Adjuvant Targeted Treatment of Early Hormone Receptor-positive HER2-negative Breast Cancer: Olaparib, Abemaciclib or Ribociclib – Which One, How and For Whom?

Abstract

With around 70000 new cases every year, breast cancer (BC) continues to be the most prevalent form of cancer. Hormone receptor-positive, HER2-negative (HR+/HER2−) BC is the most common type and accounts for around 70% of cases of early BC (eBC). The development of new drugs in recent years has significantly improved the survival of patients with eBC. Alongside established endocrine therapy (ET) options such as tamoxifen, aromatase inhibitors (AI), and GnRH analogs, additional treatment options such as CDK 4/6 inhibitors (abemaciclib and ribociclib) and the PARP inhibitor (olaparib) are now also available. To facilitate their use in clinical practice, this article provides a summary of the current information on the use of these drugs in clinical practice.

Abemaciclib was approved for the adjuvant treatment of HR+/HER2− eBC in cases with positive lymph node involvement in 2022. The MonarchE trial showed that the addition of abemaciclib to ET improved invasive disease-free survival (iDFS) after 5 years by around 7.6% in patients with a high risk of recurrence. Ribociclib, another CDK4/6 inhibitor, was recently approved based on the results of the NATALEE trial. When combined with non-steroidal AIs, ribociclib showed a significant iDFS benefit of 4.9% after 4 years in node-positive and node-negative patients with a high risk of recurrence. The PARP inhibitor olaparib may be used to treat patients with BRCA germline mutation and HR+/HER2− eBC and a high risk of recurrence (CPS-EG score ≥ 3). The OlympiA approval study showed an iDFS benefit of 7.3% after four years and a benefit of 3.4% for overall survival.

In summary, targeted therapies are expanding the range of adjuvant treatment options for patients with HR+/HER2− eBC and a higher risk of recurrence. Treating physicians are increasingly facing the challenge of choosing the optimal therapy for their patients. To do so, it is essential to carefully weigh up potential side effects against the expected benefit of treatment on a case-by-case basis.

Keywords

abemaciclib - ribociclib - olaparib - breast cancer - adjuvant therapy

Introduction

With around 70000 new cases every year, breast cancer (BC) continues to be the most prevalent form of cancer [1]. Hormone receptor-positive, HER2-negative (HR+/HER2−) BC is the most common type and accounts for around 70% of cases of early BC (eBC) [1] [2]. The development of numerous new drugs in recent years has significantly improved the survival of patients with eBC, especially patients with HR+/HER2− eBC [3]. Established endocrine therapy options such as the selective estrogen-receptor modulator tamoxifen, aromatase inhibitors (AI), and gonadotropin-releasing hormone agonists (GnRH-A) have been expanded by the addition of further targeted treatment options [4] [5] [6]. They include the inhibitors of cyclin-dependent kinases 4/6 (CDK 4/6i) abemaciclib and ribociclib and the poly (ADP-ribose) polymerase inhibitor (PARPi) olaparib. In some cases, approvals and indications for these substances overlap, providing several possible treatment options. This article provides a convenient overview for clinical practice and presents a comparative summary of the information currently available for these medications.

Abemaciclib

The first CDK4/6 inhibitor approved for the adjuvant treatment of eBC, abemaciclib was approved for use by the European Medicines Agency (EMA) in April 2022 [7]. It is a CDK4/6 inhibitor with the highest level of activity against cyclin D1/CDK4. The successful establishment of abemaciclib in the treatment of metastatic HR+/ HER2− BC was the basis for the MonarchE pivotal trial [8]. A total of 5601 patients (36 men, 0.6%; 5565 women, 99.04%) with eBC and a high risk of recurrence were included in this prospective randomized phase 3 trial. 43.8% of the women (2453) were premenopausal. Other relevant inclusion criteria were adequate organ function in terms of hematological and hepatological factors (s. [Table 1]). Radiotherapy and/or chemotherapy were possible but not absolutely necessary for inclusion in the study. However almost all patients had neoadjuvant (2055; 36.69%) or adjuvant (3559; 61.86%) chemotherapy. Randomization had to occur within 16 weeks after surgery.

