Medical & Surgical Urology
Open Access

6-Month Formulations of Androgen Deprivation Therapy for Advanced Prostate Cancer: Effectiveness and Rationale for Extended Dosing

Jason Hafron^1* and Joseph F. Renzulli^{2 *}Correspondence: Jason Hafron, Department of Urology, Michigan Institute of Urology, Troy, USA, Email:

Author info »

Description

Androgen Deprivation Therapy (ADT), which reduces serum T to castration levels, is recognized as the standard treatment approach for the management of advanced Prostate Cancer (PCa). The most common ADT are Luteinizing Hormone-Releasing Hormone (LHRH) agonists and Gonadotropin-Releasing Hormone (GnRH) antagonists [1]. Elevated T concentrations are linked to a poor prognosis and increased risk of mortality in PCa [2]. Therefore, it is critical that LHRH and GnRH therapies achieve and maintain T levels below 50 ng/dL, ideally reaching below 20 ng/dL [1,3].

Adherence to dosing schedules consistently is crucial for the success of ADT. However, real-world data indicate a high rate of nonadherence to LHRH therapies, which can lead to T levels exceeding 50 and/or 20 ng/dL [4,5]. Barriers to adherence include dosing frequency, Health Care Provider (HCP) availability, appointment transportation difficulties, and cost [6]. Therefore, clinicians should evaluate which LHRH therapies provide the best balance of effectiveness and feasibility to address these common barriers, thereby avoiding nonadherence, treatment failure, and potential disease progression.

6-month LHRH formulations are proven effective for T suppression

Formulations of LHRH lasting 6 months are as effective in suppressing T compared to shorter formulations (1-, 3-, and 4 months) and compare favorably against competing products [7-12]. Research has shown that 90% of PCa patients receiving 6-month Intra-Muscular (IM) Leuprolide Acetate (LA) achieved T levels of 50 ng/dL or lower [8]. In a study of 6-month Sub-Cutaneous (SC) LA, 99% of PCa patients achieved T levels at or below 50 ng/dL by the 12^th month, and 93% achieved a T nadir of ≤ 5 ng/ dL [9,10]. Additionally, 93% of patients administered 6-month triptorelin pamoate maintained T levels at or below 50 ng/dL from the 2^nd to the 12^th month, and a pooled post hoc analysis from three phase 3 studies of triptorelin pamoate found that 96% achieved a T nadir below 0.35 nmol/L (<10 ng/dL) [11,12]. The T suppression outcomes for 6-month leuprolide mesylate were equivalent to those of other 6-month LHRH formulations [13]. However, when comparing studies, caution is advised, due to variations (e.g., different patient populations) between trials that may impact results.

Late dosing negatively impacts clinical outcomes

In real-world clinical settings, late dosing is common and has been observed to adversely affect clinical outcomes [2,5]. Therefore, LHRH formulations that minimize the possibility of delayed dosing may be preferable. A study involving 22,860 PCa patients in the United States showed that 84% of LHRH injections were administered beyond the 28-day month defined by the FDA for clinical trials, and average T levels were higher for late injections compared to those given early or on time (79 vs. 21 ng/dL) [5]. Additionally, for late injections compared to early or on-time injections the proportion of patients with T concentrations exceeding 50 ng/dL was much higher (27% vs. 4%) [5]. Consequently, LHRH formulations with longer durations of action (e.g., 6-month), which minimize the frequency of dosing, are likely to lead to more effective T suppression and improved clinical outcomes (Figure 1).

Figure 1: Expected¹ number of late² injections per year (n=85,030) by formulation [14].

Note: 1. Expected number calculated by the proportion of late injections multiplied by the number of injections per year for each formulation; 2. “Early/On-Time” if prior to, or “Late” if on/after day 33 (1-M formulation), 98 (3-M formulation), 129 (4-M formulation), or 195 (6-M formulation).

