Takeda logo

Information for healthcare professionals only.

20210329 Prostap RTD_final COVER

This round-table discussion supplement has been commissioned and funded by Takeda UK Ltd and developed in partnership with Guidelines in PracticePlease see bottom of page for full disclaimer.

View prescribing information

Download the supplement

Discussion group:

Chair: Dr Catherine Bale (CB), Consultant Medical Oncologist, Betsi Cadwaladr University Health Board

Julie Douglas (JD), Advanced Nurse Practitioner, Portsmouth Hospital University NHS Trust

Suzanne Frank (SF), Advanced Specialist Breast Cancer Pharmacist, The Christie NHS Foundation Trust, Manchester

Background

Suppression of ovarian oestrogen production using a gonadotrophin-releasing hormone (GnRH) agonist reduces recurrence of hormone-receptor-positive early breast cancer in premenopausal women.

Use of GnRH agonists has been recommended in addition to endocrine therapy for premenopausal women with hormone receptor-positive disease since the publication of two large randomised controlled trials: Suppression of Ovarian Function Trial (SOFT) and Tamoxifen and Exemestane Trial (TEXT).1–4 These studies showed that addition of ovarian suppression to tamoxifen in premenopausal women with breast cancer resulted in significantly higher 8-year rates of disease-free and overall survival than tamoxifen alone; ovarian suppression in addition to exemestane, an aromatase inhibitor (AI), resulted in even higher rates of freedom from recurrence.3,4 International consensus guidelines for breast-cancer management in young women suggest that the addition of a GnRH agonist to tamoxifen be discussed on an individualised basis.5 The American Society of Clinical Oncology (ASCO) also recommends offering GnRH agonist/antagonist and AI for some men with hormone-receptor-positive breast cancer who would benefit from hormonal therapy after surgery, but in whom tamoxifen is contraindicated, and offering endocrine therapy (including AI with GnRH agent) first line in some men with advanced or metastatic, hormone receptor-positive, HER2 -negative breast cancer.6

The GnRH agonist leuprorelin acetate has been evaluated as a hormone therapy across various indications for 35 years, and Prostap® DCS (leuprorelin acetate) is the most widely used GnRH agonist in the UK.7 In May 2019, Prostap SR DCS (1-monthly preparation) and Prostap 3 DCS (3-monthly preparation) received additional licences for use in breast cancer:8–11

  • as adjuvant treatment, in combination with tamoxifen or an AI, for endocrine-responsive early-stage breast cancer in pre- and peri-menopausal women at higher risk of disease recurrence (young age, high grade tumour, lymph node involvement)
  • as treatment in pre- and peri-menopausal women with advanced breast cancer suitable for hormonal manipulation.

The approval of the breast cancer licences for Prostap SR DCS and Prostap 3 DCS was based on studies undertaken by Takeda in pre- and peri-menopausal women with early or locally advanced breast cancer or advanced breast cancer combined with data from the SOFT and TEXT trials.3,4 Although SOFT and TEXT involved triptorelin,3,4 the view was taken that leuprorelin is expected to demonstrate similar efficacy and safety (given all GnRH agonists are believed to have the same mechanism of action), and thus approval was granted for both Prostap products in breast cancer indications.

Aims of this round-table discussion

This round-table expert discussion was arranged to:

  • discuss the potential for Prostap DCS as a 3-monthly treatment for breast cancer in the UK
  • explore the benefits of 3-monthly compared with monthly treatment options for patients, healthcare professionals, and the healthcare service as a whole
  • discuss practicalities of switching patients from existing GnRH agonists to Prostap DCS.

How well established are GnRH agonists in breast cancer?

CB: Overall, I am confident in the benefit of GnRH agonists as a whole for treatment of breast cancer. Guidelines including NICE, ESMO and ASCO 3–6,12–15 all clearly supports the role of GnRH agonists in early and metastatic breast cancer for pre- and, potentially, peri-menopausal women. For patients with metastatic disease, GnRH agonists open the opportunity to use a wider range of treatments, including cyclin-dependent kinase 4/6 (CDK4/6) inhibitors.

