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Targeting FSH in androgen-independent prostate cancer: abarelix for prostate cancer progressing after orchiectomy
ADULT UROLOGY
TARGETING FSH IN ANDROGEN-INDEPENDENT PROSTATE CANCER: ABARELIX FOR PROSTATE CANCER PROGRESSING AFTER ORCHIECTOMY TOMASZ M. BEER, MARK GARZOTTO, KRISTI M. EILERS, DIANNE LEMMON, EMILY M. WERSINGER
AND
ABSTRACT Objectives. To determine the efficacy of the gonadotropin-releasing hormone antagonist abarelix in patients with androgen-independent prostate cancer progressing after orchiectomy and to measure its effect on serum follicle-stimulating hormone (FSH). Methods. Sixteen patients with prostate cancer progressing after orchiectomy received abarelix-depot 100 mg by intramuscular injection on days 1, 15, and 29 and then every 28 days for up to 24 weeks (52 weeks in patients who met the criteria for a prostate-specific antigen [PSA] response after 24 weeks). PSA response was the primary endpoint and was defined as a 50% reduction confirmed 4 weeks later. The time to progression and effect of therapy on serum FSH were secondary endpoints. Results. No patient met the criteria for a PSA response. Five patients (31%, 95% confidence interval 11% to 58%) experienced confirmed reductions in the PSA level ranging from 9.3% to 31.8%. At the end of the six cycles of therapy, 6 patients remained stable without PSA progression or other signs of disease progression. The median time to progression was 12 weeks (95% confidence interval 6 to 18). The mean serum FSH concentration declined after 4 weeks of study treatment by nearly 90% from a baseline of 45.1 IU/L (95% confidence interval 34.0 to 56.2) and remained suppressed throughout the observation period. Treatment was well tolerated, with one grade 3 allergic reaction. Conclusions. Treatment with abarelix in patients with androgen-independent prostate cancer after orchiectomy results in marked reduction in circulating FSH. None of the patients met the PSA response criteria; nonetheless, minor reductions in serum PSA were observed in 5 of 16 patients. UROLOGY 63: 342–347, 2004. © 2004 Elsevier Inc.
P
reclinical evidence supports the hypothesis that follicle-stimulating hormone (FSH) may contribute to progression of androgen-independent prostate cancer (AIPC). FSH receptors are expressed in prostate cancer cell lines and human prostate cancer specimens,1,2 and their expression in adenocarcinoma of the prostate exceeds that This study was supported in part by Public Health Service grants 5 M01 RR00334-33S2 and 20000775-001 from Praecis Pharmaceuticals. From the Divisions of Hematology and Medical Oncology and Urology, Oregon Health and Science University; and Division of Urology, Portland Veterans Affairs Medical Center, Portland, Oregon Reprint requests: Tomasz M. Beer, M.D., Department of Medicine, Oregon Health and Science University, Mail Code L586, 3181 Southwest Sam Jackson Park Road, Portland, OR 97239 Submitted: June 10, 2003, accepted (with revisions): September 12, 2003
342
© 2004 ELSEVIER INC. ALL RIGHTS RESERVED
seen in benign prostatic epithelium.2 FSH stimulates proliferation and suppresses apoptosis in androgen-independent PC-3 cells in vitro.2 FSH may exert its effects in human prostate cancer by way of endocrine, paracrine, and autocrine mechanisms, because, in addition to the pituitary, FSH is produced in benign and malignant epithelial cells from the prostate.1– 4 FSH is not completely suppressed by standard initial hormonal therapy for prostate cancer. Patients treated with gonadotropin-releasing hormone (GnRH) agonists experience partial suppression of FSH.5–7 In contrast, FSH is elevated to greater than its physiologic range after orchiectomy.8 –10 Unlike GnRH agonists, GnRH antagonists substantially reduce circulating FSH when used in the initial management of advanced prostate cancer.11 The GnRH antagonist 0090-4295/04/$30.00 doi:10.1016/j.urology.2003.09.045
cetrorelix produced significant antitumor activity in a nude mouse, androgen-independent DU145 xenograft model.12,13 Recent data suggest that estrogens are active in AIPC.14 The addition of estrogens has a variety of effects on circulating hormones in men with AIPC, including suppression of FSH, testosterone, free testosterone, and estradiol, a reduction in dehydroepiandrosterone sulfate, and increases in sex hormone-binding globulin and cortisol.15,16 Estrogen’s activity in AIPC supports the hypothesis that FSH suppression may be a viable therapeutic target. The effect of estrogen on FSH cannot, however, be separated from its other effects on the hormonal system and its possible direct effects on tumor cells. Despite encouraging preclinical data, we previously had found no activity for abarelix in men with prostate cancer progressing during GnRH agonist therapy.17 The patient population in that study, however, had relatively low FSH concentrations before abarelix treatment and may not have been the optimal group in which to test FSH suppression as a treatment strategy in AIPC. In contrast to GnRH agonist therapy, orchiectomy is associated with a sustained increase in circulating FSH levels.8 –10 Because AIPC is a heterogeneous disease, it is possible that FSH plays a greater role in its progression after orchiectomy than after GnRH agonist therapy. For this reason, we sought to evaluate the effect of abarelix on FSH and disease status in men with disease progression after initial treatment with orchiectomy. MATERIAL AND METHODS
Prior treatment for prostate cancer with chemotherapy, radiopharmaceuticals, diethylstilbestrol or another estrogen, PC-SPES, ketoconazole, or other second-line hormonal therapy (except for androgen receptor antagonists) was not allowed. The institutional review boards at the Oregon Health and Science University and Portland Veterans Affairs Medical Center approved the protocol. All patients provided written informed consent.
