastasis (above the aortic bifurcation). To qualify, patients were required to have two or more clinically evaluable lesions (including prostate, if present), prestudy serum testosterone levels of 150 ng/dL or higher, and a performance status grade of 2 or lower as defined by the Eastern Cooperative Oncology Group (ECOG) Scale (0: normal; 1: restricted but ambulatory and able to perform light work; 2: ambulatory for more than 50% of waking hours and capable of all self-care but unable to work, 3: ambulatory for less than 50% or waking hours and capable of limited self-care; and 4: not ambulatory, completely disabled, and unable to carry out any self-care). Patients voluntarily signed an informed consent form. Patients were excluded from the study if they did not have an intact hypothalamic-pituitary-gonadal axis, if they had ever previously received a GnRH analogue, or if they had received other hormonal therapy or chemotherapy within 4 weeks preceding the initial depot injection. Ongoing radiation therapy precluded entry into the study. Patients were removed from the study if they required antiandrogen treatment during the first 32 weeks. The 30-mg leuprolide depot formulation was given by intramuscular injection every 16 weeks (112 days) for as long as there was apparent clinical benefit. This report covers the first 32 weeks of treatment. Blood collection for determination of serum LH and testosterone levels was performed at baseline, at 4 and 7 days following the initial injection, at the end of each of weeks 2 through 20, and then every 2 weeks up to week 32. Blood collection to assess hormone levels on dosing days was performed before the depot injection was given. The hormonal response to treatment was further characterized at the end of the first two dosing intervals (at half-week intervals at least 3 days apart during weeks 14, 15, 30, and 31) in a subset of 6 patients, and for several days after the second and third depot injections at weeks 16 and 32 in subsets of 9 and 10 patients, respectively. To assess the possible rise in serum testosterone levels following reinjection similar to that often seen after the initial injection, additional blood for serum testosterone and LH determinations was collected 4, 8, and 12 hours after the week-16 depot injection.
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Physical examination (including a digital rectal examination [DRE]), ECOG performance status assessment, and bone scan were performed at baseline and were repeated at weeks 16 and 32. Patients were also monitored for objective responses to treatment at weeks 16 and 32. Objective responses were graded as complete response, partial response, objectively stable (no change), or progression as defined by National Prostatic Cancer Project criteria. Prostate-specific antigen (PSA), prostatic acid phosphatase (PAP), and standard hematology and chemistry panels were obtained at baseline and were repeated at weeks 16 and 32. Testing was performed at a central laboratory. Testosterone and LH measurements were carried out at a central laboratory using standard radioimmunoassay (RIA) methodology. Testosterone was assessed by a two-step purification method prior to quantitation by RIA. The lower limit of sensitivity of the assay method was 3 ng/dL. The LH assay, which is a sequential addition, double-antibody RIA, is not specific for bioactive LH; it yields higher results than would be obtained by bioassay. The lower limit of sensitivity was 1.0 mlU/mL. DETERMINATIONOF RESPONSE Hormonal Response. A patient was considered to be a responder if, within the first 8 weeks after the first depot injection, his testosterone level was reduced to 50 ng/dL or less (castrate level) for two consecutive tests. Elevations of serum testosterone levels to greater than 50 ng/dL on two consecutive tests, after they had been reduced to castrate level for two consecutive tests, were considered to be escapes. Objective Tumor Response. Objective tumor responses to treatment were categorized as follows. Complete response was characterized by the total disappearance of all tumor masses and osteoblastic lesions, calcification of osteolytic lesions, lack of any new lesions, normalization of serum tumor markers (P&I/PAP), and the absence of significant cancer-related deterioration in body weight, symptoms, or performance status. Partial response comprised the following parameters: reduction in cross-sectional area, of at least one tumor mass by more than 50%, normalization of serum tumor markers, lack of both lesion progression and development of new malignancy, recalcification of one or more osteoblastic lesions (if present), and the absence of significant cancer-related deterioration in body weight, symptoms, or performance status. The stable disease classification included all of the following: no new lesions occurred; no measurable lesions expanded by more than 25% in cross-sectional area; serum tumor markers were reduced, not necessarily to normal; new bony metastases appeared; and there was no significant cancer-related deterioration in body weight, symptoms, or performance status. The progression classification encompassed any of the following: significant cancer-related loss of weight, increase of symptoms, or deterioration in performance status; the appearance of new areas of malignant disease; and a greater than 25% increase in cross-sectional area of any pre-existing measurable lesion. STATISTICALMETHODOLOGY The first of two consecutive visits at which testosterone levels were 50 ng/dL or less was considered to be the onset of the castrate level. If this occurred by week 8, the patient was considered to be “suppressed.” If the testosterone level was greater than 50 ng/dL for two consecutive tests after suppression was achieved, an “escape” was considered to have occurred. The proportion of patients who achieved testosterone suppression and the proportion of suppressed patients who experienced “escapes” were calculated. UROLOGY
51 (2), 1998
For hormone data, the maximum value in an interval was used in analysis. Summary statistics were provided for demographic characteristics, disease status at baseline, and testosterone and LH values at each categorized visit. Additional summaries were provided for patients who had samples obtained at 4,8, and 12 hours after the injection at week 16 and for those who participated in the expanded blood collection schedule. Within-group changes from baseline were analyzed using paired t tests. Repeated-measure analysis of variance was used to test for linear trends across time. Statistical significance indicates P 10.05.
