european urology supplements 5 (2006) 880–885

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New Research Findings on Clinical Benefits of Bisphosphonates in Patients With Advanced Prostate Cancer§ Noel W. Clarke * Christie Hospital, Department of Surgery, Wilmslow Road, Manchester, M20 4BX, United Kingdom

Article info

Abstract

Keywords: Androgen-deprivation therapy Bisphosphonates Bone mineral density Bone metastases Fracture Prostate cancer Skeletal disease Skeletal-related events Spinal cord compression Radiation to bone Zoledronic acid

Objectives: Bone metastases develop in the majority of patients with advanced prostate cancer, and this fact puts these patients at high risk for potentially debilitating skeletal complications. Emerging therapies for the prevention of these complications are important for preserving patients’ quality of life. Methods: Existing and novel therapies were identified and researched through PubMed and published guidelines. Results: Several trials have examined the effects of bisphosphonates on bone metastases. However, zoledronic acid is the only bisphosphonate to demonstrate significant objective benefits in a long-term, randomised, placebo-controlled clinical trial in men with bone metastases secondary to hormone-refractory prostate cancer. Intravenous zoledronic acid (4 mg by 15-min infusion every 3 wk) provided significant benefits compared with placebo, including a reduction in all types of skeletal complications. In addition, zoledronic acid significantly ( p < 0.05) decreased bone pain levels compared with placebo at the first on-study pain assessment, and benefits remained significant at the 24-mo time point ( p < 0.05). Conclusions: Zoledronic acid provides significant benefit to patients with bone metastases secondary to hormone-refractory prostate cancer. It reduces all types of skeletal-related events, decreases bone pain levels, and may provide additional benefits.

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# 2006 European Association of Urology. Published by Elsevier B.V. All rights reserved. §

Presented by Fred Saad, MD, FRCS. * ChM, FRCS (Urol.). Tel. +44 161 446 3364; Fax: +44 161 446 3365. E-mail address: [email protected].

Introduction

Metastasis to bone occurs in the majority of patients with advanced prostate cancer and can lead to debilitating complications [1]. Patients with prostate cancer typically survive for several years after bone

metastases are diagnosed [2], but this time is spent at high risk for skeletal complications, and if these occur, they are associated with substantial morbidity, reduced quality of life, and increased health care costs [3–5]. Bisphosphonates have become an integral component of treatment for malignant

1569-9056/$ – see front matter # 2006 European Association of Urology. Published by Elsevier B.V. All rights reserved.

doi:10.1016/j.eursup.2006.07.016

european urology supplements 5 (2006) 880–885

Fig. 1 – Treatment of prostate cancer metastases with bisphosphonates [7–13].

bone disease and are now part of the guidelines of the European Association of Urology for the treatment of prostate cancer [6]. These agents inhibit the osteoclast-mediated bone resorption that occurs in association with both osteolytic and osteoblastic bone lesions. Although several bisphosphonates have been investigated, only zoledronic acid has demonstrated statistically significant long-term benefits in terms of a reduced incidence and delayed onset of skeletal-related events (SREs) and durable pain palliation in a randomised, placebo-controlled trial in men with bone metastases from hormonerefractory prostate cancer (HRPC; Fig. 1) [7–13]. Zoledronic acid is a nitrogen-containing bisphosphonate that binds avidly to bone and is subsequently ingested by active osteoclasts, whereby it inhibits osteoclast activity and induces osteoclast apoptosis [14]. Preventing or delaying the onset of SREs can provide meaningful benefits to patients and may allow for the preservation of functional independence throughout the continuum of care.

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Fig. 2 – Zoledronic acid consistently reduces all types of SREs (24 mo). SRE = skeletal-related event; HCM = hypercalcaemia of malignancy. Data from Saad et al. [7].

Zoledronic acid produced a 22% relative reduction in the proportion of patients who experienced an SRE compared with placebo ( p = 0.028), and the difference between these groups remained statistically significant when asymptomatic fractures were excluded from the analysis [7]. As assessed by Andersen-Gill multiple event analysis, 4 mg zoledronic acid reduced the ongoing risk of SREs by 36% compared with placebo ( p = 0.002) for the 24-mo trial duration [7]. The benefits of zoledronic acid were also evident in multiple exploratory analyses of the phase 3 trial data. This agent significantly reduced the risk of SREs compared with placebo in both of the prespecified trial periods, with a 36% risk reduction during months 1–15 ( p = 0.004) and a 53% risk

Results of clinical trials

In a multicenter, phase 3, randomised trial enrolling men with bone lesions secondary to HRPC, intravenous zoledronic acid (4 mg) every 3 wk for up to 24 mo provided significant benefits compared with placebo [7]. In the 24-mo analysis, zoledronic acid (4 mg) reduced all types of SREs, including fractures, spinal cord compression, requirement for change in antineoplastic therapy to treat bone pain, the requirement for surgery to bone, hypercalcaemia of malignancy, and the requirement for palliative radiotherapy to bone (Fig. 2) [7].

