Introduction

Novel drugs such as immune checkpoint inhibitors, inhibitors of cyclin-dependent kinase (CDK) 4/6 or poly(ADP-ribose)polymerase (PARP) as well as small molecule tyrosine kinase inhibitors (TKIs), novel antioestrogens and antibody–drug conjugates (ADCs) have changed treatment standards in breast cancer, resulting in reduced recurrence risk in early stage disease and/or in improved progression-free survival (PFS) or overall survival (OS) in the metastatic setting. Still, room for further improvement remains and novel treatment approaches are urgently required in patients relapsing despite adjuvant therapy and metastatic breast cancer patients progressing on the currently available standard treatment options. This article aims at summarizing data on promising novel drugs or treatment strategies that might find a place in clinical routine in the near future; it is not intended as a systematic review of all novel drugs in clinical development.

ADCs and novel antibodies

The concept of magic bullet targeted drugs—initially intended for the treatment of infective agents—dates back more than a century [1]; trastuzumab emtansine (T-DM1), an ADC consisting of trastuzumab and the antimicrotubule agent emtansine linked by a noncleavable thioether linker molecule, was the first ADC approved for use in solid cancers. Based upon the results of the EMILIA trial, T‑DM1 became the standard-of-care as second-line therapy in metastatic HER2-positive breast cancer [2] and remains the standard for the postneoadjuvant treatment of HER2-positive early breast cancer in patients without pathologic complete response (pCR) to date with an OS benefit recently demonstrated in the KATHERINE study [3, 4]. While well tolerated, the next generation ADC trastuzumab deruxtecan (T-DXd) was shown to vastly improve PFS and OS over T‑DM1 in metastatic HER2-positive disease [5], usually attributed to a higher drug-to-antibody ratio (DAR), a cleavable linker technology and high membrane permeability of the payload deruxtecan, a potent topoisomerase‑1 inhibitor, resulting in a bystander effect targeting neighbouring cells [6]. Besides its established role in the HER2-positive subtype, the DESTINY-Breast04 trial recently showed T‑DXd to improve progression-free survival (PFS; hormone-receptor positive 10.1 vs. 5.4 months; hazard ratio [HR] 0.51; 95% confidence interval [CI] 0.40–0.64; p < 0.0001) and OS (hormone-receptor positive 23.9 vs. 17.5 months; HR 0.64; 95% CI 0.48–0.86; p = 0.0028) over conventional chemotherapy in pretreated patients with HER2-low expressing disease as well, defined as 1+ by immunohistochemistry or as 2+ in the absence of ERBB2 gene amplification [7]. Therefore, T‑DXd is the first HER2-directed drug active in tumours where HER2 is not the driver of progression but rather serves as target antigen for ADC binding. What degree of HER2 expression—if any—is required for T‑DXd remains a matter of debate and the DESTINY-Breat06 (NCT04494425) trial includes a group of patients with ultralow HER2 expression, potentially broadening the indication for T‑DXd in the future. In HER2-positive breast cancer, DESTINY-Breast09 (NCT04784715) compares T‑DXd with or without pertuzumab with a standard first-line taxane, trastuzumab and pertuzumab regimen, while DESTINY-Breast05 (NCT04622319) compares T‑DXd with T‑DM1 in the postneoadjuvant setting in patients with residual disease at surgery after neoadjuvant treatment.

TROP2 is a surface antigen commonly expressed in human malignancies making it an attractive target antigen for ADCs as well. Sacituzumab govitecan (SG), an ADC consisting of a TROP2-directed antibody and SN38, the active metabolite of irinotecan, improved OS over conventional chemotherapy in pretreated metastatic triple-negative breast cancer (mTNBC) in the phase III ASCENT trial [8]. More recently, improvement of PFS (5.5 months vs. 4.0 months; HR 0.66; 95% CI 0.53–0.83; p = 0.0003) and OS (14.4 vs. 11.2 months; HR 0.79; 95% CI 0.65–0.96, p = 0.020) over conventional chemotherapy were also shown in patients with heavily pretreated luminal disease in the phase III TROPiCS-02 trial [9, 10]. Several trials are currently investigating SG in earlier treatment lines and in early stage disease. Among them, the phase III ASCENT-03 (NCT05382299) trial compares SG with nab-paclitaxel or paclitaxel as first-line therapy in patients with PD-L1-negative mTNBC or in patients with PD-L1-positive mTNBC if they had received prior therapy with an immune checkpoint inhibitor (IO) in the early setting. ASCENT-04 (NCT05382286) is of particular interest, as this phase III trial compares SG plus pembrolizumab with chemotherapy of physician’s choice plus pembrolizumab in patients with PD-L1-positive mTNBC; therefore, this study could establish the superiority of ADC plus IO over conventional chemotherapy plus IO. Furthermore, ASCENT-05 (NCT05633654) and the German Breast Group SASCIA trial (NCT04595565) are investigating SG in the postneoadjuvant setting in patients without pathologic complete response (pCR) to neoadjuvant chemotherapy. Beside several other smaller studies, the phase II SWOG 2007 trial (NCT0464791) is of clinical relevance: patients with mTNBC are at high risk for developing brain metastases (BM). In contrast to HER2-positive breast cancer, however, no established systemic treatment option is yet available. This trial therefore investigates the potential activity of SG in a mTNBC population with active (i.e. newly diagnosed or progressing) BM.