TREATMENT Abarelix depot 100 mg was given by intramuscular injection on days 1, 15, and 29 and then every 28 days for 24 weeks. Patients were observed for 30 minutes after each injection. Patients who met the criteria for a PSA response after 24 weeks continued treatment up to a maximum of 52 weeks. Treatment was discontinued for any evidence of progression, including a confirmed 50% increase in serum PSA from baseline in nonresponders and from the nadir value in patients with a PSA reduction. Patients who completed 24 weeks of therapy without progression were followed up until progression or censored when another form of therapy was initiated.
MONITORING The initial evaluation included a complete history and physical examination, complete blood count with automated differential, serum alanine transaminase, alkaline phosphatase, bilirubin, lactate dehydrogenase, creatinine, testosterone, FSH, radionuclide bone scan, and computed tomography of the abdomen and pelvis. The complete blood count with automated differential, serum PSA, alanine transaminase, alkaline phosphatase, bilirubin, creatinine, and FSH were measured every 4 weeks. Serum testosterone was measured after 4 and 8 weeks of therapy. Adverse events were graded according to the National Cancer Institute’s Common Toxicity Criteria. In patients who had measurable disease on the initial evaluation, disease was reassessed using the same modality every 8 weeks. Each patient had his serum PSA and FSH measured in the same laboratory throughout the study. The PSA assays used were Hybritech PSA (Beckman Coulter 37200) and AxSYM PSA (Abbot). The FSH assays used were Elecsys FSH (Roche 1775863) and Architect FSH (Abbot 6C24).
PATIENTS Histologically confirmed prostate cancer progressing after orchiectomy was required for enrollment. Progression was defined as a 50% rise in the prostate-specific antigen (PSA) level confirmed by two measurements at least 2 weeks apart, the appearance of new metastatic lesions, or progression of known metastatic disease. In patients receiving androgen receptor antagonists in addition to orchiectomy, progression had to be confirmed after withdrawal of these agents (6 weeks for bicalutamide, 4 weeks for flutamide or nilutamide). Patients were excluded for Eastern Cooperative Oncology Group performance status greater than 2, age younger than 18 years, serum testosterone level greater than 50 ng/dL, PSA level less than 5 ng/mL, white blood cell count less than 3000/ mm3, platelet count less than 100,000/mm3, serum creatinine more than 1.5 times the upper limit of normal, bilirubin (direct or total) more than 1.5 times the upper limit of normal, alanine transaminase more than 1.25 times the upper limit of normal, allergy to a GnRH agonist or antagonist, major surgery within 4 weeks of the study, peripheral neuropathy of grade 3 or worse, serious medical illness, New York Heart Association class III or IV congestive heart failure, unstable angina, myocardial infarction within 6 months, acute deep venous thrombosis, acute pulmonary embolism, or active second malignancy other than nonmelanoma skin cancer. UROLOGY 63 (2), 2004
ASSESSMENT OF ENDPOINTS The PSA response was defined as a 50% reduction in the PSA level confirmed 4 weeks apart.18 Measurable disease was evaluated using the Response Evaluation Criteria in Solid Tumors.19 The time to progression was reported according to consensus criteria.18
STATISTICAL ANALYSIS The sample size of 25 was calculated on the basis of the primary endpoint of PSA response. A two-stage study design was used with a plan to reject the regimen if the response rate was less than 10% and recommend the regimen for additional study if the response rate was at least 30%. An alpha of 0.05 and power of 80% would reject the regimen if fewer than 2 of the first 15 patients responded and would recommend the regimen for additional study if at least 5 of 25 patients responded.20 Enrollment was permitted to continue while activity in the first 15 patients was assessed. Repeated measures analysis of variance was used to examine the changes in the mean FSH and testosterone with treatment, and the Wilcoxon signed rank test was used to examine changes in median FSH with treatment. The Kaplan-Meier method was used to estimate the time to progression. A sec343
TABLE I. Patient characteristics on entry Characteristic
Value
Patients (n) Age (yr) Median Range ECOG performance status (n) 0 1 2 PSA (ng/mL) Median Range Alkaline phosphatase (U/L) Median Range FSH (IU/L) Median Range Site of metastases (n) Bone only Lymph nodes only Liver only Bone and lymph nodes None Prior therapy for local disease External beam radiotherapy Radical prostatectomy None Prior hormonal therapy (n) Orchiectomy alone Orchiectomy ⫹ androgen receptor antagonist
16 78 57–86 9 6 1 20 5–445 75 37–114 43.7 17–80 5 1 1 1 8 8 1 7 5 (31) 11 (69)
KEY: ECOG ⫽ Eastern Cooperative Oncology Group; PSA ⫽ prostate-specific antigen; FSH ⫽ follicle-stimulating hormone. Numbers in parentheses are percentages.
ondary analysis that compared the characteristics and outcomes in the previously studied GnRH-agonist treated patients with those observed in this study was performed. The Mann-Whitney U test was used for comparison of continuous variables and the chi-square test and Fisher’s exact test were used for comparison of the categorical variables. The log-rank test was used to compare the time to progression in the two groups, and Cox proportional hazards analysis, including all baseline characteristics that differed with a P value of less than 0.2 between the two groups, was used to exclude the possibility that the observed outcome differences were a result of imbalances in the baseline patient characteristics.
