Navigând în era postinhibitorilor CDK4/6: un algoritm clinic pentru cancerul mamar metastatic cu receptori hormonali pozitivi

1. Introduction

Breast cancer remains the most diagnosed malignancy and the leading cause of cancer-related death in women worldwide. Globally, the burden is projected to escalate significantly by 2050, with new annual cases expected to rise by 38% to 3.2 million and deaths by 68% to 1.1 million⁽¹⁾. This trajectory is particularly alarming for Romania, where the epidemiological landscape presents a unique and urgent challenge.

While Romania reports a lower age-standardized incidence rate compared to the EU average (approximately 69.2 versus 142.8 per 100,000), it paradoxically suffers from a disproportionately high mortality-to-incidence ratio⁽²⁾.

Current data indicate approximately 12,700 new cases and nearly 4000 deaths annually. This discrepancy is largely driven by late-stage diagnosis. Unlike Western European counterparts where early detection is common, a significant percentage of Romanian patients present with stage III or IV disease at the initial diagnosis.

The primary driver of this trend is the critical gap in screening coverage⁽³⁾. In 2020, only 9% of eligible Romanian women underwent mammography screening – a stark contrast to the European average of roughly 60%⁽³⁾. This lack of an effective, nationwide organized screening program creates a “survival gap”, where the projected global increase in cases will likely translate into a more severe mortality burden locally if left unaddressed⁽⁴⁾. Consequently, the implementation of the National Plan for Combating Cancer, with its focus on operationalizing regional screening pilot programs and improving access to innovative therapies in the metastatic setting, represents not just a policy goal but a clinical necessity to avert the looming crisis predicted for the coming decades.

Endocrine therapy combined with CDK4/6 inhibitors has established itself as the standard of care for the first-line treatment of patients diagnosed with de novo metastatic breast cancer or those experiencing progression following prior adjuvant endocrine therapy⁽⁵⁾. In this setting, the combination of a CDK4/6 inhibitor (palbociclib, ribociclib or abemaciclib) with an aromatase inhibitor has consistently demonstrated a median progression-free survival (PFS) ranging from 24 to 28 months across pivotal phase III clinical trials⁽⁶⁾. While the PFS benefit is consistent across the class, the overall survival (OS) outcomes vary significantly among the agents in the first-line setting^(7-9).

2. First-line treatments

2.1. Cyclin-dependent kinases 4/6 inhibitors

The three approved agents in this class – ribociclib, abemaciclib and palbociclib – have distinct efficacy profiles that influence clinical decision-making. A closer examination of their respective pivotal trials reveals critical differences in survival benefits that differentiate these molecules.

Ribociclib (MONALEESA-2): this trial demonstrated a statistically significant survival benefit. The median OS was 63.9 months with ribociclib plus letrozole compared to 51.4 months with placebo (HR 0.76; p=0.008), establishing it as the only CDK4/6 inhibitor with a proven, significant OS benefit in the first-line setting⁽⁷⁾.

Abemaciclib in the MONARCH-3 trial demonstrated a clinically meaningful numeric improvement in median OS, reaching 67.1 months versus 54.5 months in the control arm at the second interim analysis (HR 0.754). However, the statistical significance was not met at this timepoint, nor at the final analysis (HR 0.804; p=0.0664)^(8,9).

Palbociclib (PALOMA-2): despite achieving a significant PFS benefit comparable to other CDK4/6 inhibitors, palbociclib did not demonstrate a statistically significant improvement in OS. At a median follow-up of 90 months, the median OS was 53.9 months in the palbociclib arm versus 51.2 months in the placebo arm (HR 0.956; 95% CI; 0.777-1.177), indicating no survival advantage over endocrine therapy alone⁽¹⁰⁾.