SF: My centre also has confidence in GnRH agonists based on available evidence.3–6,12–15 Use of CDK4/6 inhibitors locally has increased in pre- and perimenopausal patients, would always be in combination with GnRH agonists. However, although shared care protocols are in place locally, these often overlook men, which can be a barrier to use of these treatments in men with breast cancer.

CB: Men are often a forgotten cohort, but they are an important patient population despite the small numbers. Men should be treated as for premenopausal women, with consideration of GnRH agonists, particularly in the metastatic setting and in any man taking an AI.

Tolerability of GnRH agonists

JD: The GnRH agonists are usually well tolerated. Side-effects often depend on the drugs with which they are combined but mainly include menopausal symptoms such as hot flushes, joint aches and pains, and mood swings—the latter being the biggest complaint for most patients. Side-effects often improve over time, and most patients do persist with treatment, although the few who experience severe side-effects may have to be switched. In general, patients with metastatic disease are more amenable to continuing a treatment despite side-effects. 

SF: The drive to stay on a medicine is certainly much higher in the metastatic setting than for early breast cancer, where treatments have a more preventative role. A concomitant AI is often the cause of side-effects, so it can be helpful to switch AI if side-effects are troublesome. However, many patients with stable disease do not want to risk switching and so will tolerate high levels of side-effects, while others are reluctant to take additional tablets to manage side-effects such as hot flushes. 

JD: In the adjuvant setting, we encourage patients to persevere with monthly injections, as it provides extra treatment options, and many can go on to have an AI and adjuvant bisphosphonates.

SF: The drive to stay on GnRH agonists when used for fertility preservation during chemotherapy is high, but overall compliance with endocrine treatment up to 5 and even 10 years now is poor. 

CB: When addressing fertility preservation, it is important to discuss plans for future treatment options with patients early on, so they are mentally prepared for next steps and are more amenable to taking treatments that may make them feel unwell. In the adjuvant setting, the benefit is fairly modest for many women, and it is important to discuss the risks versus benefits, potential side-effects, impact in terms of menopause and menopausal symptoms, and the possible impact on the relationship with their partner. Support should be provided for those experiencing menopausal symptoms, including discussing whether to stop and try an alternative. Some women simply do not tolerate GnRH agonists, with mood swings and depression more common reasons for discontinuation than fatigue and muscle aches/pain.

SF: Our consultants take a stepwise approach, starting patients on tamoxifen and then referring to the ovarian suppression clinic for a GnRH agonist. Once that is tolerated, the patients are switched to an AI. 

JD: We follow a stepwise approach as well, but usually start patients on GnRH agonist injections first and then introduce an AI about two months later. 

CB: Patients can escalate from a combination of GnRH analogue and tamoxifen to GnRH and AI, with a step-down if they do not tolerate dual blockade. 

Bone health

SF: In patients prescribed ovarian suppression, adjuvant bisphosphonates are discussed from the outset to prepare patients for their introduction. They start receiving bisphosphonates from cycle 5–6 of chemotherapy and continue them for 3 years. 

CB: As chemotherapy is known to cause osteopenia and osteoporosis, the threshold to continue should be low in order to protect bone health. 

Other side-effects

CB: GnRH agonists can affect blood sugar levels making diabetes harder to control.  It can also lead to hepatic dysfunction. Glucose and liver function should be measured in all patients taking GnRH agonists alongside routine monitoring of oestradiol and follicle-stimulating hormone (FSH). 

SF: Some evidence suggests that tamoxifen increases the risk of venous thromboembolism (VTE),16 in addition to the increased risk due to the cancer itself. VTE should be discussed with patients, so they are aware of the signs and how to respond. 

CB: Treatment-specific consent forms developed by Cancer Research UK (CRUK) provide a useful framework for discussing risks with patients, including VTE.

