Six-month leuprorelin acetate depot formulations in advanced prostate cancer: a clinical evaluation

Figures & data

Table 1 Indications for hormonal therapy

Hormonal therapy indications for castration	Benefits	LE
General guidelines	In advanced PCa, all forms of castration used as monotherapy (eg, orchiectomy, LHRH, diethylstilbestrol) have equivalent efficacy In metastatic PCa, the addition of a nonsteroidal antiandrogen to castration (CAB) results in a small advantage in OS over castration alone but is associated with increased adverse events, reduced QoL, and high costs(br/)IAD should no longer be regarded as experimental, even though long-term data from prospective clinical trials are still awaited.(br/)“Minimal” ADT, however, should continue to be seen as experimental	1
M1 symptomatic	To palliate symptoms and to reduce the risk for potentially catastrophic sequelae of advanced disease (spinal cord compression, pathologic fractures, ureteral obstruction, extraskeletal metastasis).	1
	Even without a controlled randomized trial, this is the standard of care and must be applied and considered as level 1 evidence	1
	LHRH antagonists might be used with rapid decrease of serum testosterone	1
M1 asymptomatic	Immediate castration to defer progression to a symptomatic stage and prevent serious complications related to disease progression.	1b
	An active clinical surveillance protocol might be an acceptable option in clearly informed patients if survival is not the main objective	3
N+	Immediate castration to prolong PFS and even OS.	1b
	Might be questioned in single micrometastasis after extended lymph node dissection and radical prostatectomy	3
Locally advanced M0	Immediate castration to improve cancer-free survival	1b
Locally advanced disease treated with radiotherapy	Adjuvant ADT to improve cancer-free survival	1b
Localized disease treated with radiotherapy
High-risk d’Amico^Citation43	Adjuvant ADT to improve cancer-free survival	1b
Intermediate-risk d’Amico	If low dose (<75 Gy) radiotherapy: 6 months of ADT.
	If high dose (>75 Gy) radiotherapy: ADT questionable	2
Locally advanced asymptomatic unfit for local definitive treatment Antiandrogens	Limited OS improvement not related to a CSS benefit	1
	Immediate ADT to improve PFS and symptom-free survival
Short-term administration	To reduce the risk of the “flare-up” phenomenon in patients with advanced metastatic disease who are to receive an LHRH agonist	1b
Nonsteroidal antiandrogen monotherapy	Primary monotherapy as an alternative to castration in patients with locally advanced PCa (T3–4, any N, or any T).(br/)No place in localized disease as a single-treatment modality(br/)Combined with radiotherapy: according to the EPC trial, improvement in PFS and OS in locally advanced disease.(br/)Combined with RP: no place so far in an adjuvant setting	2

Note: Reprinted from European Urology, Vol 59/edition 4, Mottet N, Bellmunt J, Bolla M,et al, EAU Guidelines on Prostate Cancer. Part II: Treatment of Advanced, Relapsing, and Castration-Resistant Prostate Cancer, 572–583, Copyright (2011), with permission from Elsevier.¹⁰

Abbreviations: IAD, intermittent androgen deprivation; ADT, androgen-deprivation therapy; CAB, complete androgen blockade; CSS, cancer-specific survival; EPC, Early Prostate Cancer Trialists’ Group; LE, level of evidence; LHRH, luteinizing hormone-releasing hormone; QoL, quality of life; OS, overall survival; PCa, prostate cancer; PFS, progression-free survival; RP, radical prostatectomy; M1, metastatic patient; M0, no metastases; N, nodes; T, tumor; Gy, gray.