The most relevant, severe adverse events of palbociclib and ribociclib are neutropenia (despite grade 3/4 rates above 60%, febrile neutropenia is very rare – 1%) and fatigue. Ribociclib leads to the highest rates of abnormal liver function among all CDK4/6 inhibitors, and may additionally lead to QTc interval prolongation. Patients treated with abemaciclib mainly experience clinically relevant diarrhea (especially at the beginning of treatment), abnormal liver function, nausea and fatigue, but less hematotoxicity.

2.2. PI3CA inhibitors

While the combination of CDK4/6 inhibitors and aromatase inhibitors has established itself as the standard of care for the majority of patients with HR+/HER2- mBC, a significant challenge remains for the subset of tumors harboring PIK3CA mutations. Present in approximately 40% of HR+ mBC cases, PIK3CA mutations are associated with a more aggressive phenotype. Targeting the PI3K/AKT signaling cascade at the level of the PI3Ka isoform, inavolisib has emerged as a highly selective, next-generation inhibitor. It uniquely functions through a dual mechanism: it not only inhibits the kinase activity of the PI3Ka isoform, but also induces the specific degradation of the mutant p110a protein.

This distinct mechanism of action provided the rationale for the pivotal phase III INAVO120 trial. This study evaluated the safety and efficacy of an “all-oral triplet” regimen – combining inavolisib with palbociclib and fulvestrant – specifically in patients with PIK3CA-mutated, HR+/HER2- locally advanced or mBC who experienced disease recurrence during or within 12 months of completing adjuvant endocrine therapy. This specific population represents a group with primary endocrine resistance and poor prognosis, where the standard doublet therapy may be insufficient.

The primary objective was to determine if adding inavo­lisib to a standard backbone could overcome PI3K-driven resistance. To test this, patients were randomized to receive either the experimental triplet regimen of inavolisib com­bined with palbociclib and fulvestrant, or a control re­gi­men of placebo with palbociclib and fulvestrant.

The efficacy data proved to be robust, establishing the triplet regimen as a superior first-line option. The addition of inavolisib more than doubled the median PFS compared to the standard of care, reaching 15 months versus just 7.3 months in the control arm. This improvement represented a 57% reduction in the risk of disease progression or death, with a HR of 0.43. Furthermore, updated analyses have reinforced these findings, showing even more robust data with the median PFS in the inavolisib arm extending to 17.2 months⁽¹¹⁾.

Regarding safety, inavolisib demonstrated a manageable toxicity profile. While hyperglycemia was a common adverse event, affecting 85% of patients, it was generally manageable; the median time to onset was roughly one week. The cases improved quickly with intervention, and only 1.2% of patients required discontinuation of the drug due to this side effect. Similarly, stomatitis and diarrhea were frequent, but they rarely led to treatment discontinuation, the discontinuation rates being 0.6% and 1.2%, respectively. These compelling results led directly to the European Commission’s approval of inavolisib in July 2025.The INAVO120 trial successfully demonstrated that intensifying first-line therapy with a targeted triplet regimen significantly improves outcomes for patients with PIK3CA mutations, offering a way to effectively delay disease progression in a population that has historically faced early resistance⁽¹¹⁾.

2.3. Selective estrogen receptor degraders

To truly maximize patient outcomes, we need to look beyond the traditional boundaries of first-line therapy and focus on sustaining disease control for as long as possible. By identifying molecular changes early within the first-line setting, we can adapt our strategy to prevent progression before it becomes visible.

The SERENA-6 phase III trial represents a significant shift in treatment strategy for HR-positive, HER2-negative metastatic breast cancer, moving from treating radiological progression to treating molecular progression (detected via ctDNA)⁽¹²⁾.

The results from the study (presented at ASCO 2025) demonstrated that switching patients to camizestrant upon detection of an ESR1 mutation – before the tumor grows on scans –significantly improves outcomes.

