Key Takeaways

• For patients with HR-positive/HER2-positive metastatic breast cancer whose disease has not progressed following induction therapy, palbociclib in combination with trastuzumab, with or without pertuzumab, and endocrine therapy is now FDA approved for maintenance treatment.
• Use of intensified first-line maintenance therapy involves consideration of patient goals, including delaying progression for as long as possible, medication burden, monitoring requirements, and potential adverse events.

In this commentary, Erika Hamilton, MD, and Otto Metzger, MD, address key questions raised during a recent workshop series titled, “Optimizing First-line Maintenance for HER2+ MBC: Equipping the Multidisciplinary Team With the Latest Evidence and Guidance on Novel Regimens.” During the workshops, the expert faculty discussed the evolving first-line maintenance therapy landscape for HER2-positive breast cancer based on the recent findings from the PATINA and HER2CLIMB-05 trials, integration of trastuzumab deruxtecan (T-DXd) plus pertuzumab into first-line care, and practical strategies for treatment selection and toxicity management. The following commentary is built on audience questions and highlights the faculty’s perspectives on personalizing maintenance therapy for patients with HER2-positive metastatic breast cancer.

How do you explain the purpose and potential benefits of first-line maintenance therapy to a patient with HER2-positive metastatic breast cancer?

Erika Hamilton, MD:
When counseling patients, I explain that maintenance therapy is intended to preserve the disease control achieved with initial treatment while reducing the cumulative adverse events (AEs) associated with continued taxane chemotherapy. Historically, many patients have received approximately 6 cycles of induction taxane with trastuzumab and pertuzumab, followed by discontinuation of the taxane and continuation of dual anti-HER2 therapy. For patients with hormone receptor (HR)–positive disease, endocrine therapy (ET) should be added to ongoing HER2-targeted therapy after chemotherapy is discontinued to provide continued suppression of hormone receptor signaling.

The options for maintenance have increased for therapy selected patients based on the phase III PATINA trial.  Here, adding palbociclib to maintenance therapy anti-HER2 therapy (HP) and endocrine therapy prolonged median progression-free survival (PFS) from 29.1 months to 44.3 months (hazard ratio [HR], 0.75; 95% CI, 0.59-0.96; P = .02). This improvement of approximately 15 months is meaningful for a patient whose primary goal is to delay progression without continuing conventional cytotoxic chemotherapy.

I also emphasize that maintenance therapy does not mean treatment is unnecessary or that monitoring can stop. Rather, we are changing the treatment strategy to sustain disease control with a regimen that may be more suitable for long-term use.

Otto Metzger, MD:
I agree. In addition, I explain why the terms “induction” and “maintenance” are used, which reflect a shift from an initial, more intensive taxane-containing regimen to achieve disease control to a less toxic ongoing regimen intended to maintain that control after the taxane is discontinued. It does not mean that every patient requires increasingly intensive therapy at each phase.

Many patients experience an excellent response after a relatively short course of induction with a taxane, trastuzumab, and pertuzumab (THP). In PATINA, approximately 70% of patients achieved a complete or partial response to induction therapy, a response rate similar to that observed before randomization in the phase III HER2CLIMB-05 trial, which evaluated the addition of tucatinib to trastuzumab and pertuzumab as first-line maintenance in patients with newly diagnosed HER2-positive metastatic breast cancer. These findings provide a strong rationale for discontinuing chemotherapy and continuing a better-tolerated long-term strategy.

For patients with HR-positive/HER2-positive disease, I explain that the cancer is being driven by both HER2 and estrogen receptor signaling. Maintenance therapy therefore provides an opportunity to target both pathways, with palbociclib added based on its potential to address mechanisms of resistance to endocrine and anti-HER2 therapies. This makes the palbociclib-containing maintenance strategy biologically rational as well as clinically supported.

Which patients with HR-positive/HER2-positive metastatic breast cancer are appropriate candidates for palbociclib-based first-line maintenance therapy?

Otto Metzger, MD:
Palbociclib is FDA approved in combination with trastuzumab with or without pertuzumab and ET for the maintenance treatment of adults with HR-positive/HER2-positive locally advanced or metastatic breast cancer following induction treatment. PATINA is particularly relevant because it was conducted in settings where patients had access to contemporary subsequent therapies.

The PATINA population provides the clearest clinical framework for which patients are appropriate candidates. Patients had received 4-8 cycles of taxane-based chemotherapy with anti-HER2 therapy, with a median of 6 induction cycles, and had no evidence of disease progression before beginning maintenance therapy. Nearly all (94%) had received trastuzumab plus pertuzumab during induction. However, a patient did not need to achieve a complete response to be eligible. Patients with stable disease after induction were also enrolled.