RESULTS PATIENTS Sixteen men were recruited between July 2001 and July 2002 (Table I). The median age was 78 years, and the median Eastern Cooperative Oncology Group performance status was 0. The median PSA level was 20 ng/mL (range 5 to 445). Eight patients had distant metastases, and a rising PSA level was the only manifestation of AIPC in 8 pa344
tients. The median follow-up for the entire study population was 43 weeks (range 14 to 77). TREATMENT Sixteen patients received treatment for a median of 16 weeks (range 5 to 28). Treatment was discontinued because of a nonresponse at the end of 24 weeks in 6 patients, progression before completing 24 weeks of treatment in 8 patients, and toxicity in 2 patients. TOXICITY No deaths occurred during treatment. One patient died 15 days after discontinuing treatment due to unconfirmed progression. Treatment was generally very well tolerated. Two patients discontinued treatment because of toxicity. One patient experienced a grade 3 allergic reaction (hives and facial edema) on the initial treatment day and one had a grade 2 allergic reaction (hives) after 8 weeks on study. No other grade 3 toxicities occurred. The only other grade 2 or worse treatment-related toxicity was hyperphosphatemia in 1 patient. EFFICACY None of the patients had a confirmed 50% reduction in the PSA level. Five patients (31%, 95% confidence interval [CI] 11% to 58%) experienced confirmed reductions in the PSA level ranging from 9.3% to 31.8%. At the end of the six cycles of therapy, 6 patients remained stable without PSA progression or other signs of disease progression. The median time to progression was 12 weeks (95% CI 6 to 18 weeks). Three patients had measurable disease at study enrollment. Two had stable disease throughout treatment. EFFECTS ON FSH AND TESTOSTERONE All patients had a decline in their FSH concentration with the introduction of therapy. The mean FSH concentration declined from 45.1 IU/L (95% CI 34.0 to 56.2) to 5.3 IU/L (95% CI 3.7 to 6.8) after 4 weeks and to 5.6 IU/L (95% CI 3.7 to 7.5) after 8 weeks (repeated measures analysis of variance, P ⬍0.0001). Similarly, the median FSH decreased from 43.7 IU/L (range 17.0 to 84.0) to 4.2 IU/L (range 2.0 to 11.0) and to 4.0 IU/L (range 1.0 to 13.6) at the same intervals (P ⬍0.0001, Wilcoxon signed rank test). The FSH concentration remained suppressed after 20 weeks (mean 3.6 IU/L, 95% CI 2.2 to 4.9). Of the 16 patients, 15 achieved an FSH concentration of less than 10 IU/L and 13 achieved an FSH concentration of less than 5 IU/L. The median serum testosterone level at study entry was 15 ng/dL (mean 16, range 7 to 30). Serum testosterone remained in the anorchid range: median 11 ng/dL (mean 14 ng/dL, range 8 to 20 ng/dL) at week 4 and median 10 ng/dL (mean 15 UROLOGY 63 (2), 2004
nificantly longer (P ⫽ 0.050) in a multivariate Cox proportional hazards analysis (not shown). COMMENT
FIGURE 1. Percentage of change in serum PSA of patients with failure after GnRH agonist therapy (solid line) and orchiectomy (dashed line).
ng/dL, range 10 to 33 ng/dL) at week 8 (P ⫽ 0.2 by repeated measures ANOVA). OUTCOME IN PATIENTS WITH ORCHIECTOMY FAILURE COMPARED WITH PREVIOUSLY STUDIED PATIENTS WITH GnRH FAILURE Because the FSH concentration differed markedly in these two populations, we sought, in an exploratory analysis, to compare the outcome in the orchiectomy population with that of the previously studied patients treated with a GnRH agonist.17 The two studies were initiated simultaneously at the same institution and were identical in their design. The baseline characteristics of the two populations did not differ with respect to age, Eastern Cooperative Oncology Group performance status, serum PSA level, presence of distant metastases, or prior use of androgen receptor antagonists. The FSH levels were significantly greater in the orchiectomy failure group (median 44 IU/L versus 4 IU/L, P ⬍0.0001). A trend was found toward a greater alkaline phosphatase level in the GnRH group (median 87 U/L versus 75 U/L, P ⫽ 0.07). Although no patients in either study had a confirmed PSA response, any PSA reduction confirmed by two measurements was more common in the orchiectomy group (31% versus 5%, P ⫽ 0.04). The fraction of patients completing the planned 6-month course of therapy was also greater in the orchiectomy group (38% versus 10%, P ⫽ 0.049). The serum PSA changes from baseline for these two populations are shown in Figure 1. The time to progression was longer in the orchiectomy group than in the GnRH agonist group (orchiectomy patients: median 12.0 weeks, 95% CI 6.0 to 18.0, mean 29.1 weeks, 95% CI 16.0 to 42.2; GnRH treated patients: median 8 weeks, 95% CI 5.7 to 10.3, mean 9.5 weeks, 95% CI 6.4 to 12.5 weeks; P ⫽ 0.025, log-rank test) and remained sigUROLOGY 63 (2), 2004