Round-table recommendations

  • Evidence clearly supports the role of GnRH agonists in early and metastatic breast cancer for pre- and, potentially, peri-menopausal women
  • Men should be treated as for premenopausal women, with GnRH agonists considered in the metastatic setting and in any man taking an AI
  • Side-effects of GnRH agonists usually improve over time, so patients should be encouraged to persist unless side-effects are severe
  • Glucose and hepatic function should be measured alongside 3-monthly monitoring of oestradiol and FSH
  • The increased risk of VTE from GnRH agonists and cancer itself should be discussed with patients, so they are aware of the signs and how to respond.

GnRH=gonadotrophin-releasing hormone; AI=aromatase inhibitor; FSH=follicle-stimulating hormone; VTE=venous thromboembolism

How well established is Prostap DCS (leuprorelin) in breast cancer?

CB: Leuprorelin has been used to treat over 24 million patients globally since 1996 across all licensed indications.17 Prostap DCS is widely used in Europe and worldwide for oncological indications, particularly prostate and breast cancer, as well as non-oncological diseases, but has often been overlooked for breast cancer, primarily because it was not licensed specifically for this indication in the UK until May 2019.8–11

SF: Although confidence in monthly Prostap SR DCS is strong, some consultants are concerned about whether 3-monthly dosing sustains adequate levels of ovarian suppression between injections and whether required monitoring every 3 months is achievable in primary care. 

JD: Monthly Prostap is prescribed frequently in our clinic, but Prostap 3 DCS is not prescribed widely—despite GPs often asking to change to 3-monthly administration—also due to reticence about sustained ovarian suppression. The opportunity to miminise healthcare contacts during the coronavirus disease 2019 (COVID-19) pandemic has encouraged some prescribers to use Prostap 3 DCS, which has increased confidence in this product, and this is likely to persist even after the pandemic. 

SF: The COVID-19 pandemic has also necessitated a change in our local practice, with primary care more involved in management of metastatic patients. This approach is also likely to continue beyond the pandemic, although 3-monthly injections would be more manageable for outpatient clinics. 

CB: Widespread reticence about 3-monthly preparations persists despite a study published in 2012 that showed the effects of monthly goserelin and trimonthly leuprorelin on oestradiol, FSH and luteinising hormone (LH) levels were equivalent in the early breast cancer adjuvant setting.18 With almost 88% of patients achieving postmenopausal levels in both groups, the 3-monthly regimen was efficacious and well tolerated, but it was a small cohort, 13% of patients did not gain adequate ovarian suppression, and hormone levels were checked only after 1 month. Since then, long-term follow-up in SOFT, TEXT and prostate cancer studies has confirmed that androgen suppression is sustained up to 5 years3,4,19–23 —the recommended maximum treatment duration for Prostap preparations.8,9

The key to reassuring patients and prescribers in clinical practice is to check oestrogen and FSH levels every 3 months, as advocated in the summary of product characteristics.8,9 If levels show adequate and sustained ovarian suppression is not being achieved, an alternative treatment option can be considered.

Round-table recommendations

  • Prescribers are reticent about 3-monthly dosing, but adequate androgen suppression is sustained up to 5 years in clinical practice
  • Ovarian suppression should be checked every 3 months to confirm sustained benefit.

What are the benefits of 3-monthly dosing compared with other treatment options for breast cancer?

CB: Given the choice, few patients would prefer 12–13 injections per year over just four injections per year. For many young patients, the diagnosis of breast cancer turns their life upside down and having to receive monthly injections can be a regular upsetting reminder. Reducing the number of visits to healthcare professionals for injections will undoubtedly help them to feel they are getting back to ‘normality’. As patients become aware of Prostap 3 DCS, some are keen to try this 3-monthly regimen and are approaching clinics about switching, but others remain cautious. 

JD: As long as patients are aware that the benefits of the two regimens are the same and are given a full explanation of the sustained mechanism of delivery, most are likely to be enthusiastic about switching. 

SF: Some women report that district nurses cannot always attend at 4-week intervals to administer injections, and consequent delays can be worrying for patients, who often ask to attend clinic to have injections on schedule. Reduced injection frequency would minimise pressure on district nurses, while also minimising both delays and worry for patients and healthcare contacts, particularly during the COVID-19 pandemic.

