Next generation of drugs in breast cancer

Recent years have seen the introduction of several novel drugs in the field of metastatic breast cancer (mBC), improving treatment options and outcomes in patients with recurrent or progressive disease. Cyclin-dependent kinase 4/6 inhibitors (CDKi) in combination with endocrine therapy are the standard-of-care for the first-line treatment of hormone receptor (HR)-positive/human epidermal growth factor receptor (HER) 2 negative disease, but patients will eventually progress and require further treatment lines. In addition, novel strategies are also sought in patients recurring after prior adjuvant CDKi-containing therapy. In HER2-positive mBC, first-line therapy consists of chemotherapy and the monoclonal antibodies trastuzumab and pertuzumab; in the second-line setting, the antibody–drug conjugate (ADC) trastuzumab deruxtecan (T-DXd) is the standard-of-care; defining the optimal treatment approach in patients progressing on T‑DXd has become a major focus of scientific and clinical interest. Finally, novel drugs or combination strategies are urgently sought in metastatic triple-negative breast cancer (TNBC), where treatment options remain limited. This article is intended as a nonsystematic overview of promising novel therapies that may shape the field of mBC therapy in the near future.

Currently, the combination of endocrine therapy and a CDKi is the standard first-line approach in luminal (HR-positive/HER2-negative) mBC. In frail patients, single-agent endocrine therapy may remain an option, while in patients with primary endocrine resistance and life-threatening disease, upfront chemotherapy or ADCs may be preferred [1]. Second-line endocrine therapy is recommended when reasonable, with different options according to disease biology considering—among others—ESR1 mutation status, genetic alterations in the PI3K/AKT/mTOR pathway and germline BRCA mutation status. Elacestrant is currently the only oral selective estrogen-receptor degrader (SERD) approved for the treatment of patients with ESR1 mutant disease progressing on prior endocrine therapy plus CDKi, with several other SERDs currently in clinical development [2]. As primary resistance to single-agent second-line endocrine therapy is evident in approximately half of this population, the phase 3 ADELA trial (NCT06382948) compares elacestrant with the mTOR inhibitor everolimus with single-agent elacestrant in ESR1 mutant tumors progressing on prior endocrine therapy plus CDKi. The ongoing phase 1b/2 ELEVATE trial (NCT05563220) is an umbrella study evaluating the combination of elacestrant with either the CDKi palbociclib or ribociclib or drugs targeting the PI3K/mTOR/AKT signaling pathway (everolimus, alpelisib, capivasertib). In the phase 1 part of the study, no new safety signals were observed, and results indicate a toxicity profile in line with that of the individual targeted agents [3]. ELECTRA is another phase 1b/2 trial specifically investigating the combination of elacestrant with the CDKI abemaciclib in the context of patients with brain metastases (NCT05386108). In the phase 1 part, brain metastases were not required for inclusion; again, the safety profile of the combination was consistent with previous abemaciclib data [4]. In addition, the phase 3 TREAT cTDNA trial (NCT05512364) compares elacestrant with standard-of-care in early-stage breast cancer patients with ctDNA relapse.

Clinical development of the oral SERD amcenestrant, in contrast, has been discontinued. In the phase III AMEERA-5 trial, first-line amcenestrant plus palbociclib was not superior to letrozole plus palbociclib at an interim analysis (HR progression-frees survival [PFS] 1.209; 95% confidence interval [CI] 0.939–1.557; p = 0.9304) and the trial was therefore discontinued for futility [5]. Development of several other oral SERDs is ongoing, and this review will discuss drugs in late stages of clinical development.