RESULTS Of the 49 patients enrolled, 4 were excluded from the analysis of efficacy, either because no pretreatment testosterone level was available (2 patients), or because of uncertainty of disease stage (2 patients). Hormone, PSA, PAP, and DRE results for week 32 were excluded for 1 additional patient because these evaluations were performed late. The mean age of the 45 evaluable patients was 70 years (range 54 to 84), mean height was 69 inches (range 64 to 74), and mean body weight was 172 pounds (range 100 to 270). Fifty-one percent were white, 47% were black, and 2% were Hispanic. The mean time interval from histopathologic diagnosis of prostate cancer to the start of leuprolide treatment was approximately 7 months. Sixty-nine percent of the patients had been diagnosed within 3 months of enrollment, and 96% had been diagnosed within 3 years. Sixty-four percent of the patients had not had any previous treatment for prostate cancer. The remaining patients had had transurethral prostatic resection, radical prostatectomy, radiation therapy, or a combination of these treatments. One patient had been treated with ketoconazole for 17 days; however, treatment was discontinued 2 months prior to this study. Six patients were terminated from the study prematurely: 2 died of prostate cancer at weeks 16 and 28; 3 discontinued treatment at weeks 16,22, and 26 because of disease progression; and 1 withdrew at week 32 per his request to be followed by his local physician. TE~TOSTERONEAND
LH
LEVELS
The initial testosterone response was that characteristically seen after administration of a GnRH analogue. Mean serum testosterone increased from a baseline value of 423.7 ng/dL to a day 4 value of 659.6 ng/dL. This was followed by a steady decline to the castrate range by week 3 (Fig. 1). Mean levels declined further to 10.7 ng/dL by week 6 and then remained steady, fluctuating between 9.7 and 21.0 ng/dL through week 32. Castrate levels of testosterone occurred in all evaluable patients. The median time to onset of castrate levels was 22 days (range 9 to 43). Castrate levels were achieved in 39 (87%) and in 43 (96%) UROLOGY
51 01, 1998
Mean (? standard deviation) serum tes1. tosterone levels after administration of leuprolide depot 30 mg injected intramuscularly every 16 weeks. FIGURE
of the 45 evaluable patients by weeks 3 and 4, respectively, and in all 45 patients by week 6. All patients were therefore considered to be “suppressed.” A transient “escape” from the castrate range was experienced by 1 patient (2%) (one-sided 95% upper confidence bound for the proportion of patients with an escape was 10%). The testosterone value 12 hours after the week 16 injection was 74 ng/dL, and subsequent determinations at weeks 16.5 and 17 were 87 and 55 ng/dL, respectively. There were no associated symptoms, and serum PSA was less than 0.5 ng/dL from a baseline of 51 ng/dL; therefore, the rise in testosterone was not considered clinically significant. Testosterone levels returned to the castrate range by week 18 and remained there through week 32. The depot injection at week 16 or 32 was delayed in 5 patients by 3 to 21 days. Nonetheless, on those injection days, as well as at the next time measured, testosterone values for these patients remained within the castrate range and below the mean values for all patients. Thus, delay of an injection by up to 3 weeks did not result in weakening or loss of hormonal suppression. The pattern of change in serum LH levels was similar to that for testosterone. There was an initial increase in mean LH on day 4 to a value above the pretreatment level (19.5 mIU/mL), followed by a decline to slightly below the pretreatment level by week 1 (13.4 mIU/mL), and a further decline to the lower end of the normal range (3 to 10 mIU/mL) by week 3, at which it remained throughout the 32week treatment period. Mean testosterone and LH values obtained at half-week intervals during the last 2 weeks of the first and second dosing intervals did not indicate any weakening of hormonal suppression during these periods. No significant linear trend in mean testosterone or LH values was seen during this segment of either dosing interval (testosterone ranges 273
TABLE 1. Summary of objective responses for 4-month, 3-month, and monthly depot formulations of leuprolide Number (%) of Patients Formulation 4-month Week Week 3-month Week Week
(30 mg) 16 32 (22.5 mg)* 12 24
Monthly (7.5 mg) Week 12+ Week 24
n
Complete Response
39 44
1 (3) 1 (2)
8 (21)
85 83
0 (0)
50 44
0 (0)
1 (1)
1 (21
Partial Response
Stable (No Change)
No Progression
26 (67) 25 (57)
35 (90) 35 (80)
4 (101 9 (20)
23 (27) 25 (30)
47 (55) 40 (48)
70 (82) 66 (80)
15 (18) 17 (20)
7 (141 11 (25)
32 (64) 24 (55)
39 (78) 36 (82)
6(12) 8 (18)
9 (201
Progression
* Two studies combined. ’ Five patients (10%) had a “mixed” response.
8.8 to 11.2 and 8.6 to 14.4 ng/dL, respectively; LH ranges 5.1 to 5.7 and 4.8 to 5.4 mIU/mL, respectively) . There was no evidence that the characteristic increases in serum testosterone and LH observed on day 4 following the initial injection of leuprolide also occurred after subsequent injections. At 3 to 5 days after the week 16 and week 32 injections, mean testosterone increased to 21.3 from 12.8 ng/dL and to 14.2 from 13.5 ng/dL, respectively. The transient increase in mean serum testosterone was not statistically or clinically significant. Changes in mean LH levels following week 16 (5.8 from 5.6 mIU/mL) and week 32 (5.2 from 4.7 mIU/ mL) injections were minimal and of no clinical significance. However, the change (-0.5 mIU/mL) following the week 32 injection was statistically significant (P = 0.01). In addition, mean PSA levels at weeks 16 and 32 (93.2 and 104.2 ng/mL) remained well below baseline. Furthermore, mean PAP levels were 27.5 and 21.9 ng/mL at week 16 and week 32, respectively, compared with a level of 161.5 ng/mL at baseline. Other than the patient described above for whom an “escape” was seen, no patient had a notable increase in testosterone at 4, 8, or 12 hours after the second depot injection at week 16. Mean changes in LH at 4,8, and 12 hours following the week 16 injection were all statistically significant (P
RESPONSE
Thirty-nine patients were evaluated at week 16, and 44 patients were evaluated at week 32 for the objective response assessment. Patients who were prematurely terminated from the study because of disease progression or death from prostate cancer 274
TABLE II. Serum PSA and PAP levels at baseline, 16 weeks, and 32 weeks Baseline
16 Weeks
32 Weeks
PSA (ng/dL) n Mean Maximum Minimum
45 1096.1 1251 1.0 2.2
43 93.2 1452.0 0.5
37 104.2 1331 .o 0.5
PAP (ng/mL) n Mean Maximum Minimum
45 161.5 2750.0 1.o
44 27.5 360.0 1.0
40 21.9 211.3 1.0
KEY: PAP = prostatic acidphosphatase;
PSA = prostate-specific antigm.