In practice, I would consider this approach for a patient with confirmed HR-positive/HER2-positive disease who has achieved disease control with induction therapy, is able to reliably take an oral agent, and does not have a contraindication to the regimen. I would assess baseline blood counts, prior marrow tolerance, comorbidities, concomitant medications, endocrine therapy history, and the patient’s willingness to undergo regular laboratory monitoring.

Erika Hamilton, MD:
I would discuss palbociclib-based maintenance with eligible patients with HR-positive/HER2-positive disease after successful THP induction. The magnitude of benefit observed in PATINA was larger than many anticipated, and it was achieved without requiring continued conventional cytotoxic chemotherapy.

With that said, eligibility does not automatically mean the treatment is right for every patient. I would consider the quality and duration of response to induction, baseline blood counts and prior neutropenia, functional status and comorbidities, tolerance to anti-HER2 therapy and ET, feasibility of oral adherence and laboratory monitoring, quality-of-life priorities, and whether the patient considers the additional PFS benefit worth the additional toxicity and treatment burden.

Some patients may prioritize the most intensive available strategy to delay progression for as long as possible, whereas others may place greater value on minimizing pills, monitoring, and AEs. Both are legitimate considerations.

How do you select the ET to combine with palbociclib and anti-HER2 therapy?

Otto Metzger, MD:
ET should not be treated as an optional or secondary component in HR-positive/HER2-positive metastatic breast cancer. The disease is biologically distinct from HR-negative/HER2-positive disease, and targeting estrogen receptor signaling remains important.

Most patients (91%) in PATINA received an aromatase inhibitor (AI). For a patient with de novo metastatic disease or no meaningful prior endocrine exposure, an AI is a straightforward option. Prior adjuvant therapy exposure does not necessarily rule out another AI. For example, a patient previously treated with anastrozole or letrozole may reasonably switch to exemestane in the metastatic setting for maintenance therapy, depending on the timing of recurrence and prior endocrine sensitivity.

Fulvestrant was also permitted and may be appropriate for patients whose disease recurs while receiving an AI, recurs shortly after completing one, or who cannot tolerate AIs. PATINA allowed flexibility in ET selection, with either an AI or fulvestrant permitted, and LHRH agonist therapy was required for premenopausal women. The choice should reflect prior exposure, timing of recurrence, menopausal status, tolerability, bone health, route-of-administration preferences, and adherence considerations.

Erika Hamilton, MD:
I use prior endocrine history to guide the decision. If a patient completed an AI several years earlier and then developed metastatic disease, I would still be comfortable using an AI, but I may select a different agent. If the disease recurred while the patient was actively receiving an AI or shortly after stopping it, fulvestrant may be more appropriate.

I would also involve the patient in the decision. Some patients prefer oral therapy and want to avoid injections. Others have substantial arthralgias, bone density concerns, or difficulty adhering to daily medication and may favor fulvestrant. The goal is to select an endocrine partner that the patient can realistically continue over the long term.

How are you going to be thinking about first-line maintenance therapy considering results from both the PATINA and HER2CLIMB trials?

Erika Hamilton, MD:
Both PATINA and HER2CLIMB-05 demonstrated that adding another targeted agent to trastuzumab and pertuzumab maintenance can delay disease progression, but they studied different populations and should not be compared as though they were head-to-head trials.

PATINA was limited to patients with HR-positive/HER2-positive disease and required ET. HER2CLIMB-05 enrolled patients regardless of HR status, and ET was permitted but not required for HR-positive disease. In HER2CLIMB-05, adding tucatinib to trastuzumab and pertuzumab improved median PFS from 16.3 months to 24.9 months (hazard ratio: 0.641; 95% CI: 0.514-0.799; P < .0001).

For a typical patient with HR-positive/HER2-positive disease who has completed taxane plus trastuzumab-based induction therapy without disease progression, palbociclib-based maintenance is a particularly compelling option because it directly addresses both HR and HER2 biology and is now FDA approved in this setting. Tucatinib-based maintenance may be more relevant to discuss in selected clinical scenarios, such as in a patient with known brain metastases or disease that appears strongly driven by HER2 biology, although tucatinib is not FDA approved in the maintenance setting. Therefore, this use would be considered off-label. The central nervous system analyses from HER2CLIMB-05 should also be interpreted carefully, because only 12.4% of patients had brain metastases at baseline, and the analysis in that subgroup was exploratory.

Otto Metzger, MD:
The most important principle is to recognize that HER2-positive breast cancer is not a single biologic entity. HR-positive/HER2-positive disease should not be managed as though the estrogen receptor pathway is irrelevant.

One limitation when interpreting HER2CLIMB-05 data is that fewer than half of the patients with HR-positive disease received concurrent ET. This differs from how many healthcare professionals manage HR-positive/HER2-positive disease and may partly explain why the control arm in HER2CLIMB-05 performed differently than the control arm in PATINA, along with differences in the enrolled populations, including that only about half of patients in HER2CLIMB-05 had HR-positive disease.