Round-table recommendations

  • Reducing injection frequency to 3-monthly is more convenient for clinics and primary care, and less onerous for patients
  • Many patients are keen to switch to 3-monthly dosing; a full explanation of the mechanism of delivery will provide reassurance for those who are more cautious.

What else does Prostap DCS offer compared with other treatment options for breast cancer?

SF: The Prostap DCS devices use the smallest gauge needle of all GnRH agonists—0.6 mm compared with, for example, 1.6 mm for Zoladex® (goserelin)—which is a benefit for patient comfort and preference.8–11, 24–28 

CB: Prostap DCS devices are also fitted with a safety mechanism to prevent injuries, which is reassuring for healthcare professionals administering the injections. 

CB: Prostap 3 DCS costs the same as three doses of Prostap SR DCS, so there is no increase in acquisition cost but potential benefits from reduced clinic time and resources due to fewer injections and associated appointments.

Round-table recommendations

  • Prostap DCS devices use the smallest gauge needle of all GnRH agonists and are fitted with safety mechanisms to prevent injuries
  • Acquisition costs for Prostap 3 DCS are the same as for Prostap SR DCS.

What do you see as the potential role for Prostap 3 DCS?

CB: I see a potential role for the 3-monthly preparation from the outset of treatment—as in prostate cancer—or clinicians may choose to use the monthly preparation initially to evaluate tolerability before moving to 3-monthly dosing.

JD: As tolerability is the biggest issue, I agree that it may be beneficial for those already taking the monthly regimen to switch to 3-monthly dosing if they are tolerating it well. It may also be pragmatic to start using Prostap 3 DCS initially just in the metastatic setting to gain confidence before using in those patients with early disease. 

SF: I also agree that it is sensible to start using Prostap 3 DCS in the metastatic setting, as this patient cohort is seen every 3 months in the clinic for blood tests and scans, which would provide regular opportunities to monitor ovarian suppression. Patients could be initiated on the monthly dose to assess tolerability while they are still attending clinic on a monthly basis, with a view to switching to 3-monthly when they are settled on Prostap SR DCS. Discussing such a switch when GnRH agonist treatment first starts will prepare them in advance for a later change in regimen. Patients could be discharged to primary care on 3-monthly dosing or discharged on the 1-monthly regimen with a view to switching to Prostap 3 DCS in primary care.

As patients with early breast cancer are usually discharged to primary care on ovarian suppression and hormone therapy, it will be more difficult to ensure hormone levels are monitored regularly, but once effectiveness and sustained benefit for patients with metastatic disease are confirmed in the clinic, prescribers will be more comfortable using the 3-monthly regimen for adjuvant therapy.

Round-table recommendations

  • Prostap 3 DCS could be used from the outset of treatment, or the monthly preparation could be trialled first to evaluate tolerability before switching
  • Prostap 3 DCS is ideal for the metastatic setting, allowing a move to fewer visits, which is beneficial for healthcare systems and reduces the impact on patients
  • Once clinicians are confident of the sustained effectiveness of the 3-monthly preparation demonstrated in metastatic disease, Prostap 3 DCS could be rolled out for early breast cancer.

What is your experience of switching to Prostap 3 DCS? 

CB: The local medicines management group is currently reviewing Prostap 3 DCS, so there is no local experience of switching patients at the moment. 

SF: We also do not yet have experience of switching patients to Prostap 3 DCS, but we would likely perform a GnRH agonist switch in a similar way to a previous biosimilar trastuzumab switch. 

JD: Specialist nurses can advise patients on the benefits of 3-monthly dosing. 

SF: Signposting patients to reliable independent resources, such as Breast Cancer Now, will give them confidence to switch to the 3-monthly preparation. 

CB: Most discussions with patients are about giving them confidence in the options being offered, so how patients are approached about 3-monthly dosing will be critical. If they understand how the prolonged dosing works, they will be more amenable to using this regimen. Such discussions should not be rushed, as young patients with cancer in particular often keep themselves very well informed and are willing to engage in complex and valuable ongoing conversations. 