Although both orchiectomy and GnRH agonist therapy effectively induce the castrate state in men with prostate cancer, the levels of circulating FSH were repressed only in the GnRH agonist-treated patients. Circulating FSH could serve as a mitogenic factor in patients with AIPC, as has been shown in several preclinical systems. In this study, we sought to determine the effect of FSH downregulation by treating patients whose prostate cancer was progressing after orchiectomy with the GnRH antagonist abarelix. Patients with orchiectomy failure had serum FSH concentrations approximately 10-fold higher than patients whose initial treatment had consisted of GnRH agonists in our previous study. Treatment with abarelix resulted in a rapid and sustained reduction in circulating FSH concentrations; however, the absolute concentrations of FSH during therapy were greater than those achieved in our previous trial carried out in GnRH agonist-treated patients or those reported by Garnick and Campion11 when abarelix was used in hormone-naive patients with prostate cancer. Thus, FSH suppression may be more difficult in the orchiectomy population. Despite producing markedly lower FSH concentrations, abarelix did not produce any confirmed clinical responses in this patient group. Thus, in its present form, abarelix cannot be recommended for patients with AIPC. It is not known whether strategies that more completely suppress circulating FSH would prove more effective. An exploratory comparison of the outcome in patients with failure after orchiectomy to the previously studied patients with progression while receiving GnRH agonists showed that the time to progression and the fraction of patients with any confirmed PSA reduction were greater in the orchiectomy group. It is difficult to determine in a small nonrandomized study whether these findings were a result of differences in tumor sensitivity to FSH manipulation between prostate cancer that progresses after orchiectomy and cancer that progresses after GnRH agonist therapy or simply chance observations, the result of uneven patient selection, or the result of small variations in serum PSA concentrations. If these observations were confirmed, it may be possible to develop therapeutic approaches that further reduce circulating FSH, and such approaches may prove more effective. Although inadequate suppression of circulating FSH is one possible explanation for the lack of activity of abarelix in this trial, other possibilities 345
should also be considered. If autocrine and paracrine FSH production contributes to the proliferation of prostate cancer, as some preclinical studies have suggested,1– 4 even complete suppression of circulating FSH may not adequately target FSHreceptor mediated tumor growth, and agents that block the FSH receptor directly may be needed. Finally, it is possible that despite preclinical evidence, FSH is not an important mediator of prostate cancer proliferation in patients. It is also important to note that although FSH was the focus of this investigation, it is possible that the changes in FSH and clinical outcomes were coincidental and that GnRH antagonists act by way of another unsuspected mechanism. Direct effects on tumor GnRH receptors or effects of leuteinizing hormone suppression should be considered. GnRH receptor expression has been reported in benign and neoplastic prostate cancer cells21; however, the role of these receptors is unclear. Although GnRH receptors are expressed in LNCaP, TSU-Pr1, PC-3, and DU-145 prostate cancer cell lines, the proliferation of these cells was unaffected by exogenous GnRH,22 possibly because most extrapituitary GnRH receptors have a low affinity for GnRH.23 When prostate cancer cells are transfected with high-affinity pituitary GnRH receptors, GnRH agonists exert antiproliferative activity.23 These findings suggest that GnRH antagonists are unlikely to produce clinical responses by binding tumor GnRH receptors. Leuteinizing hormone receptors are also expressed in benign and malignant prostate epithelium24; however, at present, no data have demonstrated that signaling through these receptors mediates cancer proliferation or resistance to apoptosis. CONCLUSIONS Treatment with abarelix in patients with AIPC after orchiectomy results in a marked reduction of circulating FSH; however, FSH suppression was not complete. None of the patients met the PSA response criteria; nonetheless, minor reductions in serum PSA were observed in 5 of 16 patients. Approaches that further reduce circulating FSH or target the FSH receptor directly may prove more effective. REFERENCES 1. Dirnhofer S, Berger C, Hermann M, et al: Coexpression of gonadotropic hormones and their corresponding FSH- and LH/CG-receptors in the human prostate. Prostate 35: 212– 220, 1998. 2. Ben-Josef E, Yang SY, Ji TH, et al: Hormone-refractory prostate cancer cells express functional follicle-stimulating hormone receptor (FSHR). J Urol 161: 970 –976, 1999. 3. Garde SV, Sheth AR, Shah MG, et al: Prostate—an extrapituitary source of follicle-stimulating hormone (FSH): occurrence, localization, and de novo biosynthesis and its hor346
monal modulation in primates and rodents. Prostate 18: 271– 287, 1991. 4. Hurkadli KS, Sheth AR, Garde SV, et al: Immunocytochemical localisation of follicle stimulating hormone (FSH) in normal, benign and malignant human prostates. Br J Cancer 61: 225–229, 1990. 5. Huhtaniemi I, Venho P, Jacobi G, et al: Response of circulating gonadotropin levels to GnRH agonist treatment in prostatic cancer. J Androl 12: 46 –53, 1991. 6. Mahler C, Verhelst J, Chaban M, et al: Prolactin and pituitary gonadotropin values and responses to acute luteinizing hormone-releasing hormone (LHRH) challenge in patients having long-term treatment with a depot LHRH analogue. Cancer 67: 557–559, 1991. 7. Khan MS, and O’Brien A: An evaluation of pharmacokinetics and pharmacodynamics of leuprorelin acetate 3Mdepot in patients with advanced and metastatic carcinoma of the prostate. Urol Int 60: 33–40, 1998. 8. Bracci U, Di Silverio F, Sciarra F, et al: Hormonal pattern in prostatic carcinoma following orchidectomy: 5-year follow-up. Br J Urol 49: 161–166, 1977. 