The treatment paradigm for hormone receptor–positive breast cancer post-CDK4/6 inhibition is entering a rapid state of evolution, reflecting the need for novel endocrine therapies and targeted agents that improve historically low survival outcomes for patients in the second-line setting and beyond, according to Kevin Kalinsky, MD, MS, FASCO.

“How we're treating patients in 2025 is going to be different in subsequent years, because we're [developing] additional agents like more selective PI3K and AKT inhibitors,” Kalinsky stated in an interview with 

.“What's going on now is only going to continue to evolve.”

In the interview, Kalinsky discussed the need for additional endocrine-based treatments and targeted therapies in the post–CDK4/6 inhibitor setting; spotlighted key data from the 

 that could support potential FDA approvals in this space, including data from the phase 3 VIKTORIA-1 (NCT05501886) and evERA (NCT05306340) trials; and underscored the importance of personalizing approaches based on patient-specific factors and mutational profiles.

Kalinsky is a professor and director in the Division of Medical Oncology of the Department of Hematology and Medical Oncology at Emory University School of Medicine, as well as director of the Glenn Family Breast Center at Winship Cancer Institute in Atlanta, Georgia.

: In recent years, we’ve seen a plethora of trials and agents evaluated in the post–CDK4/6 inhibitor setting in HR-positive breast cancer. What has driven the need to improve strategies in this setting?

 There has been a need for us to have additional endocrine-based treatments, along with targeted therapies, that could really improve how patients do post–CDK4/6 inhibition with endocrine therapy, which we commonly give as frontline therapy. This need is demonstrated by the fact that for some time, including recent studies like [the phase 3] postMONARCH study [NCT05169567] and others, we've had a challenging time with that second line of therapy going beyond 6 months. What's been exciting is that we've seen some recent data where we can exceed that, often with combinations. That's been the real need: having agents that do better than what we've historically [seen].

With several agents receiving FDA approval in recent years in the post–CDK4/6 inhibitor setting, what are some of the factors that inform treatment selection for this patient population?

When we're giving agents after frontline CDK4/6 inhibitor plus endocrine therapy, these decisions are based upon a few things. What's the cadence of disease? Was that patient on that frontline therapy for 6 months? Were they on it for 3 years? [For] patients who are on [CDK 4/6 inhibitor therapy] for a short period of time…how endocrine-sensitive is their tumor, really? Do we need to pivot with a different sort of approach, like capecitabine [Xeloda] or an antibody-drug conjugate, depending upon what's going on? Does the patient have bone-only disease or visceral disease? Is that visceral disease really starting to take off? Those are all important considerations.

[We should also be asking about] the [tumor] genomics, [namely whether] patients have 

 mutations, because we have the approval of 2 single-agent, oral selective estrogen receptor degraders [SERDs]—[elacestrant (Orserdu) and imlunestrant (Inluriyo)]. [I also want to know whether] patients have a 

 pathway alteration, [because] we have approval for fulvestrant [Faslodex] plus capivasertib [Truqap]. Those sort of considerations influence what we give.

At what point in the disease stage are you testing for these alterations?

The most important time when one is thinking about doing testing at the time [a patient is] diagnosed with metastatic disease, is really when you have a patient who is a candidate for alpelisib [Piqray]. They have endocrine therapy that they received in the early-stage setting, and they recurred on or within 12 months of said endocrine therapy. If they have a 

 mutation, then I would argue that the standard of care [SOC] at this point is fulvestrant plus palbociclib [Ibrance] plus alpelisib, which is a PI3K inhibitor, as we've now seen an overall survival benefit [with this agent]. Otherwise, it is very important that we've at least performed genomic testing at the time of progression on that frontline endocrine therapy plus a CDK4/6 inhibitor, because we have targeted therapies based upon patients’ mutational profiles.

What data from ESMO 2025 could help further shape the post-CDK4/6 inhibitor treatment paradigm?

ESMO 2025 was a very good meeting that had data across all of our subtypes of breast cancer. In the metastatic estrogen receptor–positive setting, we saw some interesting data with gedatolisib [PF-05212384], which is a PI3K/mTORC1/2 inhibitor, from [VIKTORIA-1].

 wild-type disease, where we saw that giving gedatolisib along with endocrine-based therapy was better than giving endocrine-based therapy—in this case, fulvestrant—by itself.

[Outcomes with] the triplet of gedatolisib along with palbociclib [and fulvestrant] were numerically even better [than the doublet].Those data were quite interesting. We saw a really nice median PFS in both arms, although [it was] slightly better with the triplet compared to the doublet, [at 9.3 months (95% CI, 7.2-16.6) and 7.4 months (95% CI, 5.5-9.9), respectively]. This comes with the understanding that the adverse effects of that drug include stomatitis, and we do need to monitor for blood sugar. Also, the drug is given intravenously for 3 weeks on and 1 week off.

Then the other interesting study that we saw was the evERA study, which was for patients who were randomly assigned to fulvestrant plus endocrine-based treatment, of which a good proportion of them had fulvestrant plus everolimus [Afinitor] vs giredestrant, which is an oral SERD, along with everolimus.

 In that study, we saw a very nice median PFS favoring the giredestrant arm [vs the SOC]. There was a benefit in the intention-to-treat [ITT] population [HR, 0.56; 95% CI, 0.44-0.71; 

 mutations [HR, 0.38; 95% CI, 0.27-0.54; 

 <.0001]. In a smaller exploratory analysis, they did not see benefit for those who are

 wild-type [HR, 0.84; 95% CI, 0.59-1.18], though I did mention that the ITT population was positive. We'll see if the drug ultimately gets approved and what the indication will be.

The other thing just to note is that there were really no added toxicities with giredestrant. A lot of the toxicities were due to everolimus, like stomatitis. Those were the larger randomized studies that will likely lead to approvals for our patients in terms of therapeutics and clinic.

How do these data underscore the need for a personalized approach to treatment within this setting?

What's been clear is that after frontline therapy, it's complicated. We have different options available. Do you switch the endocrine therapy and give a CDK4/6 inhibitor? Do you use fulvestrant plus capivasertib? Do you give an oral SERD? Will we have access to giving, for instance, elacestrant plus abemaciclib [Verzenio]?