Several further ADCs are currently under clinical development. Datopotamab deruxtecan (Dato-DXd) binds deruxtecan via the same cleavable linker as in T‑DXd to a TROP2 directed antibody. In the TROPION-PanTumor01 phase I basket trial, 44 patients with heavily pretreated mTNBC were included [11]. In this population having received a median of three prior treatment lines, Dato-DXd yielded a clinically relevant activity with a 32% response rate; median PFS was 4.4 months and median OS 13.5 months. Of note, activity was lower in patients having received prior topoisomerase‑1 inhibitor-based ADCs (total n = 14; prior SG n = 11), suggesting that sequential administration of ADCs with identical target and cytotoxic payloads of the same class may not be feasible. Besides mTNBC, Dato-DXd is also being investigated in pretreated metastatic luminal disease. In the HR-positive/HER2-negative cohort of TROPION-PanTumor01, 41 patients were included [12]; virtually all patients had received prior CDK4/6-inhibitor therapy and the median number of prior treatment lines for metastatic disease was n = 5. Dato-DXd yielded an objective response rate (ORR) of 27% and median PFS was 8.3 months. Based upon these results, Dato-DXd was compared to chemotherapy by physician’s choice in luminal/HER2-negative patients after prior exposure to endocrine therapy and 1–2 lines of prior chemotherapy in the randomized phase 3 TROPION-Breast01 trial (NCT05104866) [13]. In this population, median PFS was prolonged from 4.9 months to 6.9 months (HR 0.63; 95% CI 0.52–0.76); OS survival data are not yet mature, and these data are required to fully anticipate the potential role of Dato-DXd in the continuum of luminal breast cancer treatment. Regarding tolerability, stomatitis and nausea were the most common side effects, with approximately 10% of patients experiencing ≥ 3 grade stomatitis [11, 12]. In addition, ocular dryness may occur [13]. Therefore, an appropriate mitigation plan for stomatitis is required.

Further development of Dato-DXd in breast cancer is focusing on earlier treatment lines (TROPION-Breast02; NCT05374512) and the postneoadjuvant setting with or without the immune checkpoint inhibitor durvalumab in non-pCR patients (TROPION-Breast03; NCT05629585); similar to SWOG 2007, the phase II TUXEDO-2 trial is investigating Dato-DXd in the context of active TNBC BM (NCT05866432).

HER3 is another option for ADC targeting. Patritumab deruxtecan (HER3-DXd) was found to induce responses in all three breast cancer subtypes (luminal disease: RR 30.1%; HER2-positive disease: RR 42.9%; TNBC: RR 22.6%) [14]. At the 2023 Annual Meeting of the American Society of Clinical Oncology, preliminary results of a single-arm phase II trial of HER3-DXd in patients with pretreated HER2-negative metastatic breast cancer were presented. ORR in the overall population (n = 60) was 35.0%, and irrespective of the degree of HER3 expression; numerically lower ORR were observed in TNBC compared with luminal BC (21.1% vs. 41.1%). Nausea, fatigue and diarrhoea were the most common side effects, but only few grade 3/4 adverse events were recorded. Currently, the phase 2 TUXEDO-3 trial is evaluating HER3-DXd in patients with active brain metastases from breast and non-small cell lung cancer as well as patients with leptomeningeal disease (NCT05865990).

In summary, these data support the concept of ADC therapy in advanced breast cancer (aBC) but point at the urgent need to better understand mechanism of resistance to ADCs and generate clinical data on the potential activity of ADCs after ADCs.