The trial was designed to answer whether “switching” endocrine therapy early (upon molecular signs of resistance) is better than waiting for the disease to physically progress. Patients on first-line therapy (aromatase inhibitor plus CDK4/6 inhibitor) who had not yet progressed clinically or radiologically underwent regular ctDNA monitoring. If an ESR1 mutation was detected in their blood before the cancer grew on scans, they were randomly allocated to either remain on the existing aromatase inhibitor or switch to camizestrant, while maintaining the same CDK4/6 inhibitor in both arms. The SERENA-6 trial successfully met its primary endpoint, demonstrating a highly statistically significant improvement in PFS. Patients who switched to camizestrant achieved a median PFS of 16 months, compared to only 9.2 months for those continuing on an aromatase inhibitor. This difference corresponds to a HR of 0.44, representing a 56% reduction in the risk of disease progression or death. Importantly, this progression-free survival benefit was consistent across all subgroups, regardless of the specific background CDK4/6 inhibitor (palbociclib, ribociclib, or abemaciclib) administered. Regarding patient-reported outcomes, the switch strategy significantly preserved the quality of life, delaying the time to deterioration in pain symptoms to 21 months, compared to 6.4 months in the control arm⁽¹²⁾.

These results validate the concept demonstrated with PADA1 trial before of molecular interception – monitoring patients with simple blood tests to catch resistance early (ESR1 mutation) and switching the endocrine backbone to a next-generation SERD (camizestrant) to double the duration of disease control compared to the standard of care⁽¹³⁾.

The rationale for this approach is based on the critical need to extend the first-line treatment window. Maximizing this initial phase is vital, as the transition to second-line therapy is typically associated with a substantial drop in efficacy, with progression-free survival often reduced by approximately 60% compared to the first-line setting⁽¹⁴⁾.

3. Second-line treatments

Despite the efficacy of first-line regimens, disease progression is common. Once patients progress through initial endocrine and CDK4/6 inhibitor therapy, the clinical benefit of subsequent treatments diminishes rapidly. The median PFS for standard second-line endocrine monotherapy (e.g., fulvestrant) is historically poor, averaging approximately three to four months⁽¹⁵⁾. This high reduction in disease control highlights a critical unmet need for novel therapeutic strategies capable of improving survival outcomes beyond the first line.

Given the complexities of post-CDK4/6 progression, therapy selection requires a multifactorial approach to identify the optimal regimen⁽¹⁶⁾. Key considerations include:

• Duration of response – evaluating the progression-free interval on first-line therapy to assess the degree of endocrine resistance.
• Genomic profiling – screening for actionable mutations that drive resistance or offer therapeutic targets, specifically focusing on PIK3CA, ESR1 and AKT pathway alterations⁽¹⁷⁾.
• Endocrine sensitivity – determining whether the tumor remains phenotypically endocrine-sensitive or has transitioned to a refractory state, which dictates whether to continue an endocrine backbone or switch to non-endocrine therapies⁽¹⁸⁾.

When selecting the therapy options, it is essential to evaluate the patient-specific characteristics, including disease burden, medical comorbidities and the specific toxicity profile of the drug, alongside patient preference and quality of life.

In the second-line setting for patients with endocrine-sensitive tumors, the treatment strategies are increasingly guided by mutation-driven therapies⁽¹⁹⁾.

Up to 50% of patients with HR-positive, HER2-negative metastatic breast cancer may harbor alterations in the PIK3CA, AKT1 or PTEN pathway. These alterations – particularly those involving PIK3CA – are associated with a poorer prognosis⁽²⁰⁾.

3.1. Phosphoinositide 3-kinase inhibitors

The pivotal SOLAR-1 phase III trial was the landmark study that established the clinical utility of targeting PIK3CA mutations in HR-positive, HER2-negative advanced breast cancer. Before this study, PIK3CA mutations were known to be common drivers of resistance to endocrine therapy, but no targeted agent had successfully improved outcomes without unacceptable toxicity.

SOLAR-1 was designed to test whether alpelisib, a PI3K-alpha specific inhibitor, could reverse this resistance when combined with fulvestrant.