Ultimately, this is going to be an ever-evolving field. We always need to do what's best for our patients, and that includes [asking]: how long were they on their prior therapy? Is the disease endocrine-sensitive? How aggressive is it? Where are the sites? What are the patient's comorbidities? Does the patient have significant diabetes? Are they going to be able to tolerate something like capivasertib?

How we're treating patients in 2025 is going to be different in subsequent years, because we're [developing] additional agents like more selective 

mutation inhibitors; we're also having specific CDK inhibitors. What's going on now is only going to continue to evolve.

Hurvitz SA, Layman RM, Curigliano G, et al. Gedatolisib plus fulvestrant, with & without palbociclib, vs fulvestrant in patients with HR+/HER2-/PIK3CA wild-type advanced breast cancer: first results from VIKTORIA-1. Presented at: 2025 ESMO Congress; October 17-21, 2025; Berlin, Germany. Abstract LBA17.

Mayer E, Tolaney SM, Martin M, et al. Giredestrant (GIRE), an oral selective oestrogen receptor (ER) antagonist and degrader, + everolimus (E) in patients (pts) with ER-positive, HER2-negative advanced breast cancer (ER+, HER2– aBC) previously treated with a CDK4/6 inhibitor (i): Primary results of the phase III evERA BC trial. Presented at: 2025 ESMO Congress; October 17-21, 2025; Berlin, Germany. Abstract LBA16.

Articles

 Kevin Kalinsky, MD, MS, FASCO, discusses treatments and targeted therapies in the post–CDK4/6 inhibitor setting of HR+ breast cancer.

Evolving Post–CDK4/6 Inhibitor Strategies Reflect Need for Precision Approaches in HR+ Breast Cancer

, which provides oncology professionals with the resources and information they need to provide the best patient care. In both digital and print formats, 

 covers every angle of oncology practice, from new technology to treatment advances to important regulatory decisions.

In today’s episode, we had the pleasure of speaking with Kevin Kalinsky, MD, MS, FASCO, about the evolving treatment paradigm for hormone receptor (HR)–positive breast cancer post-CDK4/6 inhibition, as well as the need for more advanced therapies to improve patient outcomes in this setting. Dr Kalinsky is a professor and director in the Division of Medical Oncology of the Department of Hematology and Medical Oncology at Emory University School of Medicine, as well as the director of the Glenn Family Breast Center and the Louisa and Rand Glenn Family Chair in Breast Cancer Research at Winship Cancer Institute in Atlanta, Georgia.

In our exclusive interview, Dr Kalinsky discussed combination therapies that have shown promise for the management of HR-positive breast cancer following endocrine therapy, factors influencing treatment selection for patients who have received prior CDK4/6 inhibition, best practices for genomic testing in this population, and breast cancer research highlights from the 2025 ESMO Congress.

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Podcasts

Dr Kalinsky discusses the treatment paradigm for HR-positive breast cancer post-CDK4/6 inhibition and the need for therapeutic advances in this setting.

Research Innovations Spark Promise for Broadening the HR+ Breast Cancer Armamentarium Post-CDK4/6 Inhibition: With Kevin Kalinsky, MD, MS, FASCO

Dr Kalinsky on the Importance of Novel Second-Line Therapies for HR+ Breast Cancer 

“Additional endocrine-based treatments, along with targeted therapies, could improve how patients do post–CDK4/6 inhibition with endocrine therapy, which we commonly give as frontline therapy.”

Kevin Kalinsky, MD, MS, FASCO, professor and director in the Division of Medical Oncology in the Department of Hematology and Medical Oncology at Emory University School of Medicine, as well as the Louisa and Rand Glenn Family Chair in Breast Cancer Research and the director of the Glenn Family Breast Center at Winship Cancer Institute, discussed the need for additional research to improve treatment strategies in the post–CDK4/6 inhibitor setting for patients with advanced hormone receptor (HR)–positive breast cancer. He also noted factors that inform treatment selection following progression on a CDK4/6 inhibitor–based regimen in this patient population.

Kalinsky began by emphasizing the necessity for additional endocrine-based treatments in the HR-positive breast cancer treatment paradigm, which could enhance patient outcomes after prior CDK4/6 inhibition—a standard frontline treatment. The need for these advances is underscored by the persistent historical challenge associated with determining optimal second-line therapies, he said. In light of clinical data such as those from the phase 3 postMONARCH study (NCT05169567) of abemaciclib (Verzenio) plus fulvestrant (Faslodex) in advanced breast cancer following CDK4/6 inhibitor progression, achieving second-line treatment benefit lasting beyond 6 months remains a clinical challenge, he added.

What has generated considerable excitement, Kalinsky stated, is the observation of recent data demonstrating that this traditional 6-month efficacy threshold can often be surpassed through the strategic use of combination therapies. However, the selection of appropriate second-line therapy is highly individualized, according to Kalinsky, as these clinical decisions are influenced by several key factors.

One consideration involves assessing the cadence of disease progression, he continued. Oncologists must determine the duration of time the patient remained stable on the initial frontline therapy. Benefit for only a brief period raises concern regarding the true endocrine sensitivity of a patient’s tumor, he explained. In situations where endocrine sensitivity is questioned, pivoting toward a different treatment approach, such as the use of capecitabine or an antibody-drug conjugate, may be warranted, he concluded.

Videos

Kevin Kalinsky, MD, MS, FASCO, discusses research needs to improve treatment strategies in the post-CDK4/6 inhibitor setting for HR-positive breast cancer.

Dr Kalinsky on the Importance of Novel Second-Line Therapies for HR+ Breast Cancer

Dr Jhaveri on the Association Between ADCs and Ocular Toxicities in Breast Cancer

“Overall, there are certain toxicities that we see with certain ADCs due to on-target, off-target mechanisms.”

Komal Jhaveri, MD, FACP, section head of the Endocrine Therapy Research Program, clinical director of Early Drug Development Service, and the Patricia and James Cayne Chair for Junior Faculty at Memorial Sloan Kettering Cancer Center, discussed ocular toxicities associated with antibody-drug conjugates (ADCs) commonly used to treat patients with breast cancer.