9. Huhtaniemi IT, Dahl KD, Rannikko S, et al: Serum bioactive and immunoreactive follicle-stimulating hormone in prostatic cancer patients during gonadotropin-releasing hormone agonist treatment and after orchidectomy. J Clin Endocrinol Metab 66: 308 –313, 1988. 10. Varenhorst E, Wallentin L, and Carlstrom K: The effects of orchidectomy, estrogens, and cyproterone acetate on plasma testosterone, LH, and FSH concentrations in patients with carcinoma of the prostate. Scand J Urol Nephrol 16: 31– 36, 1982. 11. Garnick MB, and Campion M: Abarelix depot, a GnRH antagonist, v LHRH superagonists in prostate cancer: differential effects on follicle-stimulating hormone. Mol Urol 4: 275– 278, 2000. 12. Lamharzi N, Schally AV, and Koppan M: Luteinizing hormone-releasing hormone (LH-RH) antagonist cetrorelix inhibits growth of DU-145 human androgen-independent prostate carcinoma in nude mice and suppresses the levels and mRNA expression of IGF-II in tumors. Regul Pept 77: 185– 192, 1998. 13. Lamharzi N, Halmos G, Jungwirth A, et al: Decrease in the level and mRNA expression of LH-RH and EGF receptors after treatment with LH-RH antagonist cetrorelix in DU-145 prostate tumor xenografts in nude mice. Int J Oncol 13: 429 – 435, 1998. 14. Smith DC, Redman BG, Flaherty LE, et al: A phase II trial of oral diethylstilbestrol as a second-line hormonal agent in advanced prostate cancer. Urology 52: 257–260, 1998. 15. Kitahara S, Umeda H, Yano M, et al: Effects of intravenous administration of high dose-diethylstilbestrol diphosphate on serum hormonal levels in patients with hormonerefractory prostate cancer. Endocr J 46: 659 –664, 1999. 16. Kitahara S, Yoshida K, Ishizaka K, et al: Stronger suppression of serum testosterone and FSH levels by a synthetic estrogen than by castration or an LH-RH agonist. Endocr J 44: 527–532, 1997. 17. Beer TM, Garzotto M, Eilers KM, et al: Phase II study of abarelix depot for androgen independent prostate cancer progression during gonadotropin-releasing hormone agonist therapy. J Urol 169: 1738 –1741, 2003. 18. Bubley GJ, Carducci M, Dahut W, et al: Eligibility and response guidelines for phase II clinical trials in androgenindependent prostate cancer: recommendations from the Prostate-Specific Antigen Working Group. J Clin Oncol 17: 3461–3467, 1999. 19. Therasse P, Arbuck SG, Eisenhauer EA, et al, for the European Organization for Research and Treatment of CanUROLOGY 63 (2), 2004
cer, National Cancer Institute of the United States, National Cancer Institute of Canada: New guidelines to evaluate the response to treatment in solid tumors. J Natl Cancer Inst 92: 205–216, 2000. 20. Simon R: Optimal two-stage designs for phase II clinical trials. Control Clin Trials 10: 1–10, 1989. 21. Bono AV, Salvadore M, and Celato N: Gonadotropinreleasing hormone receptors in prostate tissue. Anal Quant Cytol Histol 24: 221–227, 2002. 22. Bahk JY, Hyun JS, Lee H, et al: Expression of gonadotropin-releasing hormone (GnRH) and GnRH receptor mRNA
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in prostate cancer cells and effect of GnRH on the proliferation of prostate cancer cells. Urol Res 26: 259 –264, 1998. 23. Franklin J, Hislop J, Flynn A, et al: Signaling and antiproliferative effects mediated by gonadotrophin-releasing hormone receptors after expression in prostate cancer cells using recombinant adenovirus. J Endocrinol 176: 275–284, 2003. 24. Tao YX, Bao S, Ackermann DM, et al: Expression of luteinizing hormone/human chorionic gonadotropin receptor gene in benign prostatic hyperplasia and in prostate carcinoma in humans. Biol Reprod 56: 67–72, 1997.
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TARGETING FSH IN ANDROGEN-INDEPENDENT PROSTATE CANCER: ABARELIX FOR PROSTATE CANCER PROGRESSING AFTER ORCHIECTOMY TOMASZ M. BEER, MARK GARZOTTO, KRISTI M. EILERS, DIANNE LEMMON, EMILY M. WERSINGER
AND
ABSTRACT Objectives. To determine the efficacy of the gonadotropin-releasing hormone antagonist abarelix in patients with androgen-independent prostate cancer progressing after orchiectomy and to measure its effect on serum follicle-stimulating hormone (FSH). Methods. Sixteen patients with prostate cancer progressing after orchiectomy received abarelix-depot 100 mg by intramuscular injection on days 1, 15, and 29 and then every 28 days for up to 24 weeks (52 weeks in patients who met the criteria for a prostate-specific antigen [PSA] response after 24 weeks). PSA response was the primary endpoint and was defined as a 50% reduction confirmed 4 weeks later. The time to progression and effect of therapy on serum FSH were secondary endpoints. Results. No patient met the criteria for a PSA response. Five patients (31%, 95% confidence interval 11% to 58%) experienced confirmed reductions in the PSA level ranging from 9.3% to 31.8%. At the end of the six cycles of therapy, 6 patients remained stable without PSA progression or other signs of disease progression. The median time to progression was 12 weeks (95% confidence interval 6 to 18). The mean serum FSH concentration declined after 4 weeks of study treatment by nearly 90% from a baseline of 45.1 IU/L (95% confidence interval 34.0 to 56.2) and remained suppressed throughout the observation period. Treatment was well tolerated, with one grade 3 allergic reaction. Conclusions. Treatment with abarelix in patients with androgen-independent prostate cancer after orchiectomy results in marked reduction in circulating FSH. None of the patients met the PSA response criteria; nonetheless, minor reductions in serum PSA were observed in 5 of 16 patients. UROLOGY 63: 342–347, 2004. © 2004 Elsevier Inc.