The study design was a randomized, double-blind, placebo-controlled trial that stratified patients based on their mutation status. It enrolled men and postmenopausal women whose disease had progressed on or following treatment with an aromatase inhibitor. Crucially, the study population was comprised almost exclusively of patients who had not previously received CDK4/6 inhibitors. This distinction is vital for interpreting the results, as the trial reflected a treatment landscape where CDK4/6 inhibitors were not yet the routine standard of care in the first-line setting.

Patients were divided into two distinct cohorts: those with confirmed PIK3CA mutations and those without the mutation. Within each cohort, the participants were randomized to receive either alpelisib plus fulvestrant or placebo plus fulvestrant^(21,22).

The primary endpoint was PFS, specifically in the cohort of patients with PIK3CA mutations.

The efficacy results validated the targeted nature of the therapy. In the PIK3CA-mutant cohort, the combination of alpelisib and fulvestrant nearly doubled the median PFS compared to fulvestrant alone, achieving 11 months versus 5.7 months in the control arm. This improvement corresponded to a HR of 0.65, representing a 35% reduction in the risk of disease progression or death. Crucially, the trial also demonstrated that this benefit was exclusive to the mutated population; in the cohort of patients without PIK3CA mutations, adding alpelisib provided no survival advantage, underscoring the necessity of biomarker testing prior to treatment.

While the efficacy data were robust, the safety profile presented distinct management challenges. The administration of alpelisib was associated with specific adverse events, most notably hyperglycemia, diarrhea and rash⁽²³⁾.

Hyperglycemia was the most prominent toxicity, requiring careful monitoring of blood glucose levels and often necessitating the use of anti-diabetic medications or dose adjustments. Unlike the newer generation of inhibitors, discontinuation rates due to adverse events in SOLAR-1 were notable, occurring in approximately 25% of patients in the alpelisib arm, highlighting the importance of proactive side effect management in clinical practice⁽²³⁾.

The results led to the regulatory approval of alpelisib, marking the arrival of the first targeted therapy for this substantial subgroup of breast cancer patients.

3.2. AKT inhibitors

For patients progressing on first-line CDK4/6 inhibitors, hyperactivation of the PI3K/AKT pathway remains a primary mechanism of resistance⁽²⁴⁾. Addressing this challenge, capivasertib has emerged as a first-in-class pan-AKT inhibitor. Distinct from therapies that target only the PI3K alpha isoform, capivasertib inhibits the central AKT node. This broader mechanism allows it to remain effective across a wider spectrum of genetic alterations, including PIK3CA, AKT1 and PTEN⁽²⁵⁾. The clinical utility of this approach was established in the phase III CAPItello-291 trial. CAPItello-291 is a double-blind, phase 3, randomized study that showed that the addition of AKT inhibitor capivasertib to fulvestrant resulted in a significant improvement in progression-free survival among patients with HR+, HER2-negative advanced breast cancer that had progressed during previous aromatase inhibitor therapy with or without a CDK4/6 inhibitor.

Patients were randomized 1:1 to receive capivasertib plus fulvestrant or placebo plus fulvestrant. The dual primary endpoint was investigator-assessed PFS according with RECIST both in the overall population and patients with AKT pathway-altered (PIK3CA, AKT1 or PTEN) tumors.

In the overall population, the median PFS was 7.2 months in the capivasertib-fulvestrant group versus 3.6 months in the placebo-fulvestrant group. In the AKT pathway-altered population, the median PFS was 7.3 months in the capivasertib-fulvestrant group versus 3.1 months in the placebo-fulvestrant group⁽²⁶⁾.

The most frequent side effects of grade 3 or higher in patients receiving capivasertib-fulvestrant were rash in 12.1% of patients versus 0.3% in those receiving placebo-fulvestrant, and diarrhea in 9.3% versus 0.3%.

The results from the CAPItello-291 study showed that capivasertib plus fulvestrant compared with placebo plus fulvestrant improved PFS in participants with HR-positive/ HER2-negative advanced breast cancer evolve despite hormone therapy (with/without a CDK4/6 inhibitor)⁽²⁶⁾.