ADCs deliver a specific payload in a targeted manner, thereby minimizing systemic adverse effects (AEs) and achieving a better toxicity profile than would be possible otherwise, Jhaveri began. The ADC construct is essential because it allows oncologists to offer cytotoxic agents that could not be administered as naked payloads or via the naked antibody, she said. However, despite the conceptual benefits of this targeted delivery, there remains room for improvement in optimizing the ADC platform, she emphasized. Efforts must focus on refining aspects like better linker technologies and improving the technology related to how the payload is delivered to the target, she continued. The overarching goal of these technological advancements is the minimization of off-target toxicities, she summarized.

One category of AEs that has been frequently observed with certain ADCs, particularly TROP-2–directed agents such as datopotamab deruxtecan-dlnk (Datroway) and sacituzumab govitecan-hziy (Trodelvy), is ocular toxicities, according to Jhaveri. Fortunately, ocular AEs are typically low grade and do not often lead to severe clinical complications, she stated. High-grade AEs, such as severe grade 3 keratitis or permanent blindness, are rare, she noted. Rather, symptoms like dry eyes are typically observed, she reported.

These ocular AEs may be related to both on-target and off-target mechanisms, Jhaveri clarified. The potential on-target toxicities are believed to stem from the expression of TROP-2 in the cells of the eye, she explained. In contrast, the off-target toxicities are related to the payload itself and how it is cleaved, leading to a bystander effect that can subsequently affect surrounding tissues, she said.

Ocular toxicities are also seen with sacituzumab tirumotecan, which is an investigational TROP-2–directed ADC currently in late-phase development, Jhaveri stated. Although exciting data for sacituzumab tirumotecan were presented at the 

, the molecule is not yet approved by the FDA, she contextualized.

Komal Jhaveri, MD, FACP, discusses ocular toxicities that can be seen with the use of ADCs when treating patients with breast cancer.  

Dr Dent on the Efficacy of First-Line Dato-DXd in TNBC

“What's remarkable is how consistent the data are.”

Rebecca Dent, MD, MSc, FRCP, deputy chief executive officer (clinical) and a senior consultant at the National Cancer Centre Singapore, discussed key efficacy findings from the phase 3 TROPION-Breast02 trial (NCT05374512) investigating first-line datopotamab deruxtecan-dlnk (Dato-DXd; Datroway) vs investigator’s choice of chemotherapy in patients with locally recurrent inoperable or metastatic triple-negative breast cancer (TNBC) who were ineligible for immunotherapy.

The study met its dual primary end points of progression-free survival (PFS) as assessed by blinded independent central review (BICR), and overall survival (OS), Dent began. Regarding the PFS findings, Dato-DXd demonstrated a statistically significant and clinically meaningful improvement compared with chemotherapy, with a median PFS for the Dato-DXd group (n = 323) of 10.8 months (95% CI, 8.6-13.0) compared with 5.6 months (95% CI, 5.0-7.0) for the chemotherapy group (n = 321), representing a 5.3-month difference and a 43% reduction in the risk of progression or death (HR, 0.57; 95% CI, 0.47-0.69; 

The median OS for patients receiving Dato-DXd reached 23.7 months (95% CI, 19.8-25.6) compared with 18.7 months (95% CI, 16.0-21.8) for those who received chemotherapy; Dato-DXd reduced the risk of death by 21% (HR 0.79; 95% CI, 0.64-0.98; 

 = .0291). This survival benefit observed in the first-line setting is significant because the study population predominantly had a PD-L1 combined positive score of less than 10, according to Dent. She stated that observing such results in this TNBC population and setting had not been seen before these findings.

A remarkable aspect of the data was its consistency across key efficacy measures, Dent emphasized. When evaluating clinical effectiveness, the initial focus often lies on whether a patient is achieving a response, she noted. Dato-DXd achieved more than a doubling of the confirmed objective response rate (ORR) compared with chemotherapy. The ORR for patients receiving Dato-DXd was 62.5% compared with 29.3% for those who received chemotherapy. Furthermore, the study demonstrated a higher complete response rate with Dato-DXd (9.0%) vs chemotherapy (2.5%).

With Dato-DXd, the median duration of response reached 12.3 months (95% CI, 9.1-15.9) compared with 7.1 months (95% CI, 5.6-8.9) for chemotherapy. Despite the median total treatment duration for Dato-DXd being more than double that of chemotherapy (8.5 months, range, 0.7-38.0 vs 4.1 months, range, 0.1-32.0), the rates of grade 3 and serious treatment-related adverse effects were similar between the arms, and discontinuation rates were lower with Dato-DXd.

Rebecca Dent, MD, MSc, FRCP, discusses data from the TROPION-Breast02 trial of frontline Dato-DXd vs chemotherapy in locally recurrent metastatic TNBC.

As antibody-drug conjugates (ADCs) become further integrated into the breast cancer treatment paradigm, proactive management of ocular toxicities and other adverse effects (AEs), along with patient education regarding these toxicities, are key to ensuring patients derive full benefit from treatment, according to Komal Jhaveri, MD, FACP.

“ADCs are here to stay. I envision a time that we might replace traditional systemic chemotherapy, perhaps with multiple sequential ADCs. We might also see a new wave of combination strategies with ADCs and newer-generation ADCs as well. We’re going to see newer datasets where we’re going to start utilizing these agents in early-stage settings,” Jhaveri said. “It’s important that we appreciate what we have learned from our current experiences with these ADCs in the metastatic setting and apply those [AE] management strategies and toxicity management measures. We must educate our patient-facing staff and our patients so we can use these drugs to their most intended benefit for our patients.”

®, Jhaveri discussed how the integration of ADCs has affected the management of various advanced breast cancer subtypes, detailed management strategies for ADC-related toxicities, and explained how awareness and early intervention are crucial for mitigating these AEs.

Jhaveri is the section head of the Endocrine Therapy Research Program, clinical director of Early Drug Development Service, and the Patricia and James Cayne Chair for Junior Faculty at Memorial Sloan Kettering Cancer Center in New York, New York.

: How has the emergence of ADCs affected the management of advanced breast cancer?