The phase I SERENA-1 trial evaluated camizestrant as monotherapy and in combination with palbociclib and other targeted agents after at least one prior endocrine treatment line and up to two prior lines of chemotherapy. In the dose escalation phase of single-agent camizestrant, at doses ≤ 150 mg, no treatment-emergent adverse events (TEAEs) grade 3 or higher or serious AEs (SAEs) were observed [6]. Overall, most common TRAEs were visual disturbances (56%), bradycardia (44%), fatigue (26%), and nausea (15%). Clinical activity was observed across all dose levels, including responses in patients with prior CDKi and/or fulvestrant treatment. The phase II SERENA-2 trial randomized 240 patients (68.8% second-line; 49.6% prior CDKi; 37.7% ESR1mut disease) after a maximum of one line of prior endocrine therapy for advanced breast cancer without prior fulvestrant to fulvestrant or three different dosing cohorts of camizestrant (75 mg, 150 mg, and 300 mg) [7]. Recruitment to the 300 mg cohort was discontinued early. Numerically, more overall and grade 3/4 TEAE were observed in the 150 mg cohort. In the 75 mg cohort, PFS was 7.2 months as compared with 3.7 months in participants receiving fulvestrant (hazard ratio [HR] 0.58; 95% CI 0.41–0.81), suggesting a relevant improvement. In patients with detectable ESR1 mutation, there was a pronounced decrease in variant allele frequency in the camizestrant arms compared with fulvestrant. Ongoing phase 3 trials include SERENA‑4 comparing camizestrant plus palbociclib with an aromatase inhibitor (AI) plus palbociclib (NCT04711252) and SERENA‑6 evaluating an early switch to camizestrant upon detection of ESR1 mutation (NCT04964934).

Imlunestrant was evaluated in the phase 1a/b EMBER study as a single agent in patients with advanced breast cancer and endometrial cancer and in different combinations with targeted agents. In the monotherapy part, 114 advanced breast cancer patients and 24 endometrial cancer patients were accrued [8]. In the advanced breast cancer cohort, more than 90% had received prior treatment with endocrine therapy (approximately 50% fulvestrant) and CDKi as well. Grade 3 toxicity rate was low at 3.6%; the most common TEAEs were nausea (33.3%), fatigue (27.5%), and diarrhea (23.2%). None of the participants discontinued treatment due to an AE. Regarding activity, an objective response rate (ORR) of 8% and a clinical benefit rate (CBR) of 40.4% was reported; responses were observed regardless of ESR1 mutation status. Median PFS for the overall population was 4.3 months and encouraging 6.5 months in the group of patients receiving imlunestrant as second-line therapy. In the phase Ib dose expansion cohort of EMBER evaluating imlunestrant plus abemaciclib with or without an AI [9], the toxicity profile was in line with safety results of the MONRACH-2 trial of fulvestrant and abemaciclib [10]. ORR was approximately 40% and CBR 70%, suggesting relevant clinical activity. Clinical development of imlunestrant is currently ongoing, with the phase 3 EMBER-3 trial (NCT04975308) comparing imlunestrant plus abemaciclib with endocrine therapy plus abemaciclib as second-line therapy for advanced breast cancer and the phase 3 EMBER-4 trial (NCT05514054) investigating imlunestrant in high-risk early-stage breast cancer after 2–5 years of conventional antihormonal treatment.

Giredestrant is an oral SERD with higher inhibitory potency compared with fulvestrant and other oral SERDs in a preclinical study [11]. In the phase II acelERA trial, giredestrant was compared with fulvestrant or an aromatase inhibitor in the second- and third-line settings [12]. At a median follow-up of 7.9 months, no significant PFS difference was detected in the overall population (HR 0.81; 95% CI 0.60–1.10; p = 0.1757). In the prespecified subgroup of patients with detectable ESR1 mutation, the numerical advantage was more pronounced (HR 0.60; 95% CI 0.35–1.03); in addition, response rate and clinical benefit rate favored the giredestrant arm as well. No differences between the study arms were observed in terms of grade 3–4 TEAEs, SAEs, and discontinuation rates due to toxicity. Grade 1/2 bradycardia was detected in 3.3% of patients compared with 1.3% in the standard arm. Currently, the phase III trial persevERA (NCT04546009) is evaluating the combination of giredestrant and palbociclib in the first-line setting and lidERA (04961996) is an ongoing phase III trial with giredestrant as adjuvant endocrine therapy in early-stage breast cancer.

