Posted: Tuesday, May 30, 2017
An Oldie but Goody
Fulvestrant (Faslodex),1 an estrogen-receptor antagonist that belongs to a class of agents called selective estrogen-receptor down-regulators or “SERDs,” was originally approved in 2002 as monotherapy for the treatment of postmenopausal women with hormone-receptor positive (HR+) metastatic breast cancer (MBC) whose cancer has progressed after antiestrogen therapy.2,3
The Evolution of Fulvestrant—A Renaissance Moment
“In many ways, our thinking about fulvestrant has changed,” explained Maura N. Dickler, MD, an associate attending physician and Interim Chief of the Breast Medicine Service at Memorial Sloan Kettering Cancer Center, New York City, “as evidence mounts about the prevalence of ESR1 mutations and how they relate to emerging mechanisms of resistance in patients who are exposed to prior aromatase inhibitors (AIs).4 The SERDs are having a ‘renaissance’ moment because of their mechanism of action—a drug that may degrade a mutant estrogen receptor—is attractive.” This is a very active area of research, as investigators attempt to identify drugs that degrade the estrogen receptor,5,6 Dr. Dickler pointed out, “now that we have a better understanding of the selective pressure of AI therapy and the emergence of ESR1 mutations that give rise to mutant receptors.”
Initially, fulvestrant was approved in the second-line metastatic setting, after disease progression on a nonsteroidal AI. “We started with a 250-mg loading dose, followed by monthly 250-mg dose injections. Over the next 8 to 10 years, we learned that a higher loading dose was important, and then ultimately, we learned that high-dose fulvestrant was more effective than AIs in an endocrine-naïve first-line setting,” Dr. Dickler said. The lower dose may have led clinicians “to believe that fulvestrant wasn’t very active and that it did not matter which drug you chose—fulvestrant or exemestane, based on the EFECT trial—for treatment of patients with estrogen receptor-positive (ER+)/HER2-negative MBC after progression on a nonsteroidal AI.”7 It wasn’t until the CONFIRM trial, however, which demonstrated that high-dose fulvestrant was better than the ‘standard dose’ that a difference was noted.8,9 Subsequently, the FIRST and FALCON trials showed that fulvestrant was superior to AI treatment in patients who had not been exposed to prior endocrine therapy.10,11
Fulvestrant in Combination
The decision about which endocrine agent to pair with a cyclin-dependent kinase (CDK) 4/6 inhibitor for first-line treatment of a patient with HR+ MBC boils down to a distillation of prior therapy, the disease-free interval, and the time off hormone therapy, Dr. Dickler noted.
Those who present with de novo stage IV disease haven’t received any treatment, whereas others may have received years of adjuvant endocrine therapy with tamoxifen and AIs, on a sequential strategy or AIs alone.
Currently, based on PALOMA-2 or MONALEESA-2, clinicians who choose palbociclib or ribociclib will opt to start patients on letrozole as the endocrine partner.12,13 However, for those patients who experience relapse on a nonsteroidal AI in the adjuvant setting, data from PALOMA-3 and MONARCH 2, for example, support use of fulvestrant with palbociclib or abemaciclib, as a reasonable choice.14,15 [Editor's Note: See update at the end of this article.]
Data are also available about fulvestrant in combination with nonsteroidal AIs (eg, fulvestrant plus anastrozole),16,17 which can inform clinician choice, especially in endocrine-naïve patients.
The preCOG study presented at the San Antonio Breast Cancer Symposium in 201618 extended findings of the BOLERO-2 study (everolimus and exemestane).19 Progression-free survival was improved when everolimus was combined with the SERD. This is a promising approach, but, Dr. Dickler cautioned that because the data have not been published or added to guidelines yet, it may be difficult to obtain third party coverage for it.
Administration of Fulvestrant—Voices of Experience
Together with the patient, the oncologist selects appropriate treatment and monitors efficacy and safety of the therapy. Prior to starting a regimen, the oncologist explains why the treatment is appropriate, how it is administered, and what to expect in terms of adverse effects. Despite these conversations with the oncologist, however, many patients are not fully aware that treatment with fulvestrant comprises 2 injections for each visit, 1 in each buttock, observed Deborah Rimmele RN, BSN, OCN, Practice Manager Infusion at the Maggie Daley Center for Women’s Cancer Care, Robert H. Lurie Comprehensive Cancer Center of Northwestern University in Chicago. “So, when the patient comes to me [the nurse], she generally is aware that I will be administering treatment as an injection. The fact that there will be 2 injections, however, may be a surprise!”