6-month LHRH formulations minimize office visits

Beyond minimizing the chances of late dosing, 6-month LHRH treatments reduce the number of annual office visits, a change that might be favored by some HCPs and patients. A reduction in the number of visits for injections can potentially alleviate the workload for HCPs, which is important due to recent labor shortages; over 60% of US counties do not have a practicing urologist, 20% of the US population live in a rural area but only 10% of the urology workforce practices in a rural area, and federal authorities project a shortage of almost 80,000 full-time registered nurses in 2025 [15- 17]. 6-month LHRH formulations also allow clinicians to maintain control over the use of ADT in their patients (vs. daily oral therapies that are self-administered by patients). Additionally, a decrease in the number of in-person appointments might be convenient for patients who face challenges accessing healthcare facilities, such as those living in areas with limited medical services, or for patients with dual residences like “snowbirds,” patients who live in nursing homes, and patients without reliable transportation. Patients can leverage resources such as telemedicine, oncology nurse navigators, care partners, and mobile technologies to ensure ongoing care between office visits.

6-month LHRH formulations options have unique profiles

Due to the unique properties of each formulation, 6-month LHRH therapies are not necessarily interchangeable. Subcutaneous LA has a small injection volume (0.375 mL) and a short 18-gauge needle. Intramuscular LA has a 1.5 mL injection volume and a 1.5- inch 23-gauge needle [18]. A pharmacokinetic comparison between these two formulations found that 1-month SC LA had longer T suppression than 1-month IM LA (56 vs. 42 days), which is likely due to the different delivery systems for each long-acting injectable (polymeric gel for SC LA vs. Lyophilized Microspheres for IM LA) [19]. Triptorelin pamoate uses a larger injection volume (2 mL) and needle (21-gauge), and must be injected immediately after reconstitution to avoid separation of the suspension. In comparison to IM LA, triptorelin decreased T levels more slowly; by day 29%, 91% of patients on triptorelin achieved castrate T concentrations vs. 99% for IM LA, yet maintained castration T levels just as effectively [20]. Leuprolide mesylate comes as a pre-filled, pre-mixed emulsion that must be refrigerated and is administered with an 18-gauge needle. Clinicians and patients should select the LHRH formulation with features that best suit the patients’ needs and preferences.

6-month formulations may generate health care cost savings

Despite 6-month formulations being more expensive per unit, they’ve been associated with reduced overall costs in comparison to shorter-acting formulations [7,21]. One study identified the reduced frequency of required treatments as a cost driver [21]. Additionally, the lowered risk of late dosing and consequent T breakthrough linked to longer-acting formulations can lower the likelihood of treatment failures and the extra costs they incur. These longeracting formulations might also safeguard against unforeseen shortterm product shortages.

Conclusion

The efficacy, safety, and practicality provided by 6-month LHRH formulations might render them a favored option for both patients and HCPs. Despite potential limitations in the types of ADT available to clinicians, they can still work with patients to explore all available treatment options and choose the bestsuited therapy.

References

1. Mohler JL, Antonarakis ES, Armstrong AJ, D'Amico AV, Davis BJ, Dorff T, et al. Prostate cancer, Version 2.2019, NCCN clinical practice guidelines in oncology. J Natl Compr Canc Netw. 2019;17(5):479-505.

   [Crossref] [Google Scholar] [PubMed].

2. Perachino M, Cavalli V, Bravi F. Testosterone levels in patients with metastatic prostate cancer treated with luteinizing hormone-releasing hormone therapy: Prognostic significance?. BJU Int. 2010;105(5):648-651.

   [Crossref] [Google Scholar] [PubMed].

3. Oefelein MG, Feng A, Scolieri MJ, Ricchiutti D, Resnick MI. Reassessment of the definition of castrate levels of testosterone: Implications for clinical decision making. Urology. 2000;56(6):1021-1024.

   [Crossref] [Google Scholar] [PubMed].

4. Crawford ED, Hafron JM, Tagawa ST, Twardowski TW, Harris RG, Moul JW, et al. Impact of late dosing on testosterone suppression with 2 different leuprolide acetate formulations: In situ gel and microsphere. An analysis of United States clinical data. J Urol. 2021;205(2):554-560.

   [Crossref] [Google Scholar] [PubMed].

5. Crawford ED, Twardowski PW, Concepcion RS, Hafron JM, Harris RG, Moul JM, et al. The impact of late luteinizing hormone-releasing hormone agonist dosing on testosterone suppression in patients with prostate cancer: An analysis of United States clinical data. J Urol. 2020;203(4):743-750.