CB: Support from primary care will also be vital to reassure patients about the effectiveness and benefit of 3-monthly dosing. A shared care agreement with primary care for 3-monthly monitoring and covering all eligible patients, including men, will also be essential.

Round-table recommendations

  • Switching to Prostap 3 DCS is not currently widespread
  • Communication with patients about potential switches from the outset of treatment is key to managing their expectations and acceptance of future drug changes
  • Signposting patients to reliable independent resources will help give them confidence to switch to a 3-monthly preparation.

What do you think would be the ideal patient profile for switching to Prostap 3 DCS? 

CB: An example of a patient we would consider for 3-monthly dosing would be a 36-year-old patient on adjuvant chemotherapy with fairly high-risk breast cancer and young children, who wants to get their life closer to normality. 

SD: Our clinic sees a 41-year-old working mother who has been taking a GnRH agonist for 3 years. To reduce her healthcare contacts during the COVID-19 pandemic, a switch to 3-monthly injections would be ideal. 

JD: A recent patient who is receiving adjuvant exemestane and bisphosphonates would be an ideal candidate to switch. The patient is young with small children, and has returned to full time work since completing treatment. Having the 3-monthly injections would reduce the number of visits to the hospital/GP practice. Therefore, less of a reminder and more chance of getting back to a sense of normality.

Round-table recommendations

  • A switch to 3-monthly dosing would offer clear benefits to a patient who particularly wishes to minimise disruption to their daily life, such as a working parent.

Useful resources

For healthcare professionals:

For patients:

Conflicts of interest

All participants have been paid an honorarium by Takeda UK Ltd.

Suzanne Frank has received speaker fees from Amgen, Eisai, Lilly, Merck, MundiPharma, Novartis, Pfizer, and Roche; conference sponsorship from Amgen, Daiichi-Sankyo, Sanofi-Aventis, and Roche; and advisory boards from Amgen, Astra Zeneca, Chugai, Lilly, and Roche.

Acknowledgements

Jemma Lough, Medical Writer, drafted the article in this supplement, which was reviewed by the members of the discussion group.