P
reclinical evidence supports the hypothesis that follicle-stimulating hormone (FSH) may contribute to progression of androgen-independent prostate cancer (AIPC). FSH receptors are expressed in prostate cancer cell lines and human prostate cancer specimens,1,2 and their expression in adenocarcinoma of the prostate exceeds that This study was supported in part by Public Health Service grants 5 M01 RR00334-33S2 and 20000775-001 from Praecis Pharmaceuticals. From the Divisions of Hematology and Medical Oncology and Urology, Oregon Health and Science University; and Division of Urology, Portland Veterans Affairs Medical Center, Portland, Oregon Reprint requests: Tomasz M. Beer, M.D., Department of Medicine, Oregon Health and Science University, Mail Code L586, 3181 Southwest Sam Jackson Park Road, Portland, OR 97239 Submitted: June 10, 2003, accepted (with revisions): September 12, 2003
342
© 2004 ELSEVIER INC. ALL RIGHTS RESERVED
seen in benign prostatic epithelium.2 FSH stimulates proliferation and suppresses apoptosis in androgen-independent PC-3 cells in vitro.2 FSH may exert its effects in human prostate cancer by way of endocrine, paracrine, and autocrine mechanisms, because, in addition to the pituitary, FSH is produced in benign and malignant epithelial cells from the prostate.1– 4 FSH is not completely suppressed by standard initial hormonal therapy for prostate cancer. Patients treated with gonadotropin-releasing hormone (GnRH) agonists experience partial suppression of FSH.5–7 In contrast, FSH is elevated to greater than its physiologic range after orchiectomy.8 –10 Unlike GnRH agonists, GnRH antagonists substantially reduce circulating FSH when used in the initial management of advanced prostate cancer.11 The GnRH antagonist 0090-4295/04/$30.00 doi:10.1016/j.urology.2003.09.045
cetrorelix produced significant antitumor activity in a nude mouse, androgen-independent DU145 xenograft model.12,13 Recent data suggest that estrogens are active in AIPC.14 The addition of estrogens has a variety of effects on circulating hormones in men with AIPC, including suppression of FSH, testosterone, free testosterone, and estradiol, a reduction in dehydroepiandrosterone sulfate, and increases in sex hormone-binding globulin and cortisol.15,16 Estrogen’s activity in AIPC supports the hypothesis that FSH suppression may be a viable therapeutic target. The effect of estrogen on FSH cannot, however, be separated from its other effects on the hormonal system and its possible direct effects on tumor cells. Despite encouraging preclinical data, we previously had found no activity for abarelix in men with prostate cancer progressing during GnRH agonist therapy.17 The patient population in that study, however, had relatively low FSH concentrations before abarelix treatment and may not have been the optimal group in which to test FSH suppression as a treatment strategy in AIPC. In contrast to GnRH agonist therapy, orchiectomy is associated with a sustained increase in circulating FSH levels.8 –10 Because AIPC is a heterogeneous disease, it is possible that FSH plays a greater role in its progression after orchiectomy than after GnRH agonist therapy. For this reason, we sought to evaluate the effect of abarelix on FSH and disease status in men with disease progression after initial treatment with orchiectomy. MATERIAL AND METHODS
Prior treatment for prostate cancer with chemotherapy, radiopharmaceuticals, diethylstilbestrol or another estrogen, PC-SPES, ketoconazole, or other second-line hormonal therapy (except for androgen receptor antagonists) was not allowed. The institutional review boards at the Oregon Health and Science University and Portland Veterans Affairs Medical Center approved the protocol. All patients provided written informed consent.
TREATMENT Abarelix depot 100 mg was given by intramuscular injection on days 1, 15, and 29 and then every 28 days for 24 weeks. Patients were observed for 30 minutes after each injection. Patients who met the criteria for a PSA response after 24 weeks continued treatment up to a maximum of 52 weeks. Treatment was discontinued for any evidence of progression, including a confirmed 50% increase in serum PSA from baseline in nonresponders and from the nadir value in patients with a PSA reduction. Patients who completed 24 weeks of therapy without progression were followed up until progression or censored when another form of therapy was initiated.
MONITORING The initial evaluation included a complete history and physical examination, complete blood count with automated differential, serum alanine transaminase, alkaline phosphatase, bilirubin, lactate dehydrogenase, creatinine, testosterone, FSH, radionuclide bone scan, and computed tomography of the abdomen and pelvis. The complete blood count with automated differential, serum PSA, alanine transaminase, alkaline phosphatase, bilirubin, creatinine, and FSH were measured every 4 weeks. Serum testosterone was measured after 4 and 8 weeks of therapy. Adverse events were graded according to the National Cancer Institute’s Common Toxicity Criteria. In patients who had measurable disease on the initial evaluation, disease was reassessed using the same modality every 8 weeks. Each patient had his serum PSA and FSH measured in the same laboratory throughout the study. The PSA assays used were Hybritech PSA (Beckman Coulter 37200) and AxSYM PSA (Abbot). The FSH assays used were Elecsys FSH (Roche 1775863) and Architect FSH (Abbot 6C24).
PATIENTS Histologically confirmed prostate cancer progressing after orchiectomy was required for enrollment. Progression was defined as a 50% rise in the prostate-specific antigen (PSA) level confirmed by two measurements at least 2 weeks apart, the appearance of new metastatic lesions, or progression of known metastatic disease. In patients receiving androgen receptor antagonists in addition to orchiectomy, progression had to be confirmed after withdrawal of these agents (6 weeks for bicalutamide, 4 weeks for flutamide or nilutamide). Patients were excluded for Eastern Cooperative Oncology Group performance status greater than 2, age younger than 18 years, serum testosterone level greater than 50 ng/dL, PSA level less than 5 ng/mL, white blood cell count less than 3000/ mm3, platelet count less than 100,000/mm3, serum creatinine more than 1.5 times the upper limit of normal, bilirubin (direct or total) more than 1.5 times the upper limit of normal, alanine transaminase more than 1.25 times the upper limit of normal, allergy to a GnRH agonist or antagonist, major surgery within 4 weeks of the study, peripheral neuropathy of grade 3 or worse, serious medical illness, New York Heart Association class III or IV congestive heart failure, unstable angina, myocardial infarction within 6 months, acute deep venous thrombosis, acute pulmonary embolism, or active second malignancy other than nonmelanoma skin cancer. UROLOGY 63 (2), 2004
ASSESSMENT OF ENDPOINTS The PSA response was defined as a 50% reduction in the PSA level confirmed 4 weeks apart.18 Measurable disease was evaluated using the Response Evaluation Criteria in Solid Tumors.19 The time to progression was reported according to consensus criteria.18
STATISTICAL ANALYSIS The sample size of 25 was calculated on the basis of the primary endpoint of PSA response. A two-stage study design was used with a plan to reject the regimen if the response rate was less than 10% and recommend the regimen for additional study if the response rate was at least 30%. An alpha of 0.05 and power of 80% would reject the regimen if fewer than 2 of the first 15 patients responded and would recommend the regimen for additional study if at least 5 of 25 patients responded.20 Enrollment was permitted to continue while activity in the first 15 patients was assessed. Repeated measures analysis of variance was used to examine the changes in the mean FSH and testosterone with treatment, and the Wilcoxon signed rank test was used to examine changes in median FSH with treatment. The Kaplan-Meier method was used to estimate the time to progression. A sec343
TABLE I. Patient characteristics on entry Characteristic
Value
Patients (n) Age (yr) Median Range ECOG performance status (n) 0 1 2 PSA (ng/mL) Median Range Alkaline phosphatase (U/L) Median Range FSH (IU/L) Median Range Site of metastases (n) Bone only Lymph nodes only Liver only Bone and lymph nodes None Prior therapy for local disease External beam radiotherapy Radical prostatectomy None Prior hormonal therapy (n) Orchiectomy alone Orchiectomy ⫹ androgen receptor antagonist
16 78 57–86 9 6 1 20 5–445 75 37–114 43.7 17–80 5 1 1 1 8 8 1 7 5 (31) 11 (69)
KEY: ECOG ⫽ Eastern Cooperative Oncology Group; PSA ⫽ prostate-specific antigen; FSH ⫽ follicle-stimulating hormone. Numbers in parentheses are percentages.