: ADCs have truly affected the breast cancer paradigm. [This effort] initiated approximately 1 decade ago with the first prototype ADC—ado-trastuzumab emtansine [T-DM1; Kadcyla]—that got approved for HER2-positive metastatic disease based on the phase 3 EMILIA trial [NCT00829166]. Ever since, we’ve had newer-generation ADCs that initially got approved in HER2-positive breast cancer and replaced T-DM1 in the metastatic setting, but now they have blurred into this subtype modeling that we have. We think about breast cancer subtypes as hormone receptor [HR]–positive, HER2-positive, and triple-negative, but now we have ADCs approved across these subtypes in entities such as HER2-low and HER2-ultralow that could span across these HR-positive and triple-negative subtypes, as well.

We currently have 4 agents that are already approved, starting with T-DM1 initially, later with fam-trastuzumab deruxtecan-nxki [T-DXd; Enhertu] for HER2-positive, then HER2-low, and more recently, HER2-ultralow [disease]. We have had 2 TROP-2[–directed] ADCs [approved], initially with the approval of sacituzumab govitecan-hziy [Trodelvy] in triple-negative breast cancer [TNBC] and later in HR-positive disease. More recently, we have had datopotamab deruxtecan-dlnk [Dato-DXd; Datroway] approved in HR-positive breast cancer, and there were exciting data presented at the 2025 ESMO Congress, where we heard additional data for both sacituzumab govitecan

 in the first-line metastatic TNBC setting. We also heard exciting data for T-DXd in the early stage—both neoadjuvant and adjuvant treatment—of HER2-positive breast cancer. These are exciting times.

As these various ADCs went through clinical trials and eventually entered the clinic, what has been learned about the association between ADCs and ocular toxicities?

ADCs are meant to deliver their payload such that we can minimize the systemic AEs and hopefully achieve a better toxicity profile. Although that is true in a sense because we are delivering toxic payloads, which otherwise we would not be able to offer as a naked payload or the naked antibody without this ADC construct, we still have some more room for improvement in optimizing this platform of ADCs, such as better linker technologies and better technologies in terms of how the payload is delivered to the target [with the goal of] minimizing off-target toxicities.

One of the toxicities that we see has been ocular toxicities, especially with Dato-DXd. This ocular AE that we see is, thankfully, low grade, and it’s not necessarily clinically causing a lot of severe grade 3 AEs, grade 3 keratitis, or blindness. It’s more about dry eyes. We think [dry eyes] are related to both on-target and off-target mechanisms. On-target [toxicities could stem from] expression of TROP-2 in the ocular cells, and then off-target [toxicities could be related] to the payload and how the payload is cleaved, and there is a bystander effect, which can also affect this.

We are seeing [ocular toxicities] with certain molecules. We’re seeing that with another investigational TROP-2–directed ADC, sacituzumab tirumotecan, which is in late-phase development. We saw exciting data for [sacituzumab tirumotecan] as well at ESMO 2025, but that is not yet FDA approved. Overall, there are certain toxicities that we see with certain ADCs due to on-target, off-target mechanisms.

What other AEs have been associated with ADCs?

When we think about these ADCs and the most common toxicities, we have to make sure we can mitigate them in clinic. Nausea is a good example. All these ADCs, predominantly, are considered to be highly emetogenic, and having a 3- or 4-drug antiemetic regimen has been a game changer for my patients in clinic. This is a great reminder for us that there are certain things we can control, modify, and optimize for our patients, because then the tolerability becomes better. Nausea is one of those good examples. We recommend using 3- or 4-drug regimens, the fourth drug being olanzapine, for our patients who are initiating therapy, say with T-DXd or Dato-DXd.

Diarrhea is an important AE associated with sacituzumab govitecan, in addition to neutropenia. We need to be vigilant about those: monitoring the [neutrophil] counts, making sure patients can get growth factor support for neutropenia, making sure they have dietary modifications and antidiarrheals. They can reach out to immediately with the first occurrence of diarrhea, which is important to educate our patients about.

Last, but not least, a relatively rarer but important AE is interstitial lung disease [ILD]/pneumonitis. We see a lot more of that with T-DXd. We see that a little bit with Dato-DXd, but thankfully, [the incidence] is lower. We do not necessarily see ILD/pneumonitis with sacituzumab govitecan. [ILD/pneumonitis] is something we want to be vigilant about, and something we want to educate our fellows, our nursing and any other patient-facing staff, and our patients about. We want to capture [ILD/pneumonitis] on radiological scans without patients having symptoms, because we can interrupt quickly, give them steroids, and still resume therapy at the same dose or at a lower dose. If patients become symptomatic, we want to hear about [those symptoms] quickly so we can discontinue the drug permanently but still offer them steroids and help them treat this ILD/pneumonitis, which otherwise could be fatal.

It is important for us as a community to be vigilant about all these AEs. Alopecia is one other AE I would highlight, because that can happen [with ADCs]. We’re still trying to figure out if scalp cooling would help. There are some trials looking into that question. I have said yes to patients who want to try. I have explained that we don’t know if [scalp cooling] will definitely help, but it is something that we need to discuss with our patients when we initiate these therapies. It is important to know about all these [AEs] so we can help our patients.

With ocular toxicities, what are some of the specific monitoring and management strategies?

For ocular toxicities, the guidance that we have for Dato-DXd, initially in clinical trials and now in the package insert, is that one can consider an ophthalmological assessment at baseline before patients initiate therapy, and then as clinically indicated during therapy. More importantly, avoiding contact lenses and trying to use artificial tears are the best guidance we can provide our patients—that was included in the trials and is now in the package insert. This is the way we would have treated for dry eyes with, say, a given chemotherapy drug, as well. We know chemotherapy does that, too. It can act as an irritant. It causes dry eyes, so using artificial tears and avoiding contact lenses that could be irritable would be helpful in some settings.

What are some unmet needs that still need to be addressed in terms of managing some of these ADC-related toxicities?