Besides development of next-generation ADCs, other advances in the field of antibody technology include bispecific antibodies. Zanidatamab (ZW25) is an antibody targeting HER2 extracellular domains 2 and 4 (the target structures of pertuzumab and trastuzumab, respectively). In a phase 1b/2 study (n = 21 patients), the combination of zanidatamab and docetaxel as first-line therapy yielded a promising response rate of 90.5% [15]. More recently, zanidatamab combined with palbociclib and fulvestrant was investigated in a single-arm phase II study [16]. Overall, 51 patients with HER2 and hormone-receptor co-positive disease were included; virtually all participants had received prior treatment with trastuzumab, pertuzumab and T‑DM1; in addition, approximately one quarter had received prior T‑DXd as well. In this heavily pretreated population, median PFS was 12 months (95% CI 8–15) and an objective response rate of 35% was observed with even more pronounced activity in the subset of patients with centrally confirmed HER2-positive disease. Beside indicating clinically relevant activity of zanidatamab, these results also hint at the potential role of CDK4/6 inhibitors for the treatment of luminal B/HER2-positive metastatic breast cancer.

Novel options for targeting the oestrogen receptor and growth factor pathways

The combination of endocrine therapy and CDK4/6 inhibitors (CDKi) is currently regarded as the standard first-line treatment approach in patients with hormone receptor (HR)-positive/HER2-negative metastatic disease as pivotal studies have shown a consistent improvement in PFS over endocrine therapy alone; more recently, a survival benefit was also reported with the CDKis ribociclib [17,18,19] and abemaciclib [20]. Despite prolonged disease control, patients will ultimately progress and require alternative therapy. While subsequent single-agent endocrine therapy may be of limited activity in this setting, combining endocrine therapy with small molecule inhibitor of growth factor pathways is of interest. AKT is a druggable molecule in the PI3K/mTOR/AKT pathway and capivasertib is a pan-AKT kinase inhibitor [21]; the combination of capivasertib and fulvestrant was compared with placebo and fulvestrant in the prospective, randomized, placebo-controlled phase 3 CAPitello-291 trial [22]. A total of 708 patients were accrued; 75% of patients had received prior endocrine therapy for metastatic disease, and approximately two-thirds had prior exposure to a CDKi as well. Activating alterations in the PI3K/mTOR/AKT pathway were present in approximately 40% of the population. Addition of capivasertib to fulvestrant improved PFS to a clinically relevant extent from 3.6 months to 7.2 months (HR 0.60; 95% CI 0.51–0.71; p < 0.001), with a larger benefit observed in participants with tumours harbouring pathway alterations; a numerical OS improvement was also observed (HR 0.74; 95% CI 0.56–0.98). Treatment discontinuation rate in the capivasertib arm was 13%. As expected, main toxicities consisted of diarrhoea (72.4%; grade 3 diarrhoea 9.3%) and rash (38.0% all types of rash; grade 3 12.1%). Other relevant side effects were nausea (34.6%) and hyperglycaemia (16.3%). While severe hyperglycaemia was rare (grade 3/4 2.3%), the side-effect profile clearly indicates the importance of optimal toxicity management in clinical practice. Based upon the results of the CAPitello-291 trial, the US Food and Drug Administration (FDA) has meanwhile granted approval of capivasertib, while European Medicines Agency (EMA) approval is still pending.

A different approach to overcome endocrine resistance was chosen in the phase 3 INAVO120 trial. Patients with progression on adjuvant endocrine treatment or within 12 months since the end of adjuvant endocrine treatment and tumours harbouring PIK3Ca mutations were randomized to fulvestrant plus palbociclib with placebo or the novel PIK3Ca inhibitor inavolisib [23]. At the 21.3 month median follow-up, median PFS was prolonged from 7.3 months to 15.0 months with the addition of inavolisib (HR 0.43; 0.32–0.59; P < 0.0001). A trend towards improved OS was observed as well (HR 0.64; 95% CI 0.43–0.97). Of little surprise, neutropenia and hyperglycaemia were the most common adverse events, but treatment discontinuation rates of inavolisib/placebo were low at 6.2% suggesting an improved safety profile compared with older inhibitors of PIK3Ca.