3.3. Mammalian target of rapamycin inhibitors

Targeting the mTOR pathway remains a critical strategy for mitigating endocrine resistance, positioning the combination of exemestane and everolimus as a validated option⁽²⁷⁾.

The rationale centers on the pathway’s role in resistance: hyperactivation of mTOR leads to ligand-independent ER activation, and everolimus inhibits mTORC1, effectively disrupting this aberrant signaling loop to restore sensitivity to the steroidal aromatase inhibitor. This approach is supported by the pivotal phase III BOLERO-2 study, which demonstrated a statistically significant benefit in the overall population, with the combination extending median PFS to 10.6 months compared to 4.1 months with placebo plus exemestane (HR 0.36; 95% CI; 0.27-0.47)⁽²⁸⁾.

In terms of tolerability, the regimen is associated with distinct class effects, most notably stomatitis, non-infectious pneumonitis and metabolic changes such as hyperglycemia and hyperlipidemia, which often require proactive management strategies like prophylactic steroid mouthwashes to maintain dose intensity⁽²⁹⁾.

3.4. Selective estrogen receptor degraders (SERDs)

ESR1 mutations have emerged as a critical player in the progression and treatment resistance of breast cancer, particularly in metastatic HR+ cases⁽³⁰⁾. These mutations are associated with resistance to endocrine therapy, the backbone of treatment for this type of cancer. ESR1 mutations are relatively rare in primary tumors, occurring in approximately 1% of cases. However, their prevalence increases significantly in metastatic, endocrine therapy-resistant cancers, where they are found in 10-50% of cases. This suggests that these mutations may be a key mechanism of acquired resistance to endocrine therapy⁽³⁰⁾.

New oral SERDs, such as elacestrant, have been approved by the EMA (september 2023) – the approval requires ESR1 mutation testing in a liquid biopsy (circulating tumor DNA).

The EMERALD study is an open-label phase III trial that randomly assigned patients with E +/ HER2- mBC who had received 1-2 prior lines of ET, mandatory CDK4/6i, and ≤1 chemotherapy to elacestrant (345 mg daily) or SOC (aromatase inhibitor or fulvestrant)⁽³¹⁾. PFS was prolonged in all patients (hazard ratio = 0.70) and patients with ESR1 mutation (hazard ratio = 0.55). Treatment-related grade 3/4 adverse events occurred in 7.2% receiving elacestrant and 3.1% receiving SOC. Treatment-related adverse events leading to treatment discontinuations were 3.4% in the elacestrant arm versus 0.9% in SOC. Nausea of any grade occurred in 35% receiving elacestrant and in 18.8% receiving SOC (grade 3/4, 2.5% and 0.9%, respectively)⁽³¹⁾.

3.5. Poly(ADP-ribose) polymerase inhibitors

In the evolving treatment landscape for HR-positive/HER2-negative metastatic breast cancer, the identification of a germline BRCA1/2 mutation following progression on first-line CDK4/6 inhibitor and aromatase inhibitor therapy necessitates a shift toward targeted intervention.

For this distinct molecular subgroup, the therapeutic paradigm has moved away from immediate cytotoxic chemotherapy. International guidelines, including NCCN and ESMO, now preferentially recommend PARP inhibitors, specifically olaparib and talazoparib, as the standard of care⁽³²⁾. These agents leverage the concept of synthetic lethality, exploiting the homologous recombination repair deficiency inherent in BRCA-mutated tumor cells to induce cell death while sparing normal tissue⁽³³⁾.

The recommendation for olaparib is supported by the phase III OlympiAD trial. This study enrolled patients with germline BRCA mutations who had received prior chemotherapy in the neoadjuvant, adjuvant, or metastatic setting⁽³⁴⁾.