Table 1 Comparison of approved adjuvant targeted therapies for early hormone receptor-positive, HER2-negative breast cancer.

		Abemaciclib	Ribociclib	Olaparib
Data refers to intervention arm. ER+ = estrogen receptor-positive; GnRH-A = gonadotropin-releasing hormone agonist; iDFS = invasive disease-free survival; LN = lymph node; MDS = myelodysplastic syndrome; OS = overall survival * Central receptor status based exclusively on female Chinese patients
Category		CDK4/6 inhibitor	CDK4/6 inhibitor	PARP inhibitor
Brand name		Verzenios	Kisqali	Lynparza
Manufacturer		Lilly	Novartis	AstraZeneca
Standard single dose		150 mg (= 1 tablet)	400 mg (= 2 tablets)	300 mg (= 2 tablets)
Dosage scheme		2×/day	1×/day for 21 days; 7-day break	2×/day
Number of tablets taken per cycle (28 days)		56	42	112
Duration of therapy		2 years	3 years	1 year
Approved since		April 2022	November 2024	August 2022
Approved for patients with		≥ 4 involved LNs or 1–3 involved LNs and tumor size of more than 5 cm (T3 stage) or poorly differentiated tumor (G3)	node-positive or node-negative, T2 and either G3 or G2 with Ki67 ≥ 20%/high genomic risk	BRCA germline mutation and at least 4 involved lymph nodes or CPS + EG score ≥ 3
Pivotal trial		MonarchE	NATALEE	OlympiA
Primary endpoint of the trial		iDFS	iDFS	iDFS
Number of patients in the study		5637	5101	1836 (of which HR+: 325)
Percentage of patients who completed the therapy within the planned timeframe		69.0%	62.8%	89.2%
Endocrine combination therapy		Tamoxifen, letrozole, anastrozole, exemestane, GnRH-A	Letrozole, anastrozole, GnRH-A	Tamoxifen, letrozole, anastrozole, exemestane, GnRH-A
Percentage of patients who had chemotherapy	Neoadjuvant	1026 (36.5%)	1085 (42.6%)	460 (49.9%)
	Adjuvant	1734 (61.8%)	1223 (48%)	461 (50.1%)
Grading in the treatment arm	G1	209 (7.4%)	218 (8.6%)	2 (0.2%)
	G2	1377 (49.0%)	1458 (57.2%)	128 (13.9%)
	G3	1086 (38.7%)	521 (20.4%)	562 (61.0%)
Percentage of lobular carcinomas		360 (12.8%)	455 (17.9%)	Not reported
Ki67 in the treatment arm	< 20%	953 (33.9%)	Not reported	Not reported
	≥ 20%	1262 (44.9%)	Not reported	Not reported
Progesterone receptor-negative in the treatment arm		298 (10.6%)	Not reported	616 (66.9%), of which 31 (3.4%) were ER+ tumors*
iDFS benefit after 4 years		6.0% (86.0% vs. 80.0%) HR 0.68; 95% CI: 0.60–0.77	4.9% (88.5% vs. 83.6%) HR 0.72; 95% CI: 0.61–0.84	7.3% (82.7% vs. 75.4%) HR 0,63; 95% CI: 0.50–0.78
OS benefit		Data currently not mature	Data currently not mature	3.4% (89.8% vs. 86.4%) HR 0.68; 95% CI: 0.47–0.97
Special adverse events (for full particulars, see prescribing information)		Neutropenia, diarrhea, thrombosis, pneumonitis, hepatotoxicity,	Neutropenia, hepatotoxicity, QT-interval prolongation	Nausea/vomiting neutropenia, anemia, MDS
Dominant adverse effects in the trial (general)		Diarrhea, fatigue, abdominal pain, nausea, leukopenia/neutropenia	Neutropenia, arthralgia, nausea, headache, fatigue, elevated liver function tests, QT-interval prolongation	Fatigue, anemia, nausea/vomiting, headache, diarrhea, neutropenia
Discontinuation of therapy due to side effects		180 (6.4%)	477 (18.9%)	98 (10.8%)
Monitoring in addition to laboratory tests		Not recommended in the prescribing information	ECG on Day 1 and Day 14	Not necessary
Carry-over effect		Yes	Yes	Yes
Contains lactose		Lactose monohydrate	No	No
Dose reductions		100 mg and 50 mg	200 mg	200 mg und 100 mg

Patients in the intervention arm received abemaciclib 150 mg orally, twice a day for two years together with tamoxifen or an AI with or without a GnRH-A. The primary endpoint of the trial was the invasive disease-free survival (iDFS) with overall survival (OS) one of the secondary endpoints.