Besides novel agents targeting growth factor pathways, novel oestrogen receptor (ER) targeting agents are under clinical development as well and elacestrant is the first novel oral selective oestrogen receptor degrader (SERD) approved by both FDA and EMA for the treatment of patients with ESR1 mutant disease. In the phase 3 EMERALD trial, elacestrant was compared with standard-of-care (SOC) therapy in a population of HR-positive/HER2-negative metastatic breast cancer [24]; all patients had progressed on prior CDKi therapy, 43.3% had already received two prior lines of endocrine therapy for metastatic disease, making this a heavily pretreated population. ESR1 mutations were detectable in 47.8% of participants. In this trial, elacestrant improved PFS over control (69.3% fulvestrant) from 1.91 months to 2.79 months (HR 0.697; HR 0.552–0.880). The early drop of PFS curves in the intention-to-treat population suggests that single-agent endocrine therapy may be of limited activity in a large subset of patients progressing on prior ET plus CDKi due to endocrine resistance. In the subgroup still response to endocrine therapy, however, a pronounced benefit of elacestrant was observed (12-month PFS rate 22.3% and 9.4%, respectively). A recent update of this study suggested that patients harbouring ESR1 mutations who had received at least one year of prior CDKi therapy did exceptionally well on single-agent elacestrant with a median PFS of 8.61 months [25] and elacestrant today is mainly used in this subgroup in clinical routine.

Camizestrant, another oral SERD, was compared with fulvestrant in pretreated patients in the randomized phase 2 SERENA-2 trial at three different dose levels (75 mg, 150 mg, and 300 mg) [26]. While the 300 mg arm was discontinued early after the inclusion of 20 patients, the other arms continued to recruit a total of 240 patients. PFS was defined as the primary study endpoint and SERENA‑2 was not powered to compare outcomes of the different camizestrant doses. In the overall population, 49.6% of patients had received prior therapy with CDKi and 36.7% had detectable ESR1 mutations. PFS was 3.7 months in the fulvestrant arm as compared with 7.2 months (camizestrant 75 mg; HR 0.58; 95% CI 0.41–0.81) and 7.7 months (camizestrant 150 mg; HR 0.67; 95% CI 0.48–0.92). The benefit of camizestrant was more pronounced in patients with prior exposure to CDKi-based therapy, presence of visceral metastases and detectable ESR1 mutations at baseline. Still, in the subset of patients progressing on prior CDKi treatment, PFS in absolute numbers was relatively short (5.5 months camizestrant 75 mg; 3.8 months camizestrant 150 mg), again indicating the need for optimal patient selection. Clinical development of both agents in earlier treatment lines as well as in the adjuvant setting is ongoing.

Interestingly, toxicity profiles differed between different oral SERDS: while low-grade nausea was apparently more pronounced in patients receiving elacestrant (all grade nausea 35%), photopsia was the most common side effects in SERENA‑2 (grade 1/2 photopsia 75 mg camizestrant 12.2% and 150 mg camizestrant 24.7%). In addition, grade 1/2 bradycardia was observed in 5.4% in the 75 mg cohort and 26% in the 150 mg group, respectively.

Phase 2 trials investigating the oral SERDs giredestrant [27] and amcenestrant [28] were negative, hinting at potential differences in the respective trial populations or at differences regarding the activity of different drugs among the class of oral SERDs. Currently, clinical development of giredestrant is ongoing in early stage breast cancer and first-line metastatic disease (persevERA Breast Cancer, NCT04546009; lidERA Breast Cancer, NCT04961996), while further development of amcenestrant has been discontinued.

Lasofoxifene is a novel selective ER modulator (SERM) with pronounced activity in ESR1 mutant disease. In the phase 2 ELAINE 1 trial, lasofoxifene was compared with fulvestrant in patients with ESR1 mutant disease and prior exposure to CDK4/6 inhibitors [29]. In this study, lasofoxifene prolonged progression free survival from 4.04 to 6.04 months (HR 0.699; 95% CI 0.445–1.125) which did not reach statistical significance (p = 0.138). Of note, objective response rate was numerically higher in the lasofoxifene arm (5/38 vs. 1/33) as was relative median reduction of ESR1 mutant allele fraction (87.1% vs. 14.7%). Therefore, further investigation of this drug is warranted.

Take home message

The trials discussed in this short review point at novel treatment options that may further help in optimizing systemic therapy in metastatic and early stage breast cancer. Trastuzumab deruxtecan and sacituzumab govitecan are well established antibody–drug conjugates (ADCs) in metastatic breast cancer and a broad clinical development program is ongoing with both drugs. Due to its cytotoxic payload and its linker technology, datopotamab deruxtecan is a promising TROP2-directed ADC, while clinical development of patritumab deruxtecan is ongoing. In luminal breast cancer, capivasertib plus endocrine therapy improved progression-free survival to a clinically relevant extent over endocrine therapy alone in pretreated patients irrespective of the biomarker profile. Elacestrant and camizestrant were superior to standard endocrine therapy in pretreated HR-positive/HER2-negative breast cancer patients and elacestrant is the first novel oral SERD having received FDA and EMA approval; the optimal place of oral SERDs in the treatment continuum awaits further clarification.