We want to use effective drugs up-front so we can offer a better benefit with respect to efficacy to our patients, and that is exactly what we are doing with strategies [being evaluated] in the phase 3 ASCENT-03 [NCT05382299], ASCENT-04 [NCT05382286], and TROPION-Breast02 [NCT05374512] trials. All these trials recently read out and are a testament to the fact that we want to offer effective therapies up-front. This is important not just for the patients who receive these therapies, so they can have better outcomes, but we have also recognized that there is a significant attrition rate. Up to 50% of our patients with TNBC do not make it to second-line therapy, so offering them the best therapies up-front is important, and makes it even more important for us to recognize the safety profiles of these agents, which might be utilized for even longer durations when we’re giving them in the first-line setting. How should we mitigate these AEs so patients can stay on this therapy for the intended duration to derive the benefit and not have to come off that treatment for toxicity-related reasons?

We need to be vigilant about the common toxicities. What are the common grade 3 or higher toxicities that cause dose modifications, dose reductions, and treatment discontinuations? How can we mitigate those, whether with growth factor support for neutropenia; antidiarrheals, dietary management, and hydration for diarrhea; or ice chips or ice during infusions to mitigate stomatitis, which is another important AE associated with Dato-DXd?

We also recommend our patients get dexamethasone mouthwash as a way for primary prophylaxis with Dato-DXd to minimize stomatitis; use artificial tears, avoid contact lenses, and undergo ophthalmological assessments for ocular AEs; and be vigilant about detection and management of ILD/pneumonitis. If we want to use these therapies up-front, we are going to use them for a longer period of time so our patients can have a better benefit. We want to manage these toxicities even more vigilantly and with the most optimal supportive strategies available to us, so patients can stay on these therapies with better outcomes and a better, improved quality of life.

Cortés JC, Bardia A, Punie K, et al. Primary results from ASCENT-03: a randomized phase III study of sacituzumab govitecan (SG) vs chemotherapy (chemo) in patients (pts) with previously untreated advanced triple-negative breast cancer (TNBC) who are unable to receive PD-(L)1 inhibitors (PD-[L]1i). Presented at: 2025 ESMO Annual Congress; October 17-21, 2025; Berlin Germany. Abstract LBA20.

Dent RA, Shao Z, Schmid P, et al. First-line datopotamab deruxtecan (Dato-DXd) vs chemotherapy in patients with locally recurrent inoperable or metastatic triple-negative breast cancer (TNBC) for whom immunotherapy was not an option: primary results from the randomised, phase 3 TROPION-Breast02 trial. Presented at: 2025 ESMO Congress; October 17-21, 2025; Berlin, Germany. Abstract LBA21.

Komal Jhaveri, MD, FACP, discusses management strategies for ocular toxicities and other ADC-related adverse effects in breast cancer.

Education, Proactive Management Are Key to Navigating Ocular Toxicities and Other ADC-Related AEs in Breast Cancer

Consistent efficacy data and a manageable safety profile position datopotamab deruxtecan-dlnk (Dato-DXd; Datroway) to alter the frontline standard of care for patients with advanced triple-negative breast cancer (TNBC) who are ineligible for immunotherapy, particularly among patients with short disease-free intervals (DFIs) between adjuvant therapy and progression to advanced disease, according to Rebecca Dent, MD, MSc.

Findings from the phase 3 TROPION-Breast02 trial (NCT05374512)

 demonstrated that among patients with locally recurrent inoperable or metastatic TNBC who could not receive immunotherapy and were naive to treatment in the advanced setting, Dato-DXd (n = 323) generated a median progression-free survival (PFS) of 10.8 months (95% CI, 8.6-13.0) per blinded independent central review (BICR) compared with 5.6 months (95% CI, 5.0-7.0) for investigator’s choice of chemotherapy (n = 321; HR, 0.57; 95% CI, 0.47-0.69; 

Additionally, patients in the Dato-DXd arm achieved a median overall survival (OS) of 23.7 months (95% CI, 19.8-25.6) compared with 18.7 months (95% CI, 16.0-21.8) for those given chemotherapy (HR, 0.79; 95% CI, 0.64-0.98; 

"We potentially have a new standard of care in the first line [for patients with immunotherapy-ineligible TNBC]. For anybody who's back in clinic, I think we have prospective data that are very consistent. PFS by BICR, PFS by investigator assessment, OS, overall response rate [ORR], and duration of response [DOR] are all consistent,” Dent said. “We also can see this reassuring safety profile that is consistent with what we've seen previously. It is very reasonable to consider [Dato-DXd] in these [patients with] early relapsing TNBC who, to be honest, are very young when we see them in clinic.”

, Dent explained the current treatment challenges for patients with immunotherapy-ineligible advanced TNBC, highlighted the unique design aspects of TROPION-Breast02 that allowed for the enrollment of patients with short DFIs, and expanded on what the efficacy and safety data for the antibody-drug conjugate (ADC) could mean for clinical practice.

Dent is deputy chief executive officer at the National Cancer Center Singapore at SingHealth and a senior consultant in the breast medical oncology service, as well as a professor at Duke-NUS Medical School.

: For patients of advanced TNBC who are ineligible for immunotherapy, what are some of the challenges with current treatment strategies?

: When we're treating patients with advanced or metastatic TNBC, we know that this is a group of patients who—up until recently, especially if they [have] PD-L1–negative [disease]—have [not had any] new therapies for well over a decade. Chemotherapy is the mainstay, and if they've had neoadjuvant therapy, they've already [been exposed to] several types of chemotherapy, so the median PFS is extremely short in those patients [after they reach the advanced setting]. They have aggressive disease, such that many of them don't even have the opportunity to get to second-line [treatment].

Unlike hormone receptor–positive or HER2-positive breast cancers, where we think a lot about [considerations for] first-line or second-line treatment, in TNBC, there is no question. We need to give our best drug first, because approximately 50% of those patients never receive second-line therapy.

What was the rationale behind evaluating Dato-DXd as a single agent in the frontline treatment of patients with advanced TNBC who are ineligible for immunotherapy in TROPION-Breast02?

The technology around ADCs allows us to deliver more potent chemotherapy. The active metabolite for a lot of these ADCs is a topoisomerase I inhibitor, which is the active metabolite of irinotecan, a chemotherapy that we used years ago in breast cancer. It was very active, but it was just too toxic to deliver to patients. The ADC technology allows us to deliver this potent chemotherapy to a level that is easier and better tolerated. In this particular case, [where we’re] giving [Dato-DXd] to patients with TNBC, there's rationale in terms of the type of chemotherapy that's given, but also the delivery mechanism. Giving it in the first line allows us to stabilize that disease.