and did not have a subsequent evaluation were assigned an objective response rating of “progression” at the next evaluation. Ninety percent of the patients had a favorable response rating (ie, complete response, partial response, or no change) at week 16; 80% had a favorable response rating at week 32. Table I summarizes these data and compares the objective response rates of the 4-month, 3-month, and monthly depot formulations. PSA and PAP normalized or decreased in nearly all patients during the initial 32 weeks of treatment. PSA normalized (3.9 ng/dL or less) in 23 of the 42 patients (55%) with elevated pretreatment values, and PAP normalized (4.0 ng/mL or less) in 16 of the 31 patients (52%) with elevated pretreatment values. One patient had a normal pretreatment PSA and PAP. At week 32, PSA and PAP decreased by at least 50% in 97% and 76% of patients, respectively, with elevated pretreatment values. Table II summarizes serum PSA and PAP levels at baseline, week 16, and week 32. On DRE, all 44 patients who were evaluated at both weeks 16 and UROLOGY
51 (2), 1998
TABLE III. Adverse events occurring in 10% or more of patients, regardless of treatment relationship Adverse Event Hot flashes Back pain Arthralgia Asthenia Flu syndrome Pain Headache Rash
Number (%) of Patients 22 (45) 8 7 6 6 6 5 5
(161 (141 (121 (121 (121 (101 (101
32 were judged to have improved or stabilized local disease. Forty-four patients had a pretreatment performance status assessment and at least one assessment during the treatment period. Pretreatment performance status was abnormal in 19 of these patients. All 19 patients were evaluated at week 16, and 16 (84%) had responded favorably (improved or stable); at week 32,16 of the 19 evaluated (84%) had responded favorably. The remainder received a rating of “worsened.” Twenty-five of the 44 patients had a normal performance status before treatment. All 25 were evaluated at weeks 16 and 32. Twenty (80%) received a favorable rating (no change) at both evaluations, and 5 (20%) worsened.
SAFETY Data for all 49 patients were included in the analysis of safety. Adverse events, including those not considered treatment-related, were reported by 39 patients (80%). The most common were hot flashes (45%), back pain (16%), and arthralgia (14%) (Table III). Only 2% of patients complained of decreased libido and impotence. Injection site pain or reaction was reported by 8% of patients. During the initial 2 weeks of treatment, 24 of the 49 patients (49%) experienced one or more adverse events. Hot flashes (14%), back pain (8%), and arthralgia (6%) were the most frequently reported adverse events during this period. One patient experienced bone pain, and back pain was reported by 4 other patients. There were no cases of spinal cord compression. Two patients had urinary retention during this period; neither was considered by the investigator to be treatment-related. With the exception of a clinically significant decline in alkaline phosphatase, there were no noteworthy changes in laboratory parameters. This change in alkaline phosphatase is consistent with the observed reduction in bony metastatic disease. UROLOGY 51 (21, 1998
COMMENT This unblinded, multicenter study evaluated the efficacy and safety of a 30-mg depot formulation of leuprolide administered every 16 weeks to patients with Stage D2 adenocarcinoma of the prostate. Onset of castrate levels of serum testosterone was achieved within 4 weeks in 96% of patients, which compares favorably with the 96% reported for patients who received the monthly 7.5-mg leuprolide depot, and with the 95% reported for those who received the 22.5-mg leuprolide 3-month depot.zJ The median time to onset of castrate levels in all of these studies was 22 days. After falling to the castrate range, mean testosterone levels in the current study remained well within the castrate range throughout each dosing interval. All leuprolide depot formulations thus far developed have demonstrated limited unimpeded testosterone suppression following delayed injection. Specifically, with l-, 3-, and 4-month depot formulations, delays of up to 1,2, and 3 weeks, respectively, were found to have no effect on maintenance of testosterone suppression. 2~3One patient experienced a transient and minimal “escape” from suppression, but this was not associated with any clinical sequelae. A favorable (no progression) objective tumor response to treatment occurred in 90% and 80% of patients, respectively, at weeks 16 and 32; this was comparable to the response rates seen in patients who received the 22.5-mg depot and the monthly 7.5-mg depot (Table I). PSA and PAP decreased by at least 50% at week 32 in 97% and in 76% of the patients, respectively, with elevated pretreatment values. Local prostate involvement either improved or remained stable for all patients who had a DRE both before and during treatment. Ninety-four percent of the 19 patients with an abnormal pretreatment performance status who were evaluated at week 32 showed either improvement or no change in status, which paralleled the 88% rate achieved in patients treated for 24 weeks with the 22.5-mg formulation and the 96% rate achieved in those treated for 24 weeks with the 7.5-mg formulation.2*3 Safety data in the present study were consistent with the known safety profile of leuprolide. Adverse events reported were those typically seen in patients with metastatic prostate cancer or in association with hypoandrogenism. The 45% incidence of hot flashes, the most frequently reported adverse event, was similar to the incidence seen with the 3-month 22.5-mg and monthly 7.5mg depot formulations (59% and 57%, respectively).273 Changes in laboratory parameters were mostly small and clinically insignificant. Exacerbation of prostate cancer symptoms asso275