Fig. 3 – Prostate cancer: multiple event analysis by study period [15]. SRE = skeletal-related event. Data from Saad et al. [7,11].

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Fig. 4 – Prostate cancer: reduction of SRE risk by zoledronic acid, by SRE history. SRE = skeletal-related event. Data from Saad et al. [7].

Fig. 5 – Zoledronic acid has a greater efficacy (per primary end point) in patients with no pain at baseline. SRE = Skeletal-related event. Data from Eastham et al. [18].

reduction during months 16–24 ( p = 0.022; Fig. 3) [7,11,15]. These data suggest that patients continued to benefit from treatment after having received 15 mo of therapy previously. In many patients, bone metastases might not be diagnosed until the onset of skeletal morbidity. However, a post-hoc analysis indicated that zoledronic acid provided significant benefits to patients regardless of whether they had experienced any SREs before study entry (Fig. 4) [7], suggesting that patients do not need to experience an SRE before they can benefit from treatment. Moreover, many urologists may discontinue treatment if patients experience an SRE while receiving zoledronic acid, considering this to be a treatment failure [16]. However, some events may not be preventable with current therapy options, and patients may still benefit from treatment. In a post-hoc analysis that examined SRE risks in patients who had experienced an on-study SRE, zoledronic acid significantly decreased the risk of developing a second SRE by 41% (hazard ratio = 0.601; p = 0.011) [7,16,17]. Therefore, these data support the continuation of zoledronic acid in patients who experience an SRE while on therapy. Finally, an exploratory analysis of SREs in patients with or without pain at baseline showed that asymptomatic patients received greater benefit from treatment with zoledronic acid. In the subset of patients with no pain at study entry, zoledronic acid reduced the proportion of patients with an SRE by 39% relative to placebo versus 19% in patients with pain at study entry (Fig. 5) [18]. This analysis suggests that early treatment before the onset of pain may provide greater clinical benefit.

In addition to these objective benefits, zoledronic acid significantly decreased bone pain levels compared with placebo ( p < 0.05 at months 3, 9, 21, and 24) [7]. Moreover, in a post-hoc analysis of pain reduction during the study, significantly more patients in the 4-mg zoledronic acid group than in the placebo group experienced clinically meaningful decreases in bone pain (defined as a decrease of 2 points of a 10-point scale; p = 0.036) [19]. Zoledronic acid was generally well tolerated with manageable side-effects. Adverse events (AEs; e.g., mild-to-moderate fatigue, myalgia, and fever) occurred more commonly in patients treated with zoledronic acid than with placebo during the core phase; the incidence of these AEs was similar between the zoledronic acid and placebo groups during the extension phase. Moreover, the rate of study discontinuation due to AEs did not differ substantially between treatment groups. The phase 3 trial excluded patients with renal impairment, and the mean time to first notable increase in serum creatinine was comparable between the zoledronic acid (4 mg by 15-min infusion) and placebo groups ( p = 0.752) [20]. In addition to their effects on SREs, preclinical evidence suggests that bisphosphonates can inhibit cancer progression. Indeed, patients treated with 4 mg zoledronic acid showed a trend toward increased survival compared with the placebo group in a phase 3 trial in patients with bone metastases from HRPC [7]. Moreover, in preclinical studies zoledronic acid has demonstrated antitumour effects in human prostate cancer cells [21–23] and had synergistic antitumour activity when combined with docetaxel [24].

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Fig. 6 – Zoledronic acid for the prevention of bone metastases in patients with solid tumours. Adapted with permission from Mystakidou et al. [28].

metastasis to bone. This concept is supported by preclinical data from a mouse model system in which ADT increased metastasis to bone, but zoledronic acid (which inhibits osteoclast-mediated osteolysis) inhibited bone lesion development [25]. Further in vitro evidence in prostate cancer confirms the notion that bisphosphonates may act to prevent bone metastasis [23]. Supporting data in humans indicate that adjuvant clodronate delayed metastasis to bone compared with placebo in patients with high-risk breast cancer [26,27]. In a recent pilot study in 40 patients with advanced solid tumours, administration of 4 mg zoledronic acid every 3–4 wk resulted in a 12-mo bone metastasis-free survival rate of 60% compared with only 10% for the control group (Fig. 6) [28]. This was a small study, and patients with a variety of tumour types were enrolled. The preliminary results are intriguing.