The second thing is that we know that this ADC technology potentially has immunogenic effects, as well. What you're seeing across numerous ADCs is that you get a fantastic response, and in this trial, we had a more than doubling of the ORR [with Dato-DXd vs chemotherapy], but that response is sustained. Often, when you give chemotherapy in clinic, do that scan, and then a month later, the patient is already progressing. However, [responses in TROPION-Breast02] were sustained—we saw a 5-month improvement in DOR. Therefore, [Dato-DXd] is clearly having an impact on the tumor microenvironment. That's important because that means subsequent therapies are more likely to be effective as well.

How was immunotherapy ineligibility defined for enrollment in TROPION-Breast02? Were there any other key inclusion criteria to note?

This was a first-line trial, and there was no limit on DFI, which is very unusual. What that means is that patients could enroll any time after they had finished their adjuvant therapy, or even [if they had progressed while still] on their adjuvant therapy. Fifteen percent of patients [in the Dato-DXd arm and 16% in the chemotherapy arm] had a DFI was only 0 to 6 months—we capped it at 20%.

Patients were eligible if they had asymptomatic, stable brain metastases—up to 50% of patients with TNBC have brain metastases. The other thing that's unique is that this was a global trial, so we had patients from all around the world who were included. For me, when I'm in clinic, trying to get those [patients with] early relapse on a study is so important, because they really have no other options.

What were the key efficacy data from TROPION-Breast02 presented at the 2025 ESMO Congress?

We had dual primary end points for this study: PFS by BICR and OS. We saw a [5.3-month] improvement in terms of PFS and a HR that was unprecedented, with a 

 value of less than .0001. We also saw a 5.0-month improvement in OS in the first-line setting for a predominantly PD-L1–negative population. [The median OS] was 18.7 months [with chemotherapy vs 23.7 months] in patients getting Dato-DXd. Again, we just have not seen that [type of outcome] in this population in that first-line setting.

What's quite remarkable is the consistency of the data. When you're in clinic, the first thing you look at is if [a patient] is getting a response. We saw more than a doubling of ORR; in patients getting Dato-DXd, the ORR was 62.5%, with a delta of 33.2%. There was also a higher complete response rate [with Dato-DXd (9.0% vs 2.5%)], and the DOR was quite remarkable [12.3 months vs 7.1 months].

What should be known about the safety profile of Dato-DXd in TNBC?

Dato-DXd is a TROP-2–directed ADC. We know now that TROP-2 is expressed in the oral mucosa, as well as the epithelium of the cornea. Comparing patients' median DOR [in TROPION-Breast02] with some of the other trials with Dato-DXd, people were on [treatment] for almost a year.

We also saw higher rates of mucositis. They were mostly grade 1 and 2, but we did see higher rates of grade 3 [mucositis]. At the time of data cut off, 90% of [instances of mucositis] had resolved, and no patients came off study because of mucositis. However, you do need to use prophylaxis. We need to learn how to manage adverse effects [AEs], and our health care professionals who help us need to encourage patients to use the prophylaxis, because it works.

When it comes to ocular surface AEs, patients did have baseline eye exams and were followed every 3 cycles. Again, prophylaxis is important, using those eyedrops. Dose reductions will probably help, because we know [ocular toxicities] are potentially related to TROP-2 expression.

What's really reassuring is the [data for] interstitial lung disease [ILD] and pneumonitis. In both arms, ILD/pneumonitis was rare. No patients in either arm died [due to treatment-related AEs]. What differentiates Dato-DXd from other ADCs that we've seen is that we don't see myelosuppression. We don't see febrile neutropenia. We don't see sepsis.

The once-every-3-week dosing is extremely convenient. The first infusion is 90 minutes, and then subsequently, it's 30 minutes. That's important. We talk a lot about time toxicity for patients who are coming back and forth from the hospital. This is what's important for patients.

Provided that these data help support approval of Dato-DXd for patients with immunotherapy-ineligible TNBC, how might this ADC benefit patients?

Some would argue that anybody [with TNBC] likely benefits from this particular ADC. [In TROPION-Breast02,] 90% of the patients were PD-L1–low [with a combined positive score (CPS) below 10], and 10% were PD-L1–high [with a CPS of at least 10]. It certainly looks like both of those groups benefited [from Dato-DXd].

What we're anxiously awaiting is [data elucidating] whether we can augment [the efficacy of] Dato-DXd even further. We have ongoing trials looking at combining Dato-DXd with immune checkpoint inhibition, and I have a feeling we'll see even more robust data from this. There's more to come, and I think we'll [achieve] even more responses, but only time will tell.

Dent RA, Shao Z, Schmid P, et al. First-line datopotamab deruxtecan (Dato-DXd) vs chemotherapy in patients with locally recurrent inoperable or metastatic triple-negative breast cancer (TNBC) for whom immunotherapy was not an option: Primary results from the randomised, phase 3 TROPION-Breast02 trial. Presented at: 2025 ESMO Congress; October 17-21, 2025; Berlin, Germany. Abstract LBA21.

Rosa K. TROPION-Breast02 data support Dato-DXd as new first-line SOC in triple-negative breast cancer. OncLive.com. October 20, 2025. Accessed October 30, 2025. 

https://www.onclive.com/view/tropion-breast02-data-support-dato-dxd-as-new-first-line-soc-in-triple-negative-breast-cancer

Datopotamab deruxtecan-dlnk (Dato-DXd) shows promise as a new frontline treatment for advanced triple-negative breast cancer (TNBC) patients ineligible for immunotherapy, offering improved progression-free survival (PFS) and overall survival (OS) compared to chemotherapy. The phase 3 TROPION-Breast02 trial demonstrated significant efficacy, with Dato-DXd achieving a median PFS of 10.8 months and OS of 23.7 months. The safety profile is manageable, with mucositis and ocular adverse effects being the most notable concerns. Dato-DXd's potential to alter the standard of care is supported by its consistent efficacy and safety data.