ciated with the transient elevation of serum testosterone levels within the first 2 weeks after the initiation of leuprolide therapy was observed in approximately 10% of patients.l This disease flare was most often manifested by bone pain, but it can include obstructive uropathy, neurologic symptoms, or paraplegia in patients with impending spinal cord compression from epidural metastases. The occurrence of these symptoms during this time period in the present study was limited to 1 patient (2%) who experienced bone pain and 2 patients (4%) who experienced urinary retention. No cases of spinal cord compression were reported. Thus, the low incidence of symptoms possibly associated with disease flare is comparable to that seen in the 22.5mg depot study, in which 2% of patients reported bone pain or urinary retention, and to that in the 7.5mg depot study, in which evidence of disease flare was also not seen.273 CONCLUSIONS The results of this study indicate that the 30-mg 4-month depot formulation of leuprolide, which acts in a manner similar to the monthly 7.5mg and 3-month 22.5mg depot formulations, is effective in reducing serum testosterone to castrate levels in
276
all patients and demonstrated a favorable response in 80% of the patients with advanced-stage prostate cancer for the 32-week observation period. The availability of a 4-month depot formulation of leuprolide offers both patients and treating physicians another therapeutic option for prostate cancer. ACKNOWLEDGMENT. To the following investigators in the Leuprolide study group: Mark Austenfeld, M.D., Cesar Ercole, M.D., Nery Flores, M.D., Jackson Fowler, M.D., Stanley Kandzari, M.D., Steven Krasnow, M.D., John Lynch, M.D., Richard Middleton, M.D., A. Lynn Patterson, M.D., Alexander Philpott, M.D., Randolph Ross, M.D., Carl Sanfelippo, M.D., Paul Schellhammer, M.D., John Tuttle, Jr., M.D., Glen Wells, M.D., and Norman Zinner, M.D. To Robert Browneller and Brenda Erickson for their technical support and assistance.
REFERENCES 1. Plosker GL, and Brogden RN: Leuprorelin. A review of its pharmacology and therapeutic use in prostatic cancer, endometriosis, and other sex hormone-related disorders. Drugs 48: 930-967,1994. 2. Sharifi R, Soloway M, and Leuprolide Study Group: Clinical study of leuprolide depot formulation in the treatment of advanced prostate cancer. J Urol143: 68-71,199O. 3. Sharifi R, Bruskewitz RC, Gittleman MC, Graham SD Jr, Hudson PB, and Stein B: Leuprolide acetate 22.5 mg 12-week depot in the treatment of advanced prostatic cancer. Clin Ther 18: 647-657,1996.
UROLOGY 51 (2), 1998
ELSEVIER
LEUPROLIDE ACETATE (30-mg DEPOT EVERY FOUR MONTHS) IN THE TREATMENT OF ADVANCED PROSTATE CANCER ROOHOLLAH SHARIFI, L. DEAN KNOLL, JOSEPH SMITH, AND EUGENE KRAMOLOWSKY
ABSTRACT Objectives. An unblinded, multicenter study to evaluate the efficacy and safety of a long-acting depot formulation of leuprolide (30 rng injected intramuscularly every 16 weeks) was carried out in 49 patients with Stage D2 prostate cancer. Methods. Clinical evaluations were performed every 16 weeks, and serum testosterone levels were monitored biweekly or weekly for 32 weeks. Results. The mean serum testosterone level for the 45 evaluable patients fell to the castrate range (50 ng/clL or less) by week 3 after the initial depot injection and remained at that level throughout the initial 32-week treatment period. The median time to the onset of castrate levels was 22 clays (range 9 to 43). Onset of castrate levels of testosterone was achieved within 4 weeks of the initial depot injection in 96% of patients. One patient (2%) experienced a transient "escape" (testosterone levels greater than 50 ng/dL on two consecutive determinations). Delay of an injection by up to 3 weeks did not have an effect on testosterone suppression. Objective tumor response (no progression) occurred in 90% of patients at week 16 and in 80% at week 32. Prostate-specific antigen and prostatic acid phosphatase decreased by 50% or more at week 32 in 97% and 76% of patients, respectively. Assessment of local disease status and overall performance status showed improvement or stability in most patients. The most common adverse events were hot flashes (45%), back pain (16%), and arthralgia (14%). Conclusions. The 30-rag depot formulation of leuprolide, which acts in a manner similar to the 7.5- and 22.5-mg depot formulations (given monthly and every 3 months, respectively) is effective in lowering serum testosterone to castrate levels in all patients and demonstrates a favorable response in 80% of the patients with advanced prostate cancer for the 32-week observation period. The drug was well tolerated in all patients. UROLOGY51: 271-276, 1998. © 1998, Elsevier Science Inc. All rights reserved.