3. Zoledronic acid may provide benefits in addition to the prevention of SREs and preservation of patients’ functional independence. Ongoing and future studies are investigating the antitumour potential of bisphosphonates to determine whether bisphosphonate therapy can prevent or reduce the development of bone metastases. Changes in bone metabolism in patients with early prostate cancer affect the growth factor milieu in the local bone environment, thereby facilitating

Conclusions

Larger prospective, randomised trials in patients with early prostate cancer are ongoing. These include the Zoledronic Acid European Study (ZEUS; high-risk prostate cancer patients in Europe), Central European Cooperative Oncology Group (CECOG; high-risk prostate cancer patients in Austria), Systemic Therapy in Advancing or Metastatic Prostate Cancer: Evaluation of Drug Efficacy (STAMPEDE; high-risk prostate cancer patients initiating

Table 1 – Adjuvant/prevention studies of zoledronic acid in patients with prostate cancer Study/primary country ZEUS Europe (high-risk patients)

CECOG Austria

STAMPEDE United Kingdom

RADAR Australia

AD-ZAP Australia

End points

Target accrual

Rate of bone metastases, time to bone metastases, overall survival, PSA doubling time, substudies on bone markers and bone mineral density Time to occurrence of first bone metastasis, composite pain score, analgesic score, time to first event of bone pain, time to first SRE, proportion of patients having SRE, serum PSA Failure-free survival (PSA failure, new lesions, or increase of baseline lesions, death), QOL, cost effectiveness, toxicity, SREs, overall survival (AD + zoledronic acid, AD + docetaxel, AD + celecoxib, AD + zoledronic acid + docetaxel, AD + zoledronic acid + celecoxib vs. AD) PSA relapse-free survival, prevention of CTIBL and bone metastases, QOL, overall survival, local failure (6 mo vs. 18 mo ADT  zoledronic acid for 18 mo) Biochemical (PSA) relapse-free survival and safety at 2 yr, locoregional relapse, distant/bone metastases, overall survival, QOL, and health resource use

1300

654

3300

1000

116

ZEUS = Zoledronic Acid European Study; CECOG = Central European Cooperative Oncology Group; STAMPEDE = Systemic Therapy in Advancing or Metastatic Prostate Cancer: Evaluation of Drug Efficacy; RADAR = Randomised Androgen Deprivation and Radiotherapy; AD-ZAP = Adjuvant Docetaxel-Zoledronic Acid in High-Risk Early Prostate Cancer Following Prostatectomy; PSA = prostate-specific antigen; SRE = skeletal-related event; QOL = quality of life; AD = androgen suppression/deprivation; CTIBL = cancer treatment-induced bone loss.

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ADT in the United Kingdom), Randomised Androgen Deprivation and Radiotherapy (RADAR; patients undergoing short- and intermediate-term ADT in Australia), and Adjuvant Docetaxel-Zoledronic Acid in High-Risk Early Prostate Cancer Following Prostatectomy (AD-ZAP; high-risk prostate cancer patients in Australia; Table 1).

References [1] Coleman RE. Metastatic bone disease: clinical features, pathophysiology and treatment strategies. Cancer Treat Rev 2001;27:165–76. [2] Coleman RE. Skeletal complications of malignancy. Cancer 1997;80:1588–94. [3] Oefelein MG, Ricchiuti V, Conrad W, Resnick MI. Skeletal fractures negatively correlate with overall survival in men with prostate cancer. J Urol 2002;168:1005–7. [4] McKiernan JM, Delea TE, Liss M, et al. Impact of skeletal complications on total medical care costs in prostate cancer patients with bone metastases. Proc Am Soc Clin Oncol 2004;23:531 (abstract no. 6057). [5] Crawford ED. Skeletal complications in men with prostate cancer: effects on quality-of-life outcomes throughout the continuum of care. Eur Urol 2004;3(5):10–5. [6] Aus G, Abbou CC, Bolla M, et al. EAU guidelines on prostate cancer. Eur Urol 2005;48:546–51. [7] Saad F, Gleason DM, Murray R, et al. Long-term efficacy of zoledronic acid for the prevention of skeletal complications in patients with metastatic hormone-refractory prostate cancer. J Natl Cancer Inst 2004;96:879–82. [8] Dearnaley DP, Sydes MR, Mason MD, et al. A double-blind, placebo-controlled, randomized trial of oral sodium clodronate for metastatic prostate cancer (MRC PR05 Trial). J Natl Cancer Inst 2003;95:1300–11. [9] Elomaa I, Kylmala T, Tammela T, et al. Effect of oral clodronate on bone pain. A controlled study in patients with metastatic prostatic cancer. Int Urol Nephrol 1992; 24:159–66. [10] Ernst DS, Tannock IF, Winquist EW, et al. Randomized, double-blind, controlled trial of mitoxantrone/prednisone and clodronate versus mitoxantrone/prednisone and placebo in patients with hormone-refractory prostate cancer and pain. J Clin Oncol 2003;21:3335–42. [11] Saad F, Gleason DM, Murray R, et al. A randomized, placebo-controlled trial of zoledronic acid in patients with hormone-refractory metastatic prostate carcinoma. J Natl Cancer Inst 2002;94:1458–68. [12] Small EJ, Smith MR, Seaman JJ, Petrone S, Kowalski MO. Combined analysis of two multicenter, randomized, placebo-controlled studies of pamidronate disodium for the palliation of bone pain in men with metastatic prostate cancer. J Clin Oncol 2003;21:4277–84. [13] Smith Jr JA. Palliation of painful bone metastases from prostate cancer using sodium etidronate: results of a randomized, prospective, double-blind, placebo-controlled study. J Urol 1989;141:85–7.