In summary, data on SERD suggest relevant differences in the respective safety profile despite similar chemical structures. Beside oral SERDs, other approaches for optimized HR targeting include novel selective receptor modulators (SERMs), proteolysis targeting chimerics (PROTACs), complete estrogen receptor antagonists (CERANs), and selective estrogen receptor covalent antagonists (SERCAs) with the majority of drugs—with the exception of the SERM lasofoxifene—in an early clinical development stage [13]. The phase 2 ELAINE 1 trial compared lasofoxifene with fulvestrant in patients progressing on prior therapy with an AI plus a CDKi. While not statistically significant, PFS improved from 3.7 months to 5.2 months (95% CI 0.434–1.125; p = 0.138) [14]. In addition, ESR1 variant allele fraction decreased from baseline to week 8 in 82.9% of evaluable patients in the lasofoxifene arm as compared with 61.5% of patients in the control group. Numerically, a higher incidence of nausea, hot flushes, and dizziness was observed in patients receiving lasofoxifene, but all events were of grade 1/2 severity only. In the single-arm phase II ELAINE 2 trial, 29 patients with luminal breast cancer progressing on prior endocrine therapy and harboring ESR1 mutations received a combination of lasofoxifene and abemaciclib [15]. All but one patient had received prior CDKis as well. Combination therapy yielded an encouraging PFS of approximately 13 months (56.0 weeks; 95% CI 31.9–not estimable). Treatment was relatively well tolerated, with 61.4 and 17.2% of patients experiencing grade 1 and 2 diarrhea, respectively; anemia and fall were the only grade 3 adverse events occurring in more than one patient. Based upon these results, the ongoing phase 3 ELAINE 3 trial (NCT05696626) compares lasofoxifene plus abemaciclib with fulvestrant plus abemaciclib in patients with ESR1 mutant disease progressing on prior AI with either palbociclib or ribociclib.

Approximately 40% of HR-positive/HER2-negative breast cancers have PIK3CA mutations resulting in an activation of the PI3K/AKT/mTOR signal transduction pathway. PIK3CA mutations are a negative prognostic marker, and a positive predictive biomarker for small molecules targeting specific molecules within the pathway such as PI3K or AKT. While the PIK3CA (i.e., α‑specific PI3K) inhibitor alpelisib offers relevant clinical activity in combination with endocrine therapy in patients progressing on prior endocrine therapy with or without CDKi [16, 17], widespread clinical use is hampered by an unfavorable toxicity profile resulting as indicated by a treatment discontinuation rate of 25% in the pivotal SOLAR-1 trial [16]. Inavolisib is a next-generation PIK3CA inhibitor; in the phase III INAVO120 trial, 325 patients with early relapse during adjuvant endocrine therapy or within 12 months of completion of adjuvant treatment and PIK3CA mutant tumors were randomized to palbociclib plus fulvestrant with inavolisib or placebo [18]. Addition of inavolisib to standard treatment improved PFS from 7.3 months to 15 months in this high-risk population (HR 0.43; 95% CI 0.32–0.50; p < 0.0001); ORR were 58.4 and 25.0%, respectively. While a higher rate of stomatitis, hyperglycemia, diarrhea, nausea, and rash was observed in the triple-combination arm, the grade 3/4 toxicity rate was below 10% for each of these side effects. Treatment discontinuation rate was low at 6.2% as well, and health-related quality of life was maintained over the entire treatment period [19], rendering inavolisib an attractive drug for further clinical development. The phase III INAVO121 trial is currently evaluating the combination of inavolisib plus fulvestrant in patients progressing on prior CDK4/6i-based therapy (NCT05646862).

In metastatic HER2-positive breast cancer, first-line treatment consists of chemotherapy plus the HER2-directed monoclonal antibodies (mABs) trastuzumab and pertuzumab. T‑DXd is currently the second-line standard-of-care. Optimal treatment in patients progressing of prior T‑DXd, however, is currently ill defined. While the triple combination of the third-generation HER2-specific tyrosine kinase inhibitor (TKI) tucatinib with trastuzumab and capecitabine is accepted as a potential treatment option, clinical activity appears limited. With T‑DXd being evaluated as first-line treatment (DESTINY-Breast09; NCT04784715) and in the postneoadjuvant setting as well (DESTINY-Breast05; NCT04622319), novel approaches are urgently sought.