Rebecca Dent, MD, MSc, discusses data from the TROPION-Breast02 trial evaluating first-line Dato-Dxd in immunotherapy-ineligible triple-negative breast cancer

Dato-DXd Could Alter First-Line SOC in Immunotherapy-Ineligible TNBC 

Datopotamab deruxtecan-dlnk (Dato-DXd; Datroway) significantly improved overall survival (OS) and progression-free survival (PFS) compared with investigator’s choice of chemotherapy (ICC) when used as first-line treatment in patients with locally recurrent inoperable or metastatic triple-negative breast cancer (TNBC) for whom immunotherapy was not an option.

The primary results from the phase 3 TROPION-Breast02 trial (NCT05374512), shared during the 

2025 European Society for Medical Oncology (ESMO) Congress

, showed that the median PFS with Dato-DXd (n = 323) was 10.8 months (95% CI, 8.6-13.0) by blinded independent central review (BICR) vs 5.6 months (95% CI, 5.0-7.0) with ICC (n = 321), translating to a 43% reduction in the risk of disease progression or death (HR, 0.57; 95% CI, 0.47-0.69; 

< .0001). The 12-month PFS rates in the respective arms were 45.6% and 25.6%, and the rates at 18 months were 32.7% and 16.8%.

The median OS with the antibody-drug conjugate (ADC) was 23.7 months (95% CI, 19.8-25.6) vs 18.7 months (95% CI, 16.0-21.8) with ICC, translating to a 21% reduction in the risk of death (HR, 0.79; 95% CI, 0.64-0.98; 

= .0291). The 12- and 18-month OS rates with Dato-DXd were 75.2% and 61.2%, respectively; with ICC, these respective rates were 67.8% and 51.3%.

“[The trial] met both dual primary end points, [with] first-line Dato-DXd demonstrating statistically significant and clinically meaningful improvement in OS and PFS over ICC,” Rebecca Dent, MD, MSc, said in a presentation of the data. “TROPION-Breast02 results support Data-DXd as the new first-line standard of care for patients with locally recurrent inoperable or metastatic TNBC for whom immunotherapy is not an option.” Dent is head of the Department of Medical Oncology at the National Cancer Centre Singapore at SingHealth.

opline survival data from TROPION-Breast02

What Unmet Need Does TROPION-Breast02 Address?

Dent opened her presentation by underscoring that advanced or metastatic TNBC is the most aggressive cancer subtype with the fewest available therapeutic options. As such, the 5-year OS rate for those with metastatic disease is only 14.9%.

 Notably, approximately 70% of patients are not candidates for frontline immunotherapy, and for this group, no new first-line approvals have been made in over a decade. These patients receive chemotherapy in the first line, Dent said, and that approach is linked with poor outcomes. Moreover, approximately 50% of patients do not receive treatment beyond the first-line setting, underscoring the need for first-line options, she added.

 enrolled patients with histologically or cytologically documented locally recurrent inoperable or metastatic TNBC who had not previously received chemotherapy or targeted systemic treatment in the locally recurrent inoperable or metastatic setting. Patients had an ECOG performance status of no greater than 1, and immunotherapy was not an option for them. No minimum disease-free interval (DFI) was required.

Study participants were randomly assigned 1:1 to receive Dato-DXd at 6 mg/kg on day 1 every 3 weeks (n = 323) or ICC in the form of paclitaxel, nab-paclitaxel (Abraxane), capecitabine, eribulin mesylate/eribulin, and carboplatin (n = 321). Stratification factors included geographic region (US/Canada/Europe vs other regions), PD-L1 status (high vs low), and DFI (0-12 months vs ≥12 months). Treatment continued until progressive disease by investigator assessment and RECIST criteria, intolerable toxicity, or other discontinuation criteria were met. Patients were permitted to receive subsequent treatment after disease progression or discontinuation.

In addition to the dual primary end points of the trial being OS and PFS by BICR and RECIST 1.1 criteria, key secondary end points included investigator-assessed PFS, objective response rate (ORR), duration of response (DOR), and safety.

For the dual primary end points, a multiple testing procedure with an alpha-exhaustive recycling strategy was utilized. The study would be considered positive if PFS and/or OS analysis data were statistically significant. The data cutoff date for the primary PFS and final OS analysis was August 25, 2025. At this time point, PFS was at 63% maturity with 408 events observed, and OS was at 54% maturity with 349 events observed. Moreover, 14% and 3% of patients in the Dato-DXd and ICC arms, respectively, were still receiving treatment. The median follow-up was 27.5 months (range, 13.3-38.7).

What Do We Know About the Demographic and Baseline Characteristics of Patients Enrolled to TROPION-Breast02?

The median patient age was 56 years (range, 27-85) in the ADC arm vs 57 years (range, 23-83) in the ICC arm. Almost all patients were female (100%; 99%), and more than half were from geographic regions beyond the US, Canada, or Europe (63%; 63%), with an ECOG performance status of 0 (60%; 57%). In the Dato-DXd arm, 47% of patients were Asian, 41% were White, 9% were other, and 4% were Black or African American. In the ICC arm, 48% of patients were White, 41% were Asian, 7% were other, and 4% were Black or African American.

In terms of DFI history, in the Dato-DXd arm, 34% had de novo disease, 21% had a prior DFI ranging from 0 to 12 months, 15% had a prior DFI ranging from 0 to 6 months, and 46% had a prior DFI longer than 1 year; in the ICC arm, these rates were 34%, 21%, 16%, and 45%, respectively. Regarding PD-L1 status, in the ADC arm, 89% of patients had a combined positive score (CPS) of 10 or lower, and 11% had a CPS of 10 or higher; in the ICC arm, these rates were 91% and 9%, respectively. Most patients across the Dato-DXd and ICC arms had visceral metastases (78%; 73%), and about one-third had liver metastases (29%; 31%). In the respective arms, 11% and 9% of patients had brain metastases. More than half of patients had fewer than 3 metastatic sites (64%; 67%).