A total of 1938 (69.0%) patients in the intervention arm and 2312 (81.7%) out of a total of 2829 patients in the control arm completed the two-year therapy. The most common reasons for discontinuing therapy were: recurrence (155 patients), decision of the patient (149 patient), and side effects (180 patients) [4].

The study achieved its primary goal with a significant iDFS benefit in the intervention arm of 6.4% after four years and 7.6% (HR 0.68; 95% CI: 0.60–0.77) after 54 months of follow-up [4]. The effect obtained by the addition of abemaciclib persisted even after the two-year treatment period had ended (carry-over effect). A numerical (208 vs. 234) but not significant benefit was observed for overall survival, however the data for this endpoint are not yet mature [4].

Abemaciclib has been approved in Germany for patients with HR+/HER2− eBC and more than four involved lymph nodes or with 1–3 involved lymph nodes and a tumor size of more than 5 cm (T3 stage) or a poorly differentiated tumor (G3) [7].

Ribociclib

Ribociclib recently received a positive assessment by the EMA based on the results of the NATALEE trial [6] as a second CDK4/6 inhibitor for the adjuvant treatment of HR+/HER2− eBC and has now also been approved for use in Germany for the adjuvant treatment of HR+/HER2− eBC [9]. The pivotal trial included a total of 5101 patients (20 men, 0.4%) with HR+/HER2− eBC. 88.2% of patients received chemotherapy (neoadjuvant 42.6%; adjuvant 48.0%), and 43.7% of female patients were premenopausal [6]. Prior to inclusion in the study patients could receive adjuvant or neoadjuvant endocrine therapy for up to 12 months.

Patients with anatomical stage III, IIB or, under certain conditions, stage IIA (1. node-positive, or 2. node-negative with either G3 or G2 and Ki67 > 20% or G2 and a high genomic risk) were included in the study [6] [10] [11].

Patients were randomized 1 : 1 into an intervention arm to receive combination therapy consisting of ribociclib 400 mg daily (corresponds to a reduced dose compared to therapy for metastatic BC) administered orally for 21 days followed by a seven-day pause for a total of three years combined with at least five years of continuous ET. Only non-steroidal AIs (letrozole 2.5 mg/day p. o. or anastrozole 1 mg /day p. o.) were permitted, with the addition of GnRH-A for male patients and premenopausal female patients. Outcomes were compared with those of a control arm where patients received AI monotherapy (letrozole or anastrozole) with or without the addition of GnRH-A according to menopausal status.

The primary endpoint of the study was iDFS. An iDFS benefit for combination therapy with ribociclib was found after three years and after four years of 2.7% and 4.9%, respectively (90.8% vs. 88.1% after 3 years; 88.5% vs. 83.6% after 4 years) [12]. An iDFS benefit of 5.1% after four years was also found for the subgroup of node-negative patients [12]. A significant difference in overall survival has not yet been observed as the follow-up time to date is only 44.2 months (HR 0.827; 95% CI: 0.636–1.074). It is important to be aware that the data on this are not yet mature [12].

62.8% of patients completed the three-year treatment with ribociclib, 20% discontinued treatment early because of adverse effects [12]. No other reasons to discontinue treatment were reported. The most common side effects leading to discontinuation of treatment were changes in liver function tests (8.9%) and arthralgias (1.3%) [13]. These and other common, particularly important side effects are listed in [Table 1].

In summary, based on the results of the NATALEE trial, the CDK4/6 inhibitor ribociclib has been approved for adjuvant therapy since November 2024 to treat patients with HR+/HER2− eBC and a high risk of recurrence as well as, in contrast to abemaciclib, to treat patients with an intermediate risk of recurrence (see [Fig. 1]). Another difference between the two CDK4/6 inhibitors is the endocrine combination. While abemaciclib has been approved for use in combination with an AI or tamoxifen, ribociclib has only been approved in combination with a non-steroidal AI.