L
euprolide acetate, a nonapeptide analogue of gonadotropin-releasing hormone (GnRH) with up to 100 times the potency of endogenous GnRH, has been used to treat a wide range of clinical conditions responsive to changes in the sex-steroid hormone milieu. In the treatment of prostate cancer, leuprolide offers an alternative to orchiectomy or estrogens. It desensitizes the pituitary to native GnRH stimulaSupported by a grantfrom TAP Holdings Inc. From the Department of Urology, University of Illinois Medical Center, Chicago, Illinois; Center for Urological Treatment and Research, Nashville, Tennessee, Department of Urology, Vanderbilt University, Nashville, Tennessee; and The Virginia Urology Center, Richmond, Virginia Reprint requests:Roohollah Sharifi, M.D., Department of Urology. M/C 958, University of Illinois at Chicago, 840 South Wood Street, Chicago, IL 60612-7322 Submitted: April 15, 1997, accepted (with revisions):August 6, 1997 © 1998, ELSEVIERSCIENCE INC, ALL RIGHTSRESERVED
tion, thereby resulting in decreased pituitary gonadotropin release and subsequent suppression of gonadal testosterone production.1 Androgen suppression can result in stabilization, slowing, or regression of tumor (primary and metastatic) proliferation, and it usually results in a reduction of pain caused by metastatic skeletal lesions. First released for the palliative treatment of advanced prostate cancer in 1985, leuprolide was given as a daily 1-mg subcutaneous formulation. To avoid the necessity for daily injections, a depot formulation containing 7.5 mg of leuprolide for monthly intramuscular injection was developed and released in 1989. Subsequently, an extendedrelease depot formulation containing 22.5 mg of leuprolide was developed for intramuscular injection every 3 months. All three formulations result in suppression of serum testosterone to the castrate 0090-4295/98/$19.00 PII S0090-4295(97)00500-1
271
range within 2 to 4 weeks. Favorable objective response rates are not significantly different at 86%, 82%, and 80%, respectively.2,3 A 30-mg formulation of leuprolide has been developed to be administered as an intramuscular injection every 4 months. The efficacy and safety of this formulation of leuprolide were evaluated in an unblinded, multicenter study of patients with Stage D2 prostate cancer. Serum testosterone and luteinizing hormone (LH) levels were assessed to monitor the attainment of the castrate level, to identify the duration of testosterone suppression, and to determine whether there was a transient increase in serum testosterone associated with the reinjection of leuprolide acetate, and whether serum testosterone levels greater than 50 ng/dL (the castrate level) were reached during the study. Results obtained during the first 32 weeks of treatment are presented. MATERIAL
AND METHODS
A total of 49 patients were enrolled in this unblinded, multicenter study conducted at 17 centers. All patients had histologically confirmed adenocarcinoma of the prostate in Stage D2 as defined by the presence of bone, soft tissue, or lymphatic metastasis (above the aortic bifurcation). To qualify, patients were required to have two or more clinically evaluable lesions (including prostate, if present), prestudy serum testosterone levels of 150 ng/dL or higher, and a performance status grade of 2 or lower as defined by the Eastern Cooperative Oncology Group (ECOG) Scale (0: normal; 1: restricted but ambulatory and able to perform light work; 2: ambulatory for more than 50% of waking hours and capable of all self-care but unable to work, 3: ambulatory for less than 50% or waking hours and capable of limited self-care; and 4: not ambulatory, completely disabled, and unable to carry out any self-care). Patients voluntarily signed an informed consent form. Patients were excluded from the study if they did not have an intact hypothalamic-pituitary-gonadal axis, if they had ever previously received a GnRH analogue, or if they had received other hormonal therapy or chemotherapy within 4 weeks preceding the initial depot injection. Ongoing radiation therapy precluded entry into the study. Patients were removed from the study if they required antiandrogen treatment during the first 32 weeks. The 30-mg leuprolide depot formulation was given by intramuscular injection every 16 weeks (112 days) for as long as there was apparent clinical benefit. This report covers the first 32 weeks of treatment. Blood collection for determination of serum LH and testosterone levels was performed at baseline, at 4 and 7 days following the initial injection, at the end of each of weeks 2 through 20, and then every 2 weeks up to week 32. Blood collection to assess hormone levels on dosing days was performed before the depot injection was given. The hormonal response to treatment was further characterized at the end of the first two dosing intervals (at half-week intervals at least 3 days apart during weeks 14, 15, 30, and 31) in a subset of 6 patients, and for several days after the second and third depot injections at weeks 16 and 32 in subsets of 9 and 10 patients, respectively. To assess the possible rise in serum testosterone levels following reinjection similar to that often seen after the initial injection, additional blood for serum testosterone and LH determinations was collected 4, 8, and 12 hours after the week-16 depot injection.