Preparing the Fulvestrant Injections
Each injection requires a bit of preparation, but mostly, because the drug is refrigerated, warming it before administration can be helpful, Ms. Rimmele explained. “It’s a very cold, oily injection. If you hold the syringe in your hand and rotate it a bit while you talk to the patient, you will be able to tell when it has warmed up sufficiently. It will feel warmer in your hand and you will see that the bubble at the top will move more easily. It’s also gentler on the patient if the metal needle isn’t ice cold,” she said. “Imagine putting olive oil in the refrigerator. It’s very thick and doesn’t move very easily. Once you warm it up, it flows more readily.” However, warming the solution should not include shaking it vigorously or warming it in a water bath, which could affect the drug’s properties.
Positioning the Patient
Simaya (Maya) Ausikaitis, RN, BSN, OCN, a colleague of Ms. Rimmele’s in Chicago with decades of experience, commented that if the patient has a needle phobia, “you will want her to lie down on a bed or gurney. If she has been on therapy for a while and is not phobic, she may prefer just to lean forward, supporting her arms on a chair or a countertop—something stable. Whatever they choose, patients always hold on to something. Occasionally, a patient will feel faint or weak, so it’s important to make sure that she has something to hold on to.”
The injection should be administered into the dorsogluteal region rather than into an area that will cause pain or soreness when sitting. “In nursing school, we were taught 2 techniques for giving an intramuscular injection: one is in the hip area and one is in the gluteus maximus muscle, both of which avoid the sciatic nerve,” Ms. Rimmele said.
Positioning for Providers—An Important Tip
“After you’ve made the patient comfortable, try to make yourself comfortable,” Ms. Rimmele suggested, before you start giving the injection. It is a time-consuming injection, and it can be hard on your thumb. If you are uncomfortable, it’s going to be that much more difficult.”
“I usually sit on a stool. If you are leaning over, it’s likely that your back will start to hurt. If you have to administer injections to 3 or 4 of these patients in a row, your thumb could get sore. You want to make sure that you are not positioned awkwardly,” Ms. Rimmele suggested, “before you start giving the injection.”
Another helpful recommendation that facilitates administration of the injection is to instruct the patient to relax the leg on the side where the injection is being given. “In other words,” Ms. Rimmele explained, “if I am injecting the right hip, the patient should not have her weight on her right leg. Tensing the muscle makes it more difficult for me to give the injection and more painful for the patient.” To the extent possible, the patient should keep the area being injected as relaxed as possible, bend the knee, and put all the weight on the opposite leg.
According to Ms. Rimmele and Ms. Ausikaitis, it takes about 1 minute to administer each injection, which can be painful. The needle is about an inch and a half long. “The drug is very thick; you can’t push it fast,” Ms. Rimmele said. “And even if you are very strong and try to push it faster, patients will often ask you to slow down. It’s a long minute.”
The nurses said that they use that very long minute to chat with the patient, to help keep her relaxed and distracted. “We try to talk the patient through the injection by asking how therapy has been going and whether there are any issues we need to know about: ‘How are you doing? Any side effects? Anything new going on? How was it getting over to the cancer center?’—weather, traffic, etc.”
“After you’ve made the patient comfortable, try to make yourself comfortable before you start giving the injection. It is a time-consuming injection and can be hard on your thumb. If you are uncomfortable, it’s going to be that much more difficult.”
It often seems like the second injection is easier, Ms. Ausikaitis said. “First-time patients are usually nervous. Once they’ve gotten the first injection, they might say or think, ‘That wasn’t SO bad.’ So, the second one seems easier. But our job is to reassure the patient, make sure she’s okay. “I often ask the patient if she wants to take a moment between injections,” she said, “but most of them just want to get them over with.”
Data on injection site pain and local reactions are available from the FALCON study, Dr. Dickler observed.20 Fulvestrant is not soluble in an aqueous solution and must be delivered in an oil-based vehicle. “Even if it doesn’t hurt a lot,” she said, “it is often scary for patients. They eventually become accustomed to it, but because of administration issues, there is interest in developing oral SERDs that could be absorbed via the gastrointestinal tract, and in fact, there are many in development.”21
Some individuals develop redness at the injection site. “I’ve even had to send an occasional patient to the dermatologist to help manage a hive-like reaction, but overall fulvestrant is exceptionally well tolerated,” Dr. Dickler said.