Fig. 1 Clinicopathological parameters as a decision-making support for adjuvant targeted therapy with CDK4/6 inhibitors to treat early hormone receptor-positive, HER2-negative breast cancer. Drugs are listed alphabetically. * Only for G3 or tumor size of ≥ 5 cm. ^# Only for G3 or G2 with Ki67 ≥ 20% or G2 and a high genomic risk.

Olaparib

Olaparib has been approved for the adjuvant treatment of eBC since August 2022. Olaparib is a PARP inhibitor, and duration of therapy is one year. The precondition to receive this treatment is confirmation of a BRCA germline mutation. Approval was based on the OlympiA trial, which included 1828 female patients and six male patients with HER2-negative breast cancer and a high risk of recurrence. When counseling HR+/HER2− patients, it is important to know that this cohort only constituted a small subgroup in the OlympiA study (18.2% [168 people] in the olaparib arm and 17.2% [157 people] in the placebo arm) as the study included both patients with HR+/HER2− eBC and patients with triple negative eBC. Twenty-two people in the olaparib group and 11 people in the placebo group received no endocrine therapy despite having HR+ BC. A total of 572 (62.2%) premenopausal patients were included in the trial.

The primary inclusion criterion for the OlympiA trial was the indication for neoadjuvant or adjuvant chemotherapy. About 50% of cases had adjuvant and about the same percentage had neoadjuvant therapy which had to include at least one taxane or anthracycline. The definition of a high risk of recurrence for HR+ eBC was amended as follows: at least four involved lymph nodes or a CPS + EG (clinical and pathologic stage [CPS] & estrogen receptor status and histologic grade [EG]) score of at least 3 [14]. The CPS-EG score is a prognostic model used to estimate the probability of recurrence in patients with HR+/HER2− eBC after neoadjuvant chemotherapy. It is calculated based on the clinical tumor stage (cT), the clinical node status (cN), the pathological tumor stage (pT), the pathological node status (pN), the estrogen receptor status, and the grading.

Patients were randomized 1 : 1 into a placebo or an intervention arm. Patients in the intervention arm received olaparib 300 mg orally 2× daily for 12 months. Permitted endocrine therapies were an AI, GnRH analogs, and/or tamoxifen. Treatment had to be started within 2–12 weeks after conclusion of the primary therapy (radiotherapy or surgery). 25% of patients had a dose reduction and therapy was discontinued early in 9.9% of cases due to side effects [5]. The most common reasons for discontinuing therapy were nausea (2.0%), anemia (1.8%) and fatigue (1.3%). In the placebo arm, 42 (4.6%) patients discontinued therapy.

The primary endpoint of the study was iDFS. Nevertheless, the OS (secondary endpoint) also improved (hazard ratio 0.68; 95% CI: 0.47–0.97), which corresponds to an absolute OS rate benefit of 3.4% after four years [15]. Results refer to the total study population, in other words, both to patients with TNBC and to patients with HR+/HER2− eBC. The serious adverse effect myelodysplastic syndrome occurred in 2 (0.2%) and 3 (0.3%) of patients receiving olaparib or placebo respectively [5].

Olaparib has been approved in Germany to treat patients with HR+/HER2− eBC, a confirmed BRCA germline mutation, and a high risk of recurrence, who have completed neoadjuvant or adjuvant chemotherapy. The approval does not clearly define what constitutes a high risk of recurrence; in the OlympiA trial this was defined as at least four involved lymph nodes in patients who had adjuvant chemotherapy or a pathological residual tumor after neoadjuvant chemotherapy together with a CPS-EG score of ≥ 3 [5].

Real World Data

Clinical trials only partly reflect the reality of treatment. This is why real-world datasets are very important [16]. There are currently no real-world evaluations of patient populations treated for eBC with ribociclib and adjuvant therapy, as the US approval was only issued in September 2024 and the European approval followed in November 2024 [17]. A German retrospective real-world analysis showed that 43% of patients with HR+/HER2− eBC could potentially meet the inclusion criteria of the NATALEE trial, and this finding was supported by studies in other countries [18] [19] [20]. This underlines the high clinical relevance of ribociclib, although there is an overlap with the indications for treatment with abemaciclib and olaparib. This would mean that almost every second patient with HR+/HER2− eBC could potentially receive combined endocrine-based adjuvant therapy. It remains to be seen which and how many patients will actually receive these therapies in clinical practice.