ondary analysis that compared the characteristics and outcomes in the previously studied GnRH-agonist treated patients with those observed in this study was performed. The Mann-Whitney U test was used for comparison of continuous variables and the chi-square test and Fisher’s exact test were used for comparison of the categorical variables. The log-rank test was used to compare the time to progression in the two groups, and Cox proportional hazards analysis, including all baseline characteristics that differed with a P value of less than 0.2 between the two groups, was used to exclude the possibility that the observed outcome differences were a result of imbalances in the baseline patient characteristics.
RESULTS PATIENTS Sixteen men were recruited between July 2001 and July 2002 (Table I). The median age was 78 years, and the median Eastern Cooperative Oncology Group performance status was 0. The median PSA level was 20 ng/mL (range 5 to 445). Eight patients had distant metastases, and a rising PSA level was the only manifestation of AIPC in 8 pa344
tients. The median follow-up for the entire study population was 43 weeks (range 14 to 77). TREATMENT Sixteen patients received treatment for a median of 16 weeks (range 5 to 28). Treatment was discontinued because of a nonresponse at the end of 24 weeks in 6 patients, progression before completing 24 weeks of treatment in 8 patients, and toxicity in 2 patients. TOXICITY No deaths occurred during treatment. One patient died 15 days after discontinuing treatment due to unconfirmed progression. Treatment was generally very well tolerated. Two patients discontinued treatment because of toxicity. One patient experienced a grade 3 allergic reaction (hives and facial edema) on the initial treatment day and one had a grade 2 allergic reaction (hives) after 8 weeks on study. No other grade 3 toxicities occurred. The only other grade 2 or worse treatment-related toxicity was hyperphosphatemia in 1 patient. EFFICACY None of the patients had a confirmed 50% reduction in the PSA level. Five patients (31%, 95% confidence interval [CI] 11% to 58%) experienced confirmed reductions in the PSA level ranging from 9.3% to 31.8%. At the end of the six cycles of therapy, 6 patients remained stable without PSA progression or other signs of disease progression. The median time to progression was 12 weeks (95% CI 6 to 18 weeks). Three patients had measurable disease at study enrollment. Two had stable disease throughout treatment. EFFECTS ON FSH AND TESTOSTERONE All patients had a decline in their FSH concentration with the introduction of therapy. The mean FSH concentration declined from 45.1 IU/L (95% CI 34.0 to 56.2) to 5.3 IU/L (95% CI 3.7 to 6.8) after 4 weeks and to 5.6 IU/L (95% CI 3.7 to 7.5) after 8 weeks (repeated measures analysis of variance, P ⬍0.0001). Similarly, the median FSH decreased from 43.7 IU/L (range 17.0 to 84.0) to 4.2 IU/L (range 2.0 to 11.0) and to 4.0 IU/L (range 1.0 to 13.6) at the same intervals (P ⬍0.0001, Wilcoxon signed rank test). The FSH concentration remained suppressed after 20 weeks (mean 3.6 IU/L, 95% CI 2.2 to 4.9). Of the 16 patients, 15 achieved an FSH concentration of less than 10 IU/L and 13 achieved an FSH concentration of less than 5 IU/L. The median serum testosterone level at study entry was 15 ng/dL (mean 16, range 7 to 30). Serum testosterone remained in the anorchid range: median 11 ng/dL (mean 14 ng/dL, range 8 to 20 ng/dL) at week 4 and median 10 ng/dL (mean 15 UROLOGY 63 (2), 2004
nificantly longer (P ⫽ 0.050) in a multivariate Cox proportional hazards analysis (not shown). COMMENT
FIGURE 1. Percentage of change in serum PSA of patients with failure after GnRH agonist therapy (solid line) and orchiectomy (dashed line).