To manage postinjection soreness, Ms. Rimmele and Ms. Ausikaitis recommend use of ice, heat, and/or ibuprofen (if approved by the oncologist). “Some patients say they like to ‘walk it out,’ Ms. Ausikaitis observed. “They say that if they move, they feel like they are getting the drug to dissolve into the muscle.”
Some patients, especially petite women with less fat and musculature, develop “knots” at the injection sites. “Those areas can be quite sore, so we try to inject in another spot to let those previous sites settle down,” Ms. Rimmele said.
The side effects associated with SERMs (selective estrogen-receptor modulators), like tamoxifen—eg, moodiness, blood clots, slightly elevated risk for stroke22—are not generally seen with fulvestrant and it is one of the best tolerated endocrine therapies when given alone. Now that fulvestrant is part of combination regimens, Dr. Dickler noted, there may be some adverse effects that are likely attributable to the targeted agent.
Ms. Rimmele and Ms. Ausikaitis concurred that when given on its own, fulvestrant is very well tolerated. Hot flashes and tiredness are the most common complaints but patients may also have injection site pain or muscle aches. “I’ve never had a patient discontinue treatment with fulvestrant because of intolerance,” Ms. Rimmele said. And when patients report tiredness, it is sometimes difficult to tease out whether “fatigue” is drug related or is a consequence of previous treatments, advanced disease, age, anxiety, depression, or another source.
Findings from the FALCON trial in endocrine-therapy naïve patients,20 from the preCOG trial in which fulvestrant was combined with everolimus,18 and from PALOMA-3, which paired palbociclib with fulvestrant,14 have raised our awareness of how a SERD may be used to improve and enhance breast cancer treatment regimens. Moreover, Dr. Dickler concluded, “if our goal is to give a drug that interacts with the estrogen receptor rather than reducing ligand, then SERDs such as fulvestrant are highly attractive.”
In keeping with its renaissance moment, fulvestrant has been selected as the endocrine partner in ongoing clinical trials of PI3K-alpha inhibitors—taselisib23 and alpelisib.24
Update (March 1, 2018): On the basis of data from the phase III MONARCH 2 (J Clin Oncol 2017;35:2875-2884) trial, the FDA approved a new indication for fulvestrant to include combined treatment with abemaciclib for women with HR+, HER2-negative advanced or MBC who have disease progression after endocrine therapy.
Maura N. Dickler, MD, has disclosed that she is a consultant for Roche/Genentech; Pfizer; Novartis; Astra Zeneca; TapImmune; Puma; G1 Therapeutics; and Snydax. She also receives research support from Novartis; Roche/Genentech; and Eli Lilly.
Deborah Rimmele, RN, BSN, OCN, disclosed no relevant relationships.
Simaya (Maya) Ausikaitis, RN, BSN, OCN, disclosed no relevant relationships.
- Faslodex (fulvestrant) injection. Prescribing Information. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/021344s014lbl.pdf Accessed April 25, 2017.
- Drug Approval Package. Faslodex (Fulvestrant) Injection. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2002/21-344_FulvestrantFaslodex.cfm. Accessed April 25, 2017.
- Osborne CK, Pippen J, Jones SE, et al. Double-blind, randomized trial comparing the efficacy and tolerability of fulvestrant versus anastrozole in postmenopausal women with advanced breast cancer progressing on prior endocrine therapy: results of a North American trial. J Clin Oncol 2002;20:3386-3395.
- Robinson DR, Wu Y-M, Vats P, et al. Activating ESR1 mutations in hormone-resistance metastatic breast cancer. Nature Genetics 2013;45;1446-1451.
- Spoerke JM, Gendreau S, Walter K, et al. Heterogeneity and clinical significance ofESR1 mutations in ER-positive metastatic breast cancer patients receiving fulvestrant. Nat Commun 2016;7:11579.
- Angus L, Beije N, Jager A, et al. ESR1 mutations: moving towards guiding treatment decision-making in metastatic breast cancer patients. Cancer Treat Rev 2017;52:33-40.
- Chia S, Gradishar W, Mauriac L, et al. Double-blind, randomized placebo controlled trial of fulvestrant compared with exemestane after prior nonsteroidal aromatase inhibitor therapy in postmenopausal women with hormone receptor–positive, advanced breast cancer: results from EFECT. J Clin Oncol 2008;26:1664-1670.