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Physical examination (including a digital rectal examination [DRE]), ECOG performance status assessment, and bone scan were performed at baseline and were repeated at weeks 16 and 32. Patients were also monitored for objective responses to treatment at weeks 16 and 32. Objective responses were graded as complete response, partial response, objectively stable (no change), or progression as defined by National Prostatic Cancer Project criteria. Prostate-specific antigen (PSA), prostatic acid phosphatase (PAP), and standard hematology and chemistry panels were obtained at baseline and were repeated at weeks 16 and 32. Testing was performed at a central laboratory. Testosterone and LH measurements were carried out at a central laboratory using standard radioimmunoassay (RIA) methodology. Testosterone was assessed by a two-step purification method prior to quantitation by RIA. The lower limit of sensitivity of the assay method was 3 ng/dL. The LH assay, which is a sequential addition, double-antibody RIA, is not specific for bioactive LH; it yields higher results than would be obtained by bioassay. The lower limit of sensitivity was 1.0 mlU/mL. DETERMINATIONOF RESPONSE Hormonal Response. A patient was considered to be a responder if, within the first 8 weeks after the first depot injection, his testosterone level was reduced to 50 ng/dL or less (castrate level) for two consecutive tests. Elevations of serum testosterone levels to greater than 50 ng/dL on two consecutive tests, after they had been reduced to castrate level for two consecutive tests, were considered to be escapes. Objective Tumor Response. Objective tumor responses to treatment were categorized as follows. Complete response was characterized by the total disappearance of all tumor masses and osteoblastic lesions, calcification of osteolytic lesions, lack of any new lesions, normalization of serum tumor markers (P&I/PAP), and the absence of significant cancer-related deterioration in body weight, symptoms, or performance status. Partial response comprised the following parameters: reduction in cross-sectional area, of at least one tumor mass by more than 50%, normalization of serum tumor markers, lack of both lesion progression and development of new malignancy, recalcification of one or more osteoblastic lesions (if present), and the absence of significant cancer-related deterioration in body weight, symptoms, or performance status. The stable disease classification included all of the following: no new lesions occurred; no measurable lesions expanded by more than 25% in cross-sectional area; serum tumor markers were reduced, not necessarily to normal; new bony metastases appeared; and there was no significant cancer-related deterioration in body weight, symptoms, or performance status. The progression classification encompassed any of the following: significant cancer-related loss of weight, increase of symptoms, or deterioration in performance status; the appearance of new areas of malignant disease; and a greater than 25% increase in cross-sectional area of any pre-existing measurable lesion. STATISTICALMETHODOLOGY The first of two consecutive visits at which testosterone levels were 50 ng/dL or less was considered to be the onset of the castrate level. If this occurred by week 8, the patient was considered to be “suppressed.” If the testosterone level was greater than 50 ng/dL for two consecutive tests after suppression was achieved, an “escape” was considered to have occurred. The proportion of patients who achieved testosterone suppression and the proportion of suppressed patients who experienced “escapes” were calculated. UROLOGY
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For hormone data, the maximum value in an interval was used in analysis. Summary statistics were provided for demographic characteristics, disease status at baseline, and testosterone and LH values at each categorized visit. Additional summaries were provided for patients who had samples obtained at 4,8, and 12 hours after the injection at week 16 and for those who participated in the expanded blood collection schedule. Within-group changes from baseline were analyzed using paired t tests. Repeated-measure analysis of variance was used to test for linear trends across time. Statistical significance indicates P 10.05.
RESULTS Of the 49 patients enrolled, 4 were excluded from the analysis of efficacy, either because no pretreatment testosterone level was available (2 patients), or because of uncertainty of disease stage (2 patients). Hormone, PSA, PAP, and DRE results for week 32 were excluded for 1 additional patient because these evaluations were performed late. The mean age of the 45 evaluable patients was 70 years (range 54 to 84), mean height was 69 inches (range 64 to 74), and mean body weight was 172 pounds (range 100 to 270). Fifty-one percent were white, 47% were black, and 2% were Hispanic. The mean time interval from histopathologic diagnosis of prostate cancer to the start of leuprolide treatment was approximately 7 months. Sixty-nine percent of the patients had been diagnosed within 3 months of enrollment, and 96% had been diagnosed within 3 years. Sixty-four percent of the patients had not had any previous treatment for prostate cancer. The remaining patients had had transurethral prostatic resection, radical prostatectomy, radiation therapy, or a combination of these treatments. One patient had been treated with ketoconazole for 17 days; however, treatment was discontinued 2 months prior to this study. Six patients were terminated from the study prematurely: 2 died of prostate cancer at weeks 16 and 28; 3 discontinued treatment at weeks 16,22, and 26 because of disease progression; and 1 withdrew at week 32 per his request to be followed by his local physician. TE~TOSTERONEAND
LH
LEVELS
The initial testosterone response was that characteristically seen after administration of a GnRH analogue. Mean serum testosterone increased from a baseline value of 423.7 ng/dL to a day 4 value of 659.6 ng/dL. This was followed by a steady decline to the castrate range by week 3 (Fig. 1). Mean levels declined further to 10.7 ng/dL by week 6 and then remained steady, fluctuating between 9.7 and 21.0 ng/dL through week 32. Castrate levels of testosterone occurred in all evaluable patients. The median time to onset of castrate levels was 22 days (range 9 to 43). Castrate levels were achieved in 39 (87%) and in 43 (96%) UROLOGY
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Mean (? standard deviation) serum tes1. tosterone levels after administration of leuprolide depot 30 mg injected intramuscularly every 16 weeks. FIGURE
of the 45 evaluable patients by weeks 3 and 4, respectively, and in all 45 patients by week 6. All patients were therefore considered to be “suppressed.” A transient “escape” from the castrate range was experienced by 1 patient (2%) (one-sided 95% upper confidence bound for the proportion of patients with an escape was 10%). The testosterone value 12 hours after the week 16 injection was 74 ng/dL, and subsequent determinations at weeks 16.5 and 17 were 87 and 55 ng/dL, respectively. There were no associated symptoms, and serum PSA was less than 0.5 ng/dL from a baseline of 51 ng/dL; therefore, the rise in testosterone was not considered clinically significant. Testosterone levels returned to the castrate range by week 18 and remained there through week 32. The depot injection at week 16 or 32 was delayed in 5 patients by 3 to 21 days. Nonetheless, on those injection days, as well as at the next time measured, testosterone values for these patients remained within the castrate range and below the mean values for all patients. Thus, delay of an injection by up to 3 weeks did not result in weakening or loss of hormonal suppression. The pattern of change in serum LH levels was similar to that for testosterone. There was an initial increase in mean LH on day 4 to a value above the pretreatment level (19.5 mIU/mL), followed by a decline to slightly below the pretreatment level by week 1 (13.4 mIU/mL), and a further decline to the lower end of the normal range (3 to 10 mIU/mL) by week 3, at which it remained throughout the 32week treatment period. Mean testosterone and LH values obtained at half-week intervals during the last 2 weeks of the first and second dosing intervals did not indicate any weakening of hormonal suppression during these periods. No significant linear trend in mean testosterone or LH values was seen during this segment of either dosing interval (testosterone ranges 273
TABLE 1. Summary of objective responses for 4-month, 3-month, and monthly depot formulations of leuprolide Number (%) of Patients Formulation 4-month Week Week 3-month Week Week
(30 mg) 16 32 (22.5 mg)* 12 24
Monthly (7.5 mg) Week 12+ Week 24
n
Complete Response
39 44
1 (3) 1 (2)
8 (21)
85 83
0 (0)
50 44
0 (0)
1 (1)
1 (21
Partial Response
Stable (No Change)
No Progression
26 (67) 25 (57)
35 (90) 35 (80)
4 (101 9 (20)
23 (27) 25 (30)
47 (55) 40 (48)
70 (82) 66 (80)
15 (18) 17 (20)
7 (141 11 (25)
32 (64) 24 (55)
39 (78) 36 (82)
6(12) 8 (18)
9 (201
Progression
* Two studies combined. ’ Five patients (10%) had a “mixed” response.