While recent years have seen a focus on ADC development, other advances include the biparatopic antibody zanidatamab (ZW25) binding with two nonoverlapping epitopes of the HER2 receptor. These epitopes are the extracellular domains (ECD) 4 and 2, which are the binding sites of trastuzumab and pertuzumab, respectively. Therefore, zanidatamab is believed to combine mechanisms-of-action of both monoclonal antibodies in a single molecule; of note, superior in vivo activity compared with the combination of trastuzumab and pertuzumab was observed in a HER2-expressing xenograft model. Furthermore, zanidatamab uniquely induces complement-dependent cytotoxicity against high HER2-expressing tumor cells in vitro as well [20]. In a phase 1a/b trial of single-agent zanidatamab in different HER2-positive solid tumors excluding HER2-positive breast cancer, 20 mg/kg body weight was determined as the recommended dose for further development and no dose-limiting toxicities were observed [21]. In a total of 132 patients, diarrhea was the most commonly observed treatment-emergent adverse event (52% in the dose escalation and 43% in the expansion cohort, with only a single case of grade 3 diarrhea reported). In a phase 1b/2 study conducted in patients with HER2-positive metastatic breast cancer with prior therapy for advanced disease (n = 21 patients), the combination of zanidatamab and docetaxel yielded a promising response rate of 90.5% [22]. Of note, the grade 3 diarrhea rate varied by zanidatamab regimen, with 30% of patients in cohort A (zanidatamab 30 mg/kg once every 3 weeks) experiencing grade 3 diarrhea, as compared with no grade 3 event in the 1800 mg flat-dose cohort. In a single-arm phase II trial, the combination of zanidatamab with palbociclib and fulvestrant was investigated in 51 patients with HER2-positive/HR-positive disease [23]. This population was heavily pretreated with virtually all participants having received prior treatment with trastuzumab, pertuzumab, and T‑DM1; importantly, approximately one quarter had received prior T‑DXd as well. The triple combination yielded promising activity, with a median PFS of 12 months (95% CI 8–15) and an ORR of 35%. In this study, zanidatamab was administered at 30 mg/kg once every 2 weeks. Any grade diarrhea was observed in 80% of patients, with a grade 3/4 diarrhea rate of 14%, indicating the need for optimal diarrhea management. Currently, the phase III EmpowHER303 trial is comparing zanidatamab plus chemotherapy by physicians’ choice (eribulin, vinorelbine, gemcitabine, or capecitabine) with trastuzumab plus chemotherapy by physicians’ choice in HER2-positive breast cancer patients progressing on prior T‑DXd (NCT06435429) and this trial might help in defining a novel standard in the next subsequent line following T‑DXd.

Beside ADCs and antibodies, recent advances were also reported in the field of HER2-directed TKIs. ZN-1041 is a fourth-generation HER2-specific TKI which apparently is not a substrate of efflux transporters and has high blood–brain barrier (BBB) permeability [24]. In the phase Ia/b/c ZN-A-1041-101-US (NCT05593094) trial, ZN-1041 was evaluated as monotherapy or in combination with T‑DM1, T‑DXd or trastuzumab/pertuzumab [25]. In the phase Ia part with ZN-1041 monotherapy, no dose-limiting toxicities were observed up to a dose of 800 mg BID. Treatment-emerging adverse events were mainly grade 1, the most common events were grade 1 nausea (43%) and vomiting (29%); of note, no ≥ grade 2 diarrhea was reported. No dose-limiting toxicities were observed in the combination arm as well. In addition, early data suggest activity despite previous treatment with T‑DXd and tucatinib. Based upon these encouraging results, further evaluation is planned. Zongertinib (BI 1810631) is another promising fourth-generation HER2-spepcific TKI with favorable toxicity profile and high-activity in ERB2 mutant non-small cell lung cancer, but specific breast cancer data are currently not available [26].

The poly-ADP ribose polymerase inhibitors (PARPi) olaparib and talazoparib are today approved for patients with pretreated HER2-negative breast cancer harboring germline BRCA mutations where both drugs have demonstrated superiority over conventional chemotherapy in terms of activity and safety. In addition, olaparib is approved for the adjuvant treatment of high-risk early-stage BRCA mutant disease and the phase II TBCRC 048 trial also indicated activity in tumors with germline PALB2 and somatic BRCA mutations [27]. Extending the use of PARP inhibitors to tumors harboring homologous repair deficiency (HRD) beyond BRCA 1/2 and PALB2 mutations has not been successful so far in mBC. Suraparib is a second-generation PARP inhibitor with higher PARP1 selectivity, potentially improving therapeutic margins. The phase I/II PETRA trial evaluated suraparib in patients with metastatic breast, ovarian, pancreatic, and prostate cancer with mutations in BRCA 1, BRCA 2, PALB2, RAD51C, and RAD51D. In the phase I part of the trial, 60 mg was chosen as the recommended dose for the expansion phase. In 31 breast cancer patients receiving suraparib at 60 mg daily, RR was 48.4% and PFS 9.1 months, indicating relevant clinical activity.

ADCs had a major impact on treatment strategies in breast cancer in recent years. Data on the development of T‑DXd and the TROP2 directed ADCs sacitzumab govitecan (SG) and datopotamab deruxtecan (Dato-DXd) have already been extensively reviewed [2]. This article will therefore focus on sacitzumab tirumotecan and patritumab deruxtecan.