- Di Leo A, Jerusalem G, Petruzelka L, et al. Results of the CONFIRM phase III trial comparing fulvestrant 250mg with fulvestrant 500mg in postmenopausal women with estrogen receptor-positive advanced breast cancer. J Clin Oncol 201028: 4594-4600.
- Di Leo A, Jerusalem G, Petruzelka L, et al. Final overall survival: fulvestrant 500mg vs 250mg in the randomized CONFIRM trial. J Natl Cancer Inst 2014;106:djt337.
- Ellis MJ, Llombart-Cussac A, Feltl D, et al. Fulvestrant 500 mg versus anastrozole 1 mg for the first-line treatment of advanced breast cancer: overall survival analysis from the phase II FIRST study. J Clin Oncol 2015;33:3781-3787.
- Ellis MJ, Bondarenko IM, Trishkina E, et al. FALCON: a phase III randomised trial of fulvestrant 500 mg vs anastrozole for hormone receptor-positive advanced breast cancer; Ann Oncol 2016;27 (s1): Abstract LBA 14_PR.
- Finn RS, Martin M, Rugo H, et al. Palbociclib and letrozole in advanced breast cancer. N Engl J Med 2016;375:1925-1936.
- Hortobagyi G, Stemmer SM, Burris HA, et al. Ribociclib as first-line therapy for HR-positive, advanced breast cancer. N Engl J Med 2016;375:1738–1748.
- Turner NC, Huang Bartlett C, Cristofanilli M, et al. Palbociclib in hormone-receptor-positive advanced breast cancer. N Engl J Med 2015;373:1672-1673.
- Fasching PA, Jerusalem GHM, Pivot X, et al. Phase III study of ribociclib (LEE011) plus fulvestrant for the treatment of postmenopausal patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2–) advanced breast cancer (aBC) who have received no or only one line of prior endocrine treatment (ET): MONALEESA-3 [abstract]. J Clin Oncol 2016;34 (suppl). Abstract TPS624.
- Mehta RS, Barlow WE, Albain KS, et al. Combination anastrozole and fulvestrant in metastatic breast cancer. N Engl J Med 2012;367:435-444.
- Bergh J, Jönsson PE, Lidbrink EK, et al. FACT: an open-label randomized Phase III study of fulvestrant and anastrozole in combination compared with anastrozole alone as first-line therapy for patients with receptor-positive postmenopausal breast cancer. J Clin Oncol 2012; 30:1919-1925.
- Kornblum NS, Manola J, Klein P, et al. PrECOG 0102: A randomized, double-blind phase II trial of fulvestrant plus everolimus or placebo in post-menopausal women with hormone-receptor positive, HER2-negative metastatic breast cancer resistant to aromatase inhibitor therapy [abstract]. Presented at the 2016 San Antonio Breast Cancer Symposium; December 6-10, 2016; San Antonio, Texas. Abstract S1-02.
- Baselga J, Campone M, Piccart M, et al. Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. N Engl J Med 2012;366:520-529.
- Robertson JF, Bondarenko IM, Trishkina E, et al. Fulvestrant 500 mg versus anastrozole 1 mg for hormone receptor-positive advanced breast cancer (FALCON): an international, randomized, double-blind phase 3 trial. Lancet 2016;388:2997-3005.
- McDonnell DP, Wardell SE, Norris JD. Oral selective estrogen receptor downregulators (SERDs), a breakthrough endocrine therapy for breast cancer. J Med Chem 2015;58:4883-4887.
- Fisher B, Costantino JP, Wickerham DL, et al. Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P–1 Study. J Natl Cancer Inst 1998;90:1371–1388.
- A study of taselisib + fulvestrant versus placebo + fulvestrant in patients with advanced or metastatic breast cancer who have disease recurrence or progression during or after aromatase inhibitor therapy (SANDPIPER). Available at https://clinicaltrials.gov/ct2/show/NCT02340221 Accessed May 2, 2017.
- Study assessing the efficacy and safety of alpelisib plus fulvestrant in men and postmenopausal women with advanced breast cancer which progressed on or after aromatase inhibitor treatment. (SOLAR-1). Available at https://clinicaltrials.gov/ct2/show/NCT02437318 Accessed May 2, 2017.