8.8 to 11.2 and 8.6 to 14.4 ng/dL, respectively; LH ranges 5.1 to 5.7 and 4.8 to 5.4 mIU/mL, respectively) . There was no evidence that the characteristic increases in serum testosterone and LH observed on day 4 following the initial injection of leuprolide also occurred after subsequent injections. At 3 to 5 days after the week 16 and week 32 injections, mean testosterone increased to 21.3 from 12.8 ng/dL and to 14.2 from 13.5 ng/dL, respectively. The transient increase in mean serum testosterone was not statistically or clinically significant. Changes in mean LH levels following week 16 (5.8 from 5.6 mIU/mL) and week 32 (5.2 from 4.7 mIU/ mL) injections were minimal and of no clinical significance. However, the change (-0.5 mIU/mL) following the week 32 injection was statistically significant (P = 0.01). In addition, mean PSA levels at weeks 16 and 32 (93.2 and 104.2 ng/mL) remained well below baseline. Furthermore, mean PAP levels were 27.5 and 21.9 ng/mL at week 16 and week 32, respectively, compared with a level of 161.5 ng/mL at baseline. Other than the patient described above for whom an “escape” was seen, no patient had a notable increase in testosterone at 4, 8, or 12 hours after the second depot injection at week 16. Mean changes in LH at 4,8, and 12 hours following the week 16 injection were all statistically significant (P
RESPONSE
Thirty-nine patients were evaluated at week 16, and 44 patients were evaluated at week 32 for the objective response assessment. Patients who were prematurely terminated from the study because of disease progression or death from prostate cancer 274
TABLE II. Serum PSA and PAP levels at baseline, 16 weeks, and 32 weeks Baseline
16 Weeks
32 Weeks
PSA (ng/dL) n Mean Maximum Minimum
45 1096.1 1251 1.0 2.2
43 93.2 1452.0 0.5
37 104.2 1331 .o 0.5
PAP (ng/mL) n Mean Maximum Minimum
45 161.5 2750.0 1.o
44 27.5 360.0 1.0
40 21.9 211.3 1.0
KEY: PAP = prostatic acidphosphatase;
PSA = prostate-specific antigm.
and did not have a subsequent evaluation were assigned an objective response rating of “progression” at the next evaluation. Ninety percent of the patients had a favorable response rating (ie, complete response, partial response, or no change) at week 16; 80% had a favorable response rating at week 32. Table I summarizes these data and compares the objective response rates of the 4-month, 3-month, and monthly depot formulations. PSA and PAP normalized or decreased in nearly all patients during the initial 32 weeks of treatment. PSA normalized (3.9 ng/dL or less) in 23 of the 42 patients (55%) with elevated pretreatment values, and PAP normalized (4.0 ng/mL or less) in 16 of the 31 patients (52%) with elevated pretreatment values. One patient had a normal pretreatment PSA and PAP. At week 32, PSA and PAP decreased by at least 50% in 97% and 76% of patients, respectively, with elevated pretreatment values. Table II summarizes serum PSA and PAP levels at baseline, week 16, and week 32. On DRE, all 44 patients who were evaluated at both weeks 16 and UROLOGY
51 (2), 1998
TABLE III. Adverse events occurring in 10% or more of patients, regardless of treatment relationship Adverse Event Hot flashes Back pain Arthralgia Asthenia Flu syndrome Pain Headache Rash
Number (%) of Patients 22 (45) 8 7 6 6 6 5 5
(161 (141 (121 (121 (121 (101 (101
32 were judged to have improved or stabilized local disease. Forty-four patients had a pretreatment performance status assessment and at least one assessment during the treatment period. Pretreatment performance status was abnormal in 19 of these patients. All 19 patients were evaluated at week 16, and 16 (84%) had responded favorably (improved or stable); at week 32,16 of the 19 evaluated (84%) had responded favorably. The remainder received a rating of “worsened.” Twenty-five of the 44 patients had a normal performance status before treatment. All 25 were evaluated at weeks 16 and 32. Twenty (80%) received a favorable rating (no change) at both evaluations, and 5 (20%) worsened.