Sacituzumab tirumotecan (Sac-TMT; SKB264/MK-2870) is a novel TROP2-directed ADC where the topoisomerase‑1 inhibitor tirumotecan is bound via a novel cleavable 2‑methylsulfonyl-pyrimidine linker to the antibody sacituzumab with a drug-to-antibody ratio of 7.4:1. In a preclinical study, a slower payload release was observed in human plasma compared with SG, suggesting enhanced linker stability [28]. In the phase III OptiTROP trial, 263 Chinese patients with mTNBC progressing on two or more prior lines of chemotherapy were randomized to Sac-TMT or chemotherapy by physicians’ choice (capecitabine, gemcitabine, eribulin, or vinorelbine). Sac-TMT yielded a clinically relevant improvement in median PFS from 2.3 to 5.7 months (HR 0.31; 95% CI, 0.22–0.45; p < 0.00001). Despite short follow-up (10.4 months), a significant OS improvement was observed as well (not reached vs. 9.4 months; HR 0.53; 95% CI, 0.36–0.78; p = 0.0005). Most common grade 3 TEAEs were anemia, leukopenia, and neutropenia. All grade stomatitis was observed in 44% of patients, with 9% grade 3 stomatitis, suggesting the need for optimal management and prophylaxis. Overall, activity and safety appear promising and Sac-TMT alone or in combination with pembrolizumab is now compared with chemotherapy by physician’s choice in pretreated patients with HER2-negative/HR-positive mBC in the phase 3 MK-2870-010 trial (NCT06312176). The phase 3 MK-2870-012 trial (MK-2870-012) evaluates postneoadjuvant Sac-TMT in patients with early-stage TNBC without pathologic complete remission to neoadjuvant treatment.

Patritumab deruxtecan (HER3-DXd) is an ADC targeting the extracellular domain of HER3, a HER family growth factor receptor associated with worse prognosis [29]. In a phase I/II dose-escalation, dose-finding, and dose-expansion trial accruing 182 patients with previously treated mBC, responses were observed across all clinical subtypes (HR-positive/HER2-negative ORR 30.1%; PFS 7.4 months; TNBC ORR 22.6%, PFS 5.5 months; HER2-positive ORR 42.9%; PFS 11.0 months) [30]. Of note, responses were observed in tumors with high and low HER3 expression. Main grade 3/4 toxicity consisted of hematologic TEAEs: decreased neutrophil count (grade 3 26.9%; grade 4 12.6%), decreased platelet count (grade 3 12.1%; grade 4 18.7%), and anemia (grade 3 18.1%; grade 4 0.5%). In contrast, nonhematologic toxicity was mainly of low grade and included nausea (all grade 78.9%; grade 3 5.5%), diarrhea (all grade 41.2%; grade 3 3.8%), fatigue (all grade 31.9%; grade 3 2.2%), and stomatitis (all grade 30.2%; grade 3 0.5%). All grade alopecia was reported in approximately one quarter of participants and across all dose levels, 12 patients (6.6%) had adjucated treatment-related interstitial lung disease. Further development of HER3-DXd at a dose of 5.6 mg/kg once every 3 weeks is ongoing, with a focus on clinically relevant breast cancer populations: the phase 2 BRE-354 trial (NCT04699630) is evaluating HER3-DXd in patients with HER2-negative metastatic breast cancer and progression on T‑DXd and/or SG and/or Dato-DXd and HER2-positive mBC progressing on prior T‑Dxd; based upon previous data indicating relevant intracranial activity of ADCs, the phase 2 TUXEDO-3 trial (NCT05865990) is evaluating HER3-DXd in patients with active brain metastases (i.e., newly diagnosed previously untreated or progressive brain metastases) from breast and non-small cell lung cancer as well as patients with leptomeningeal disease.

Zanidatamab zovodotin (ZW49) is a zanidatamab-based ADC wherein an auristatin toxin is linked via a protease-cleavable linker to the biparatopic antibody zanidatamab. In a phase I trial, 76 patients with pretreated advanced HER2-positive solid tumors (22% breast cancer) received ZW49 [31]. One dose-limiting toxicity of grade 2 keratitis > 14 days was observed. Main toxicities included keratitis (42%), alopecia (25%), and diarrhea (21%; majority were grade 1 and 2); in addition, one participant experienced a grade 4 infusion-related reaction.