Olaparib monotherapy demonstrated a statistically significant benefit in median PFS compared to physician’s choice of single-agent chemotherapy (7 versus 4.2 months; HR 0.58; 95% CI 0.43-0.80). Furthermore, the objective response rate (ORR) was more than double that of the chemotherapy arm (59.9% versus 28.8%), indicating rapid and deep disease control⁽³⁴⁾. The safety profile favored olaparib, with a lower incidence of grade 3 adverse events (36.6% versus 50.5% for chemotherapy). The most common high-grade toxicity was anemia, requiring monitoring of hemoglobin levels, yet the discontinuation rate remained low (4.7%), supporting its utility as a tolerated oral regimen that preserves quality of life.

Validating the class efficacy of PARP inhibitors, the phase III EMBRACA trial evaluated talazoparib versus standard chemotherapy in a similar population of patients with locally advanced or metastatic gBRCA-mutated breast cancer. Talazoparib significantly prolonged median PFS compared to chemotherapy (8.6 versus 5.6 months; HR 0.54; 95% CI; 0.41-0.71). The trial also reported a robust objective response rate of 62.6% in the talazoparib arm versus 27.2% for chemotherapy⁽³⁵⁾. While generally well-tolerated, the toxicity profile of talazoparib is distinct. Hematologic adverse events are the most prominent, specifically grade 3-4 anemia (39%) and thrombocytopenia (15%), necessitating regular complete blood count monitoring. Despite these laboratory abnormalities, there were registered significantly better patient-reported outcomes (PROs) and a longer time to clinically meaningful deterioration compared to those receiving cytotoxic agents⁽³⁶⁾.

3.6. Next-generation oral selective estrogen receptor degraders

While targeting intracellular signaling pathways like PI3K and AKT is critical, optimizing the endocrine backbone itself remains a priority for overcoming resistance⁽³⁷⁾. The pharmacological limitations of intramuscular fulvestrant – including bioavailability challenges and administration burden – have driven the development of next-generation oral ER-targeting agents. Although not yet EMA-approved, several promising molecules are currently in late-stage clinical development.

Key agents include giredestrant and imlunestrant, both next-generation oral selective estrogen receptor degraders (ngSERDs) designed to achieve high receptor occupancy and efficacy even in the presence of ESR1 mutations⁽³⁸⁾. Additionally, the field is expanding with vepdegestrant, a novel PROTAC (PROteolysis TArgeting Chimera) protein degrader that leverages the ubiquitin-proteasome system to eliminate the estrogen receptor^(39,40).

4. Subsequent treatment lines

The clinical course of HR+ mBC is characterized by the eventual development of endocrine resistance, a state where the tumor becomes refractory to further hormonal blockade⁽⁴¹⁾. Despite the durability of initial CDK4/6 inhibitor-based regimens, the accumulation of acquired resistance mechanisms – such as ESR1 mutations or upregulation of the PI3K/AKT/mTOR pathway – significantly limits the efficacy of subsequent endocrine lines. In this scenario, where the potential for disease control via the estrogen receptor is compromised and PFS intervals shorten, the therapeutic strategy must shift⁽⁴²⁾. The focus moves from suppressing hormonal signaling to delivering potent cytotoxic therapy. This necessitates a careful reassessment of HER2 status, as the presence of low or ultralow expression opens the door to next-generation antibody-drug conjugates, offering a more targeted and effective approach than traditional single-agent chemotherapy⁽⁴³⁾.

Human epidermal growth factor receptor 2 (HER2) is a protein that is overexpressed because of HER2 (ERBB2) gene amplification, and plays a crucial role in the development and progression of breast cancer⁽⁴⁴⁾. The classification of breast cancer based on HER2 expression is undergoing significant changes. Until recently, HER2 status was reported as either positive or negative, with only HER2-positive patients being eligible for HER2-directed therapies. Some HER2-directed therapies are now known to be effective in treating tumors that exhibit low or even very low expression of HER2 that were previously classified as HER2-negative⁽⁴⁵⁾. To consolidate reporting, the CAP has released a new biomarker-reporting template (effective in March 2025) that recommends recording four discrete IHC HER2-negative strata (0, 0+, 1+ and 2+/ISH-negative), with the option to add a comment as to how “HER2-low” and “HER2-ultralow” were defined in the relevant clinical trials⁽⁴⁶⁾. Comprehensive guidance for pathologists in testing methodology and interpretation of low-level HER2 IHC expression remains an urgent priority to ensure diagnostic consistency and optimal patient selection for ADCs⁽⁴⁶⁾.