The preselected choice of chemotherapy for the Dato-DXd arm was nab-paclitaxel for 56% of patients, paclitaxel for 25%, eribulin mesylate/eribulin for 13%, carboplatin for 3%, and capecitabine for 2%; in the ICC arm, these rates were 54%, 29%, 11%, 4%, and 2%.

What Additional Efficacy Data Were Reported with Dato-DXd?

The investigator-assessed PFS with the ADC was 9.6 months (95% CI, 7.4-11.2) vs 5.2 months (95% CI, 4.2-5.6) with ICC, consistent with the findings reported by BICR (HR, 0.56; 95% CI, 0.47-0.67). The 12-month PFS rate with Dato-DXd was 40.7% vs 18.5% with ICC; the respective 18-month rates were 27.5% and 9.2%.

Dato-DXd elicited a confirmed ORR of 62.5% compared with 29.3% with ICC, representing a difference of 33.2% between the arms (OR, 4.24; 95% CI, 3.03-5.95). In the ADC arm, 9.0% of patients had a complete response (CR) as their best overall response, 53.6% had a partial response, and 26.9% had stable disease; 8.4% of patients experienced disease progression, and 2.2% were not evaluable. “With Dato-DXd, confirmed ORR was more than double that with ICC, and [the] confirmed CR rate was more than 3 times that with ICC,” Dent said.

The median DOR with Dato-DXd was 12.3 months (95% CI, 9.1-15.9) compared with 7.1 months (95% CI, 5.6-8.9) with ICC, translating to a 5.2-month difference.

What Was the Safety Profile of Dato-DXd in Locally Recurrent Inoperable or Metastatic TNBC?

The median treatment duration with the ADC was 8.5 months (range, 0.7-38.0) vs 4.1 months with ICC (range, 0.1-32.0). Any-grade treatment-related adverse effects (TRAEs) occurred in 93% of patients in the Dato-DXd arm (n = 319) compared with 83% of those in the ICC arm (n = 309); the rates of grade 3 or higher TRAEs were 33% and 29%, respectively. Serious TRAEs were reported in 9% of those who received Dato-DXd and in 8% of those given ICC. In the ADC arm, TRAEs led to dose interruption or reduction for 24% and 27% of patients, and treatment discontinuation for 4% of patients; in the ICC arm, TRAEs resulted in dose interruption, dose reduction, or treatment discontinuation in 19%, 18%, and 7% of patients, respectively.

“Despite more than double the median duration of treatment in the Dato-DXd arm, rates of grade 3 or higher and serious TRAEs were similar, and discontinuations were lower with Dato-DXd [than with] ICC,” Dent underscored.

In the Dato-DXd arm, the most common TRAEs reported in at least 15% of patients included dry eye (any grade, 24%; grade ≥ 3, 1%), stomatitis (57%; 8%), nausea (45%; < 1%), constipation (23%; < 1%), vomiting (20%; 1%), decreased appetite (15%; < 1%), neutropenia (12%; 3%), anemia (15%; 2%), leukopenia (8%; < 1%), peripheral neuropathy (4%; 0%), alopecia (41%; 0%), and fatigue (32%; 3%).

For the ADC, TRAEs of special interest included oral mucositis or stomatitis (grade 1, 24%; grade 2, 27%; grade ≥ 3, 8%). These effects resulted in dose interruption for 3% of patients and dose reduction for 11% of patients. For 90% of patients, grade 2 or higher effects resolved to grade 1 or lower at the time of data cutoff. Other TRAEs of special interest included dry eye (grade 1, 16%; grade 2, 7%; grade 3, 1%), keratitis (7%; 4%; 2%), and conjunctivitis (2%; 4%; <1%). These effects resulted in dose interruption for 6% of patients, dose reduction for 4% of patients, and discontinuation for fewer than 1% of patients. In 67% of patients with grade 2 or higher TRAEs, their toxicities resolved to grade 1 or lower. Adjudicated drug-related interstitial lung disease or pneumonitis (grade 1, <1%; grade 2, 2%; grade 3, <1%) was also reported.

“The Dato-DXd safety profile was manageable and generally consistent with the known profile,” Dent said.

Disclosures: Dent serves in a consulting or advisory role for AstraZeneca, Daiichi Sankyo/AstraZeneca, Eisai, Gilead Sciences, MSD, Novartis, Pfizer, and Roche. She received travel, accommodation, and expense support from AstraZeneca, Daiichi Sankyo/AstraZeneca, Eisai, MSD, Novartis, Pfizer, and Roche. She received honoraria from AstraZeneca, Daiichi Sankyo/AstraZeneca, DKSH, Eisai, Gilead Sciences, MSD, Novartis, Pfizer, and Roche. Research funding to her institution was received by Roche and AstraZeneca.

Datroway (datopotamab deruxtecan-dlnk) demonstrated statistically significant and clinically meaningful improvement in overall survival as 1st-line therapy for patients with metastatic triple-negative breast cancer for whom immunotherapy was not an option in TROPION-Breast02. News release. AstraZeneca. October 6, 2025. Accessed October 19, 2025. https://www.astrazeneca-us.com/media/press-releases/2025/DATROWAY-datopotamab-deruxtecan-dlnk-demonstrated-statistically-significant-and-clinically-meaningful-improvement-in-overall-survival-as-1st-line-therapy-for-patients-with-metastatic-triple-negative-breast-cancer-for-whom-immunotherapy-was-not-an-option-in-TROPION-Breast02.html

Datopotamab deruxtecan-dlnk (Dato-DXd) has shown significant improvements in overall survival (OS) and progression-free survival (PFS) compared to chemotherapy in patients with locally recurrent inoperable or metastatic triple-negative breast cancer (TNBC) who are not candidates for immunotherapy. The phase 3 TROPION-Breast02 trial demonstrated a 43% reduction in disease progression risk and a 21% reduction in death risk with Dato-DXd. The trial results suggest Dato-DXd as a new first-line standard of care for this patient group, addressing a critical unmet need in TNBC treatment.

Dato-DXd improved PFS, OS, and response rates compared with chemotherapy in first-line TNBC, with manageable safety, per phase 3 TROPION-Breast02 data.

TROPION-Breast02 Data Support Dato-DXd as New First-Line SOC in Triple-Negative Breast Cancer

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