To meet the criteria for treatment with olaparib, the first decisive step for patients with HR+/HER2− BC was genetic testing. A real-world analysis by Dannehl et al. provided an important pointer for clinical practice. It showed the importance of carrying out BRCA germline testing in a HR+/HER2− cohort with eBC, with the results of testing determining the choice of therapy. According to the criteria for hereditary cancer testing of the German Consortium for Hereditary Breast and Ovarian Cancer, only 26.2% of the patients who met the high-risk criteria of the OlympiA trial would have been approved for germline testing [21]. The current recommendations issued by the Gynecological Oncology Working Group (AGO) in Germany therefore support genetic testing in all patients who develop disease before the age of 65 [22]. Real-world data from Sweden and the USA also show a survival disadvantage, especially for HR+/HER2− patients who are at higher risk according to the OlympiA criteria, and suggested that considering genetic testing in clinical practice is essential [19] [23]. It is important to be aware that patients with eBC and pathogenic mutations of the BRCA1 gene are more likely to have higher grading and a triple-negative phenotype, while mutations in the BRCA2 gene are more likely to be correlated with a HR+ subtype [24].

The strongest evidence based on real-world data is available for abemaciclib as it has been approved longest. Around 17–19.5% of patients with HR+/HER2− eBC meet the inclusion criteria of the MonarchE trial [2] [19]. A study by Drowne et al. showed fewer grade 3/4 adverse effects (12.5% vs. 35.7%) and fewer discontinuations of therapy (18.8% vs. 57.1%) for abemaciclib administered in the adjuvant setting [25]. These findings were confirmed by the study of Neralla et al., although about 51% out of a total of 55 patients required dose reductions of abemaciclib [26]. Monitoring proposals for clinical practice which take account of the relevant adverse effects and are based on the prescribing information and clinical experience have been summarized for all three substances and are shown in [Fig. 2]. It is known that dose reduction in the MonarchE trial caused no survival disadvantage with regards to iDFS [27]. Dose reduction data for ribociclib is only available for the metastatic setting but no survival disadvantage was reported in this context [28].

Fig. 2 Proposed monitoring during adjuvant treatment with targeted substances to treat early hormone receptor-positive, HER2-negative breast cancer. CBC Diff.: complete blood count with differential, AST: aspartate aminotransferase, ALT: alanine aminotransferase, ECG: electrocardiogram. Recommendations in bold correspond to those given in the prescribing information, recommendations in italics are amendments proposed by the authors. Note: The authors of this article wish to point out that the information presented here should serve as an orientation. Clinical decisions must be made on a case-by-case basis and additional measures as described in the prescribing information must be taken when abnormalities are present [46] [47] [48]. The responsibility for these measures lies with the treating physician.

More than 90% of patients in both the NATALEE and the MonarchE trials had adjuvant or neoadjuvant chemotherapy. However, the real-world data of 636 patients from Brazil shows that the possible benefit of adjuvant CDK4/6 inhibitors in a chemotherapy-naive cohort is very limited and that the outcome with just endocrine therapy is already very good [31].

CDK4/6i after Olaparib

Patients were able to start treatment with the relevant CDK4/6i up to 16 months after surgery in the MonarchE trial [8] and up to 12 months after the start of endocrine therapy in the NATALEE trial [6]. For patients with a high risk of recurrence who are “very motivated,” the American Society for Clinical Oncology (ASCO) has suggested the possibility of sequential therapy, starting with olaparib followed by the appropriate CDK4/6i [32]. There are currently no clinical data available on the use of CDK4/6i after olaparib.

Role of Endocrine Therapy

Adjuvant endocrine therapy is known to reduce the risk of recurrence by about 50% compared to placebo [33] [34].