DESTINY Breast06 study is a phase 3, multicenter, open-label trial involving patients with hormone receptor-positive mBC with low HER2 expression (a score of 1+ or 2+ on IHC analysis and negative results on in situ hybridization) or ultralow HER2 expression (IHC 0 with membrane staining) who had received one or more lines of endocrine-based therapy and no previous chemotherapy for metastatic breast cancer⁽⁴⁷⁾. Patients who had received one previous line of endocrine therapy for metastatic disease were eligible if they had disease recurrence within 24 months after the initiation of adjuvant endocrine therapy or if they had disease progression within six months after the initiation of first-line endocrine therapy plus a CDK4/6 inhibitor for the treatment of metastatic disease. Patients were randomly assigned in a 1:1 ratio to receive trastuzumab deruxtecan or the physician’s choice of chemotherapy. The primary endpoint was PFS according to RECIST for patients with HER2-low disease (as determined by blinded independent central review). Secondary endpoints included progression-free survival among all patients (HER2 low and ultralow disease), overall survival and safety. Treatment with trastuzumab deruxtecan resulted in a median PFS of 13.2 months, approximately five months longer than the treatment with chemotherapy, among patients in the HER2-low, intention-to-treat, and HER2-ultralow populations. Trastuzumab deruxtecan demonstrated a statistically significant and clinically meaningful PFS versus chemotherapy in HR+, HER2-low mBC in an earlier line of treatment and the results in HER2-ultralow were consistent with HER2-low. Trastuzumab deruxtecan showed a benefit with respect to PFS regardless of HER2 expression status, previous CDK4/6 inhibitor treatment and previous taxane use for nonmetastatic disease. Confirmed ORR was 57.3% with trastuzumab deruxtecan versus 31.2% with chemotherapy in intention-to-treat population. Trastuzumab deruxtecan also demonstrated a clinically meaningful PFS2 benefit (by investigator) in intention-to-treat population: 20.3 months versus 14.7 months⁽⁴⁸⁾. Superior efficacy with trastuzumab deruxtecan was shown regardless of chemotherapy type among patients who were assigned to receive the physician’s choice of chemotherapy.

No new safety signals for trastuzumab deruxtecan were identified in this study, the three most common drug-related adverse events being nausea, fatigue and alopecia. Interstitial lung disease was reported in 11.3% of patients (most of them with grade 1 or 2), and left ventricular dysfunction was reported in 8.1% of patients⁽⁴⁷⁾.

5. Conclusions

The management of HR-positive, HER2-negative metastatic breast cancer has fundamentally shifted from a uniform endocrine approach to a precision oncology model defined by biomarker-guided sequencing. While CDK4/6 inhibitors remain the first-line standard, the post-progression landscape is now successfully navigating resistance through targeted innovations. Landmark trials such as INAVO120, CAPItello-291, Serena-6 and Destiny Breast 06 demonstrate that targeting specific alterations – including PIK3CA, AKT, ESR1 and HER2-low/ultralow status –significantly extends progression-free survival and delays the need for cytotoxic chemotherapy.

The future of treatment lies in molecular interception: utilizing ctDNA monitoring and comprehensive genomic profiling to detect and treat resistance before clinical progression occurs. By integrating these novel agents – from next-generation oral SERDs to antibody-drug conjugates – into routine practice, metastatic breast cancer can transform into a manageable chronic condition, ultimately securing longer overall survival and superior quality of life for patients.   

Corresponding author: Irina Niţă E-mail: radu_irina18@yahoo.com

Conflict of interest: none declared.

Financial support: none declared.

This work is permanently accessible online free of charge and published under the CC-BY licence.