[14] Green JR, Rogers MJ. Pharmacologic profile of zoledronic acid: a highly potent inhibitor of bone resorption. Drug Dev Res 2002;55:210–24. [15] Andersen PK, Gill RD. Cox’s regression model for counting processes: a large sample study. Ann Stat 1982;10:1100– 20. [16] Saad F, Gleason D, Murray R, et al. Continuing benefit of zoledronic acid in preventing skeletal complications after the first occurrence in patients with prostate cancer and bone metastases [poster]. Presented at the Canadian Urological Association 59th Annual Meeting, 27 June to 1 July 2004; Whistler, BC, Canada. Abstract no. 165. [17] Saad F, Gleason D, Murray R, Tchekmedyian S. Zoledronic acid provides long-term reduction in skeletal morbidity for men with prostate cancer and bone metastases. Presented at the ASCO 2006 Prostate Cancer Symposium, 23– 26 February 2006; San Francisco, California. Abstract no. 149. [18] Eastham J, McKiernan J, Gleason D, Zheng M, Saad F. Effect of zoledronic acid on bone pain and skeletal morbidity in patients with advanced prostate cancer; analysis by baseline pain. Proc Am Soc Clin Oncol 2005;23:393S (abstract no. 4561). [19] Weinfurt KP, Anstrom KJ, Castel LD, Schulman KA, Saad F. Effect of zoledronic acid on pain associated with bone metastasis in patients with prostate cancer. Ann Oncol 2006;17:986–9. [20] Saad F, Gleason D, Murray R, et al. Zoledronic acid is well tolerated for up to 24 months and significantly reduces skeletal complications in patients with advanced prostate cancer metastatic to bone. Presented at the American Urological Society 2003 Annual Meeting. 2003. [21] Oades GM, Senaratne SG, Clarke IA, Kirby RS, Colston KW. Nitrogen containing bisphosphonates induce apoptosis and inhibit the mevalonate pathway, impairing Ras membrane localization in prostate cancer cells. J Urol 2003; 170:246–52. [22] Corey E, Brown LG, Quinn JE, et al. Zoledronic acid exhibits inhibitory effects on osteoblastic and osteolytic metastases of prostate cancer. Clin Cancer Res 2003;9: 295–306. [23] Montague R, Hart CA, George NJ, Ramani VA, Brown MD, Clarke NW. Differential inhibition of invasion and proliferation by bisphosphonates: anti-metastatic potential of zoledronic acid in prostate cancer. Eur Urol 2004;46:389– 401, discussion 402. [24] Ulle´n A, Lennartsson L, Harmenberg U, et al. Additive/ synergistic antitumoral effects on prostate cancer cells in vitro following treatment with a combination of docetaxel and zoledronic acid. Acta Oncol 2005;44:644–50. [25] Padalecki SS, Carreon MR, Grubbs B, Cui Y, Guise TA. Androgen deprivation causes bone loss and increased prostate cancer metastases to bone: prevention by zoledronic acid. Presented at the ASBMR 24th Annual Meeting 2002. San Antonio, TX. [26] Body JJ, Bartl R, Burckhardt P, et al. Current use of bisphosphonates in oncology. International Bone and Cancer Study Group. J Clin Oncol 1998;16:3890–9.

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[27] Diel IJ, Solomayer EF, Costa SD, et al. Reduction in new metastases in breast cancer with adjuvant clodronate treatment. N Engl J Med 1998;339:357–63. [28] Mystakidou K, Katsouda E, Parpa E, Kelekis A, Galanos A, Vlahos L. Randomized, open label, prospective study on

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the effect of zoledronic acid on the prevention of bone metastases in patients with recurrent solid tumors that did not present with bone metastases at baseline. Med Oncol 2005;22:195–201.