Table 2 Summary of included publications

Formulation	Microsphere-based 30 mg	Microsphere-based 45 mg	Gel-based 45 mg
Title	Safety and clinical efficacy of a new 6-month depot formulation of leuprorelin acetate in patients with prostate cancer in Europe	Efficacy and Safety of leuprolide acetate 6-month depot for suppression of testosterone in patients with prostate cancer	A 12-month clinical study of LA-2585 (45.0 mg): a new 6-month subcutaneous delivery system for leuprolide acetate for the treatment of prostate cancer
Author	UW Tunn and K Wiedey^Citation1	A Spitz, JM Young, L Larsen, C Mattia-Goldberg, J Donnelly, and K Chwalisz^Citation20	E David Crawford, Oliver Sartor, Franklin Chu, Ramon Perez, Gary Karlin, and J Steve Garrett^Citation28
Journal	Prostate Cancer and Prostatic Diseases	Prostate Cancer and Prostatic Diseases	Journal of Urology

Table 3 Summary of pivotal study results

	Microsphere-based 30 mg	Microsphere-based 45 mg	Gel-based 45 mg
Study design	Randomized, open-label, European multicenter study	Randomized, open-label, multicenter study	Randomized, open-label, multicenter study
Patient population	Men (age 18–85) with newly diagnosed prostate cancer of any stage or grade requiring hormonal therapy	Male (age 18+) with confirmed prostate cancer NCI Stage 2–4	Male with prostate cancer of Stage > T1
Sample size	296 patients enrolled in study; 120 were in 30 mg 6-month depot group	151 patients entered 134 completed study	111 patients with prostate cancer enrolled; 103 completed
Primary endpoint	Safety and tolerability of a new 6-month versus 3-month depot	Efficacy measured by suppression of serum T to ≤50 ng/dL from week 4 through week 48	Efficacy measured as decrease in total serum T to ≤50 ng/dL during study
Secondary endpoints	Efficacy comparison measured by suppression of serum T to ≤50 ng/dL, PSA, LH, FSH, and EORTC response	Safety and other efficacy parameters: PSA and LH concentrations	Safety and PSA concentrations
Efficacy results	EORTC response rate: no progression in 90% of patients. Partial remission was seen in 46.6% of the 3-month group and 58.8 in the 6-month group.(br/)Response rate by month 12: 98% in 6-month depot and 100% in 3-month depot patient’s group	T suppressed to <50 ng/dL from week 4 through week 48 in 93.4% of patients.(br/)PSA decrease from .4 ng/mL to ≤4 ng/mL by 86% of patients	T-suppression by day 28 to castrate levels in 97% of patients.(br/)PSA decrease throughout the 12-month study in 96% of patients
Safety results	Most common ADRs:(br/)Flushing 34.2%(br/)Increased sweating 5.8%(br/)Injection-site induration 5.8%(br/)Fatigue 1.7%	Most common treatment related AEs:(br/)Hot flushing 58.3%(br/)Injection site pain 17.9%(br/)Fatigue 11.9%(br/)Constipation 9.9%	Most common treatment-related AEs:(br/)Hot flashes 57.6(br/)Injection site(br/)Burning 15.3%(br/)Fatigue 11.7%

Abbreviations: NCI, National Cancer Institute; T1, tumor 1; T, testosterone; PSA, prostate-specific antigen; LH, luteinizing hormone; FSH, follicle-stimulating hormone; EORTC, European Organization for Research and Treatment of Cancer; ADRs, adverse drug reactions.

D’AmicoAVWhittingtonRBruce MalkowiczSBiochemical outcome after radical prostatectomy, external beam radiation therapy, or interstitial radiation therapy for clinically localized prostate cancerJAMA1998290119699749749478

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MottetNBellmuntJBollaMEAU guidelines on prostate cancer. Part II: Treatment of advanced, relapsing, and castration-resistant prostate cancerEur Urol201159457258321315502

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TunnUWWiedeyKSafety and clinical efficacy of a new 6-month depot formulation of leuprorelin acetate in patients with prostate cancer in EuropeProstate Cancer P D20091218387

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SpitzAYoungJMLarsenLMattia-GoldbergCDonnellyJChwaliszKEfficacy and safety of leuprolide acetate 6-month depot for suppression of testosterone in patients with prostate cancerProstate Cancer P D20121519399

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CrawfordEDSartorOChuFPerezRKarlinGGarrettJSA 12-month clinical study of LA-2585 (45.0 mg): a new 6-month subcutaneous delivery system for leuprolide acetate for the treatment of prostate cancerJ Urol2006175253353616406989

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