   [Crossref] [Google Scholar] [PubMed].

6. Chan AHY, Cooper V, Lycett H, Horne R. Practical barriers to medication adherence: What do current self- or observer-reported instruments assess? Front Pharmacol. 2020;11:572.

   [Crossref] [Google Scholar] [PubMed].

7. Wex J, Sidhu M, Odeyemi I, Abou-Setta AM, Retsa P, Tombal B. Leuprolide acetate 1-, 3- and 6-monthly depot formulations in androgen deprivation therapy for prostate cancer in nine European countries: Evidence review and economic evaluation. Clinicoecon Outcomes Res. 2013;5:257-269.

   [Crossref] [Google Scholar] [PubMed].

8. Spitz A, Young JM, Larsen L, Mattia-Goldberg C, Donnelly J, Chwalisz K. Efficacy and safety of leuprolide acetate 6-month depot for suppression of testosterone in patients with prostate cancer. Prostate Cancer Prostatic Dis. 2012;15(1):93-99.

   [Crossref] [Google Scholar] [PubMed].

9. Crawford ED, Sartor O, Chu F, Perez R, Karlin G, Garrett JS. 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. J Urol. 2006;175(2):533-536.

   [Crossref] [Google Scholar] [PubMed].

10. Pieczonka CM, Twardowski P, Renzulli J, Hafron J, Boldt-Houle DM, Atkinson S, et al. Effectiveness of subcutaneously administered leuprolide acetate to achieve low nadir testosterone in prostate cancer patients. Rev Urol. 2018;20(2):63-68.

    [Google Scholar] [PubMed].

11. Lundström EA, Rencken RK, van Wyk JH, Coetzee LJE, Bahlmann JCM, Reif S, et al. Triptorelin 6-month formulation in the management of patients with locally advanced and metastatic prostate cancer: An open-label, non-comparative, multicentre, phase III study. Clin Drug Investig. 2009;29(12):757-765.

    [Crossref] [Google Scholar] [PubMed].

12. Shore N, Mincik I, DeGuenther M, Student V, Jievaltas M, Patockova J, et al. A phase 3, open-label, multicentre study of a 6-month pre-mixed depot formulation of leuprolide mesylate in advanced prostate cancer patients. World J Urol. 2020;38(1):111-119.

    [Crossref] [Google Scholar] [PubMed].

13. Klotz L, Tat T. Testosterone nadir and clinical outcomes in patients with advanced prostate cancer: Post hoc analysis of triptorelin pamoate Phase III studies. BJUI Compass. 2024;5(3):392-402.

    [Crossref] [Google Scholar] [PubMed].

14. Hafron J, Atkinson S, Boldt-Houle DM, Renzulli II JF. 6-month formulations of androgen deprivation therapy for advanced prostate cancer: effectiveness and rationale for extended dosing. Open Urol Nephrol J. 2024;17.

    [Crossref] [Google Scholar].

15. Our Priority: Address the Urologic Workforce Shortage. American Urological Association. Federal Advocacy. Workforce Shortages Web site. 2024.
16. Grunewald N. Addressing the Urology Workforce Shortage Crisis in Rural America. URO Today. 2024.
17. Nursing shortage fact sheet. American Association of Colleges of Nursing. 2024.
18. Dosing options to individualize patient care. Lupron Depot®(leuprolide acetate for depot suspension). 2021.
19. Saltzstein D, Shore ND, Moul JW, Chu F, Concepcion R, de la Motte S, et al. Pharmacokinetic and pharmacodynamics comparison of subcutaneous versus intramuscular leuprolide acetate formulations in male subjects. Ther Adv Urol. 2018;10(2):43-50.

    [Crossref] [Google Scholar] [PubMed].

20. Heyns CF, Simonin MP, Grosgurin P, Schall R, Porchet HC. Comparative efficacy of triptorelin pamoate and leuprolide acetate in men with advanced prostate cancer. BJU Int. 2003;92(3):226-231.

    [Crossref] [Google Scholar] [PubMed].

21. Odeyemi IAO, Berges R, Bolodeoku J. Economic impact of different preparations of leuprolide acetate in the management of advanced prostate cancer. J Med Econ. 2007;10(2):135-146.

    [Crossref] [Google Scholar].