Three medication classes are currently available in Germany for adjuvant endocrine treatment of HR+/HER2− eBC. They are the selective estrogen receptor modulator tamoxifen, AIs, and GnRH-A. Tamoxifen may be used to treat both premenopausal and postmenopausal patients. AIs may be used by themselves to treat postmenopausal patients but must only be administered in combination with a GnRH-A when treating premenopausal women. The combination of a GnRH-A and an AI appears to be more effective than the combination of a GnRH-A and tamoxifen but is also associated with more adverse effects. All three classes were used in the OlympiA and the MonarchE trials. The NATALEE trial did not include treatment with exemestane or tamoxifen.

The selective estrogen receptor modulator tamoxifen has demonstrated its effectiveness in numerous studies. Nowadays, tamoxifen is mainly used to treat premenopausal patients [33] [35] [36]. Tamoxifen was found to reduce the risk of recurrence by about 40% over a five-year treatment period [33]. The standard dose is 20 mg, taken once a day.

The study by Giacchetti has presented data showing that taking tamoxifen in the evening could be associated with better effectivity and improved iDFS [37]. Similarly, the ATLAS and aTTOM studies showed that taking tamoxifen over five years also appears to be beneficial with regards to overall survival [38] [39]. The Gynecological Oncology Working Group (AGO) currently recommends that patients with an increased risk of recurrence should take tamoxifen for 7–10 years [40]. In addition to other adverse effects, tamoxifen can increase the risk of thrombosis and prolong the QT-interval [41]. This needs to be taken into account when deciding on the appropriate therapy and throughout therapy [42].

AIs are grouped into non-steroidal (letrozole and anastrozole) and steroidal (exemestane) aromatase inhibitors, although clinical studies did not find any differences in efficacy between the individual AIs [43]. All three substances are administered once a day; letrozole (2.5 mg) and anastrozole (1 mg) can be taken independently of meals whereas the recommendation for exemestane (25 mg) is to take it during mealtimes. There is currently no evidence regarding a preferred time of intake for AIs [37]. AIs are indicated for cases with HR+/HER2− eBC, especially postmenopausal patients. When combined with a GnRH-A, AIs were found to have a better iDFS compared to tamoxifen and no difference in OS in premenopausal patients with a higher risk of recurrence [44].

Bisphosphonates, which target osteoclasts, are drugs which also play a role in the adjuvant treatment of HR+/HER2− eBC [40] [45] [29]. In addition to reducing the risk of osteoporosis, it was shown that administration of bisphosphonates reduces the risk of recurrence in bone and prolongs breast cancer-specific survival, but only in postmenopausal patients [45]. Bisphosphonates were permitted in trials, but in the NATALEE trial they were only used to treat osteoporosis but not to prevent bone metastasis [6]. Recommended agents are zoledronate, alendronate, ibandronate and risedronate and clodronate. Treatment should be maintained for 2–5 years [40] [29] [30].

Summary

In summary, the new targeted therapies with abemaciclib, ribociclib and olaparib are an important additional therapeutic option in the adjuvant setting for patients with HR+/HER2− eBC and a high risk of recurrence. Depending on the medication, therapy may be indicated for both node-positive and node-negative BC. Regular monitoring, including of additional adverse effects, represents a new logistical challenge in clinical practice for both patients and the treating medical teams. Decisions about the choice of therapy must be made in cooperation with the patient and the patients must give their informed consent to receive the benefit of these new therapies in addition to having endocrine therapy. Treatment decisions must always take the patient’s individual risk into consideration.

Conflict of Interest

SL: Lilly, Novartis, Roche, Gedeon Richter, Theramex. KP: Gilead, Novartis, Pfizer. HS: Novartis, Gilead, Daiichi Sankyo. EL: Astra Zeneca, Lilly. AF: Clovis, Roche, Pfizer, GSK, Novartis. BR: AstraZeneca, Novartis. VF: Solventum, Novartis, BD. WJ: AstraZeneca, Cellgene, Chugai, Daiichi Sankyo, Aisai, ExactScience, GSK, Janssen, Lilly, Menarini, MSD, Novartis, Sanofi-Aventis, Roche, Pfizer, Seagen, Gilead, Inivata, Guardant Health. SH: MSD, Novartis; AstraZeneca, SAGA; Roche, Pfizer, GSK, Clovis, Immunogen, Abbvie, Eisai.

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Publication History

Received: 28 November 2024

Accepted after revision: 15 March 2025

Article published online:
22 April 2025