SAFETY Data for all 49 patients were included in the analysis of safety. Adverse events, including those not considered treatment-related, were reported by 39 patients (80%). The most common were hot flashes (45%), back pain (16%), and arthralgia (14%) (Table III). Only 2% of patients complained of decreased libido and impotence. Injection site pain or reaction was reported by 8% of patients. During the initial 2 weeks of treatment, 24 of the 49 patients (49%) experienced one or more adverse events. Hot flashes (14%), back pain (8%), and arthralgia (6%) were the most frequently reported adverse events during this period. One patient experienced bone pain, and back pain was reported by 4 other patients. There were no cases of spinal cord compression. Two patients had urinary retention during this period; neither was considered by the investigator to be treatment-related. With the exception of a clinically significant decline in alkaline phosphatase, there were no noteworthy changes in laboratory parameters. This change in alkaline phosphatase is consistent with the observed reduction in bony metastatic disease. UROLOGY 51 (21, 1998
COMMENT This unblinded, multicenter study evaluated the efficacy and safety of a 30-mg depot formulation of leuprolide administered every 16 weeks to patients with Stage D2 adenocarcinoma of the prostate. Onset of castrate levels of serum testosterone was achieved within 4 weeks in 96% of patients, which compares favorably with the 96% reported for patients who received the monthly 7.5-mg leuprolide depot, and with the 95% reported for those who received the 22.5-mg leuprolide 3-month depot.zJ The median time to onset of castrate levels in all of these studies was 22 days. After falling to the castrate range, mean testosterone levels in the current study remained well within the castrate range throughout each dosing interval. All leuprolide depot formulations thus far developed have demonstrated limited unimpeded testosterone suppression following delayed injection. Specifically, with l-, 3-, and 4-month depot formulations, delays of up to 1,2, and 3 weeks, respectively, were found to have no effect on maintenance of testosterone suppression. 2~3One patient experienced a transient and minimal “escape” from suppression, but this was not associated with any clinical sequelae. A favorable (no progression) objective tumor response to treatment occurred in 90% and 80% of patients, respectively, at weeks 16 and 32; this was comparable to the response rates seen in patients who received the 22.5-mg depot and the monthly 7.5-mg depot (Table I). PSA and PAP decreased by at least 50% at week 32 in 97% and in 76% of the patients, respectively, with elevated pretreatment values. Local prostate involvement either improved or remained stable for all patients who had a DRE both before and during treatment. Ninety-four percent of the 19 patients with an abnormal pretreatment performance status who were evaluated at week 32 showed either improvement or no change in status, which paralleled the 88% rate achieved in patients treated for 24 weeks with the 22.5-mg formulation and the 96% rate achieved in those treated for 24 weeks with the 7.5-mg formulation.2*3 Safety data in the present study were consistent with the known safety profile of leuprolide. Adverse events reported were those typically seen in patients with metastatic prostate cancer or in association with hypoandrogenism. The 45% incidence of hot flashes, the most frequently reported adverse event, was similar to the incidence seen with the 3-month 22.5-mg and monthly 7.5mg depot formulations (59% and 57%, respectively).273 Changes in laboratory parameters were mostly small and clinically insignificant. Exacerbation of prostate cancer symptoms asso275
ciated with the transient elevation of serum testosterone levels within the first 2 weeks after the initiation of leuprolide therapy was observed in approximately 10% of patients.l This disease flare was most often manifested by bone pain, but it can include obstructive uropathy, neurologic symptoms, or paraplegia in patients with impending spinal cord compression from epidural metastases. The occurrence of these symptoms during this time period in the present study was limited to 1 patient (2%) who experienced bone pain and 2 patients (4%) who experienced urinary retention. No cases of spinal cord compression were reported. Thus, the low incidence of symptoms possibly associated with disease flare is comparable to that seen in the 22.5mg depot study, in which 2% of patients reported bone pain or urinary retention, and to that in the 7.5mg depot study, in which evidence of disease flare was also not seen.273 CONCLUSIONS The results of this study indicate that the 30-mg 4-month depot formulation of leuprolide, which acts in a manner similar to the monthly 7.5mg and 3-month 22.5mg depot formulations, is effective in reducing serum testosterone to castrate levels in
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all patients and demonstrated a favorable response in 80% of the patients with advanced-stage prostate cancer for the 32-week observation period. The availability of a 4-month depot formulation of leuprolide offers both patients and treating physicians another therapeutic option for prostate cancer. ACKNOWLEDGMENT. To the following investigators in the Leuprolide study group: Mark Austenfeld, M.D., Cesar Ercole, M.D., Nery Flores, M.D., Jackson Fowler, M.D., Stanley Kandzari, M.D., Steven Krasnow, M.D., John Lynch, M.D., Richard Middleton, M.D., A. Lynn Patterson, M.D., Alexander Philpott, M.D., Randolph Ross, M.D., Carl Sanfelippo, M.D., Paul Schellhammer, M.D., John Tuttle, Jr., M.D., Glen Wells, M.D., and Norman Zinner, M.D. To Robert Browneller and Brenda Erickson for their technical support and assistance.
REFERENCES 1. Plosker GL, and Brogden RN: Leuprorelin. A review of its pharmacology and therapeutic use in prostatic cancer, endometriosis, and other sex hormone-related disorders. Drugs 48: 930-967,1994. 2. Sharifi R, Soloway M, and Leuprolide Study Group: Clinical study of leuprolide depot formulation in the treatment of advanced prostate cancer. J Urol143: 68-71,199O. 3. Sharifi R, Bruskewitz RC, Gittleman MC, Graham SD Jr, Hudson PB, and Stein B: Leuprolide acetate 22.5 mg 12-week depot in the treatment of advanced prostatic cancer. Clin Ther 18: 647-657,1996.
UROLOGY 51 (2), 1998