ng/dL, range 10 to 33 ng/dL) at week 8 (P ⫽ 0.2 by repeated measures ANOVA). OUTCOME IN PATIENTS WITH ORCHIECTOMY FAILURE COMPARED WITH PREVIOUSLY STUDIED PATIENTS WITH GnRH FAILURE Because the FSH concentration differed markedly in these two populations, we sought, in an exploratory analysis, to compare the outcome in the orchiectomy population with that of the previously studied patients treated with a GnRH agonist.17 The two studies were initiated simultaneously at the same institution and were identical in their design. The baseline characteristics of the two populations did not differ with respect to age, Eastern Cooperative Oncology Group performance status, serum PSA level, presence of distant metastases, or prior use of androgen receptor antagonists. The FSH levels were significantly greater in the orchiectomy failure group (median 44 IU/L versus 4 IU/L, P ⬍0.0001). A trend was found toward a greater alkaline phosphatase level in the GnRH group (median 87 U/L versus 75 U/L, P ⫽ 0.07). Although no patients in either study had a confirmed PSA response, any PSA reduction confirmed by two measurements was more common in the orchiectomy group (31% versus 5%, P ⫽ 0.04). The fraction of patients completing the planned 6-month course of therapy was also greater in the orchiectomy group (38% versus 10%, P ⫽ 0.049). The serum PSA changes from baseline for these two populations are shown in Figure 1. The time to progression was longer in the orchiectomy group than in the GnRH agonist group (orchiectomy patients: median 12.0 weeks, 95% CI 6.0 to 18.0, mean 29.1 weeks, 95% CI 16.0 to 42.2; GnRH treated patients: median 8 weeks, 95% CI 5.7 to 10.3, mean 9.5 weeks, 95% CI 6.4 to 12.5 weeks; P ⫽ 0.025, log-rank test) and remained sigUROLOGY 63 (2), 2004
Although both orchiectomy and GnRH agonist therapy effectively induce the castrate state in men with prostate cancer, the levels of circulating FSH were repressed only in the GnRH agonist-treated patients. Circulating FSH could serve as a mitogenic factor in patients with AIPC, as has been shown in several preclinical systems. In this study, we sought to determine the effect of FSH downregulation by treating patients whose prostate cancer was progressing after orchiectomy with the GnRH antagonist abarelix. Patients with orchiectomy failure had serum FSH concentrations approximately 10-fold higher than patients whose initial treatment had consisted of GnRH agonists in our previous study. Treatment with abarelix resulted in a rapid and sustained reduction in circulating FSH concentrations; however, the absolute concentrations of FSH during therapy were greater than those achieved in our previous trial carried out in GnRH agonist-treated patients or those reported by Garnick and Campion11 when abarelix was used in hormone-naive patients with prostate cancer. Thus, FSH suppression may be more difficult in the orchiectomy population. Despite producing markedly lower FSH concentrations, abarelix did not produce any confirmed clinical responses in this patient group. Thus, in its present form, abarelix cannot be recommended for patients with AIPC. It is not known whether strategies that more completely suppress circulating FSH would prove more effective. An exploratory comparison of the outcome in patients with failure after orchiectomy to the previously studied patients with progression while receiving GnRH agonists showed that the time to progression and the fraction of patients with any confirmed PSA reduction were greater in the orchiectomy group. It is difficult to determine in a small nonrandomized study whether these findings were a result of differences in tumor sensitivity to FSH manipulation between prostate cancer that progresses after orchiectomy and cancer that progresses after GnRH agonist therapy or simply chance observations, the result of uneven patient selection, or the result of small variations in serum PSA concentrations. If these observations were confirmed, it may be possible to develop therapeutic approaches that further reduce circulating FSH, and such approaches may prove more effective. Although inadequate suppression of circulating FSH is one possible explanation for the lack of activity of abarelix in this trial, other possibilities 345
should also be considered. If autocrine and paracrine FSH production contributes to the proliferation of prostate cancer, as some preclinical studies have suggested,1– 4 even complete suppression of circulating FSH may not adequately target FSHreceptor mediated tumor growth, and agents that block the FSH receptor directly may be needed. Finally, it is possible that despite preclinical evidence, FSH is not an important mediator of prostate cancer proliferation in patients. It is also important to note that although FSH was the focus of this investigation, it is possible that the changes in FSH and clinical outcomes were coincidental and that GnRH antagonists act by way of another unsuspected mechanism. Direct effects on tumor GnRH receptors or effects of leuteinizing hormone suppression should be considered. GnRH receptor expression has been reported in benign and neoplastic prostate cancer cells21; however, the role of these receptors is unclear. Although GnRH receptors are expressed in LNCaP, TSU-Pr1, PC-3, and DU-145 prostate cancer cell lines, the proliferation of these cells was unaffected by exogenous GnRH,22 possibly because most extrapituitary GnRH receptors have a low affinity for GnRH.23 When prostate cancer cells are transfected with high-affinity pituitary GnRH receptors, GnRH agonists exert antiproliferative activity.23 These findings suggest that GnRH antagonists are unlikely to produce clinical responses by binding tumor GnRH receptors. Leuteinizing hormone receptors are also expressed in benign and malignant prostate epithelium24; however, at present, no data have demonstrated that signaling through these receptors mediates cancer proliferation or resistance to apoptosis. CONCLUSIONS Treatment with abarelix in patients with AIPC after orchiectomy results in a marked reduction of circulating FSH; however, FSH suppression was not complete. None of the patients met the PSA response criteria; nonetheless, minor reductions in serum PSA were observed in 5 of 16 patients. Approaches that further reduce circulating FSH or target the FSH receptor directly may prove more effective. REFERENCES 1. Dirnhofer S, Berger C, Hermann M, et al: Coexpression of gonadotropic hormones and their corresponding FSH- and LH/CG-receptors in the human prostate. Prostate 35: 212– 220, 1998. 2. Ben-Josef E, Yang SY, Ji TH, et al: Hormone-refractory prostate cancer cells express functional follicle-stimulating hormone receptor (FSHR). J Urol 161: 970 –976, 1999. 3. Garde SV, Sheth AR, Shah MG, et al: Prostate—an extrapituitary source of follicle-stimulating hormone (FSH): occurrence, localization, and de novo biosynthesis and its hor346
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