References

  1. Eifel P, Axelson J, Costa J et al. National Institutes of Health Consensus Development Conference Statement: adjuvant therapy for breast cancer, November 1–3, 2000. J Natl Cancer Inst 2001; 93: 979–989.
  2. Goldhirsch A, Glick J, Gelber R et al. Meeting highlights: International Consensus Panel on the Treatment of Primary Breast Cancer. J Clin Oncol 2001; 19: 3817–3827.
  3. Francis P, Regan M, Fleming G et al. Adjuvant ovarian suppression in premenopausal breast cancer. N Engl J Med 2014; 372: 436–446.
  4. Francis P, Pagani O, Fleming G et al. Tailoring adjuvant endocrine therapy for premenopausal breast cancer. N Engl J Med 2014; 379: 122–137.
  5. Partridge A, Pagani O, Abulkhair O et al. First international consensus guidelines for breast cancer in young women (BCY1). Breast 2014; 23: 209–220.
  6. Hassett M, Somerfield M, Giordano S. Management of male breast cancer: ASCO guideline summary. JCO Oncol Pract 2020; 16: e839–843.
  7. Takeda UK Ltd. Data on file, UK/PRS/2002/0004.
  8. Takeda UK Ltd. Prostap 3 DCSSummary of Product Characteristics. May 2020. Available at: www.medicines.org.uk/emc/product/4651/smpc
  9. Takeda UK Ltd. Prostap SR DCSSummary of Product Characteristics. May 2020. Available at: www.medicines.org.uk/emc/product/4650/smpc
  10. EMC. Prostap 3 DCS 11.25 mg Powder and Solvent for Prolonged-release Suspension for Injection in Pre-filled syringe: changes to SmPC. May 2019.
  11. EMC. Prostap SR DCS 3.75 mg Powder and Solvent for Prolonged-release Suspension for Injection in Pre-filled Syringe: changes to SmPC. May 2019.
  12. Cardoso F, Kyriakides S, Ohno S et al. Early breast cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment, and follow-up. Ann Oncol 2019; 30: 1194–1220.
  13. Cardoso F, Paluch-Shimon S, Senkus E et al. 5th ESO-ESMO international consensus guidelines for advanced breast cancer (ABC 5). Ann Oncol 2020. Available at: www.esmo.org/guidelines/breast-cancer/consensus-recommendations-advanced-breast-cancer-abc-5
  14. NICE. Advanced breast cancer: diagnosis and treatment. Clinical guideline 81. NICE, 2009. Available at: www.nice.org.uk/guidance/cg81
  15. NICE. Early and locally advanced breast cancer: diagnosis and management. NICE guideline 101. NICE, 2018. Available at: www.nice.org.uk/guidance/ng101
  16. Wockhardt UK Ltd. Tamoxifen 10mg film-coated tablets—summary of product characteristics. August 2018. Available at: www.medicines.org.uk/emc/product/2247/smpc
  17. Takeda UK Ltd. Data on file. DF120604(2).
  18. Aydinya A, Kilic L, Yildiz I et al. Two different formulations with equivalent effect? Comparison of serum estradiol suppression with monthly goserelin and trimonthly leuprolide in breast cancer patients. Med Oncol 2013; 30: 354.
  19. D’Amico A, Chen M, Renshaw A et al. Androgen suppression and radiation vs radiation alone for prostate cancer: a randomized trial. JAMA 2008; 299: 289–295.
  20. D’Amico A, Manola J, Loffredo M et al. 6-month androgen suppression plus radiation therapy vs radiation alone for patients with clinically localized prostate cancer: a randomized controlled trial. JAMA 2004; 292: 821–827.
  21. Lavadière J, Nabid A, De Bedoya L et al. The efficacy and sequencing of a short course of androgen suppression on freedom from biochemical failure when administered with radiation therapy for T2-T3 prostate cancer. J Urol 2004; 171: 1137–1140.
  22. Shiba E,  Yamashita H, Kurebayashi J et al. A randomized controlled study evaluating safety and efficacy of leuprorelin acetate every-3-months depot for 2 versus 3 or more years with tamoxifen for 5 years as adjuvant treatment in premenopausal patients with endocrine-responsive breast cancer. Breast Cancer 2016; 23: 499–509.
  23. Warde P, Mason M, Ding K, et al. Combined androgen deprivation therapy and radiation therapy for locally advanced prostate cancer: a randomised phase 3 trial. Lancet 2011; 378: 2104–2111.
  24. AstraZeneca UK. Zoladex 3.6 mg—summary of product characteristics. January 2017. Available at: www.medicines.org.uk/emc/product/1543/smpc
  25. AstraZeneca UK. Zoladex LA 10.8 mg—summary of product characteristics. January 2017. Available at: www.medicines.org.uk/emc/product/1567/smpc
  26. Ipsen Ltd. Decapeptyl SR 3 mg—summary of product characteristics. September 2017. Available at: www.medicines.org.uk/emc/product/963/smpc
  27. Ipsen Ltd. Decapeptyl SR 11.25 mg—summary of product characteristics. July 2017. Available at: www.medicines.org.uk/emc/product/780/smpc
  28. Ipsen Ltd. Decapeptyl SR 22.5 mg—summary of product characteristics. December 2016. Available at: www.medicines.org.uk/emc/product/5906/smpc

This round-table discussion supplement has been commissioned and funded by Takeda UK Ltd and developed in partnership with Guidelines in Practice. Takeda UK Ltd suggested the topic and participants, and carried out full medical approval on all materials to ensure compliance with regulations. Takeda UK Ltd paid the participants an honorarium. The views and opinions of the participants are not necessarily those of Takeda UK Ltd, or of Guidelines in Practice, its publisher, advisers, or advertisers. No part of this publication may be reproduced in any form without the permission of the publisher.

C-APROM/UK/PRS/0152

Date of preparation: April 2021