I would therefore avoid stating that 1 maintenance regimen is categorically superior based on median PFS values across separate trials. For an eligible patient with HR-positive/HER2-positive disease, PATINA provides directly applicable phase III evidence for adding palbociclib to anti-HER2 therapy and ET. For a patient with HR-negative disease, palbociclib-based maintenance does not apply, and a HER2-focused approach such as tucatinib-based maintenance may be more relevant, recognizing that this use is not currently FDA approved.

How do you select between first-line T-DXd plus pertuzumab and THP followed by palbociclib-based maintenance for a patient with HR-positive/HER2-positive disease?

Erika Hamilton, MD:
DESTINY-Breast09 demonstrated a significant PFS benefit with first-line T-DXd plus pertuzumab (median PFS: 40.7 months) vs THP (median PFS: 26.9 months) (hazard ratio: 0.56; 95% CI: 0.44-0.71; P <.00001), and the combination was FDA approved for first-line use in December 2025. In addition, complete responses were reported in 15.1% vs 8.5% of patients, respectively. These results make T-DXd plus pertuzumab a compelling first-line option.

However, the choice is not based on efficacy alone. T-DXd plus pertuzumab is associated with nausea, fatigue, cytopenias, alopecia, and interstitial disease (ILD)/pneumonitis. In DESTINY-Breast09, ILD occurred in approximately 12% of patients receiving T-DXd plus pertuzumab vs 1% receiving THP, and grade 5 ILD occurred in 2 patients. The regimen was administered until disease progression and did not allow to account for any type of maintenance regimen, so this has to be taken into account.

I am more likely to consider first-line T-DXd plus pertuzumab for a patient with aggressive or highly symptomatic disease, a need for the greatest possible depth of response, HR-negative disease, early recurrence following prior HER2-directed treatment, clinically meaningful CNS involvement, or concern that the patient may not reach later lines of therapy. Ultimately breast advances move at a rapid pace and we may also need to consider thinking about maintenance even for some patients who do receive the DB-09 regimen even in the absence of formal clinical trial data to support.

Otto Metzger, MD:
I frame this as a question of using T-DXd now or later, rather than now or never. T-DXd remains highly effective in later-line treatment, and many patients achieve substantial and sometimes very durable disease control with THP followed by maintenance.

The DESTINY-Breast09 results are clearly positive, but several factors deserve consideration. The control arm continued the taxane plus trastuzumab and pertuzumab until progression or unacceptable toxicity, which differs from routine practice, where chemotherapy is generally discontinued after several cycles. In addition, the use and availability of subsequent therapies varied across participating regions, which may complicate interpretation of outcomes beyond the initial PFS analysis.

For a patient with HR-positive/HER2-positive disease who has a good response to THP, I frequently favor a PATINA-based maintenance strategy, which targets both the HER2 and estrogen receptor pathways, provides a long period without conventional cytotoxic chemotherapy for many patients, and preserves T-DXd as an effective later-line option.

I would be more cautious about first-line T-DXd in a patient with preexisting pulmonary disease, increased risk of ILD, substantial comorbidity, difficulty tolerating nausea or fatigue, or a strong preference to avoid alopecia and ongoing intravenous antibody–drug conjugate treatment.

What should patients know about the AE profile of palbociclib-based maintenance, and how do you manage recurrent grade 3 neutropenia?

Otto Metzger, MD:
The most important and most common expected AE is neutropenia. I explain that a decline in the neutrophil count is common with palbociclib, but it differs biologically and clinically from the marrow toxicity associated with many conventional chemotherapies. Febrile neutropenia was reported in approximately 0.8% of patients receiving palbociclib in PATINA. However, infections were among the reported serious adverse reactions, so patients should be instructed to report fever or other signs of infection promptly.

PATINA also reported fatigue, stomatitis, leukopenia, and increased diarrhea. The diarrhea finding deserves thoughtful interpretation because some patients entered maintenance with residual diarrhea after THP, and pertuzumab itself can cause diarrhea. Nevertheless, healthcare professionals should respect the observed trial data and assess baseline bowel patterns before initiating treatment.

I tell patients that laboratory monitoring, treatment interruptions, and dose reductions are tools that help keep them safely on treatment. A dose reduction should not be framed as treatment failure. The goal is to find a sustainable dose that maintains disease control and quality of life.

For recurrent grade 3 neutropenia at the beginning of a cycle, palbociclib should be held and the complete blood count (CBC) repeated. The prescribing information directs that a dose reduction be considered for recurrent grade 3 neutropenia on Day 1 of subsequent cycles, and in that situation, I would generally resume at the next lower dose once the neutrophil count has recovered. I would also assess for fever, infection, unusually prolonged neutropenia, other cytopenias, interacting medications, or another explanation for marrow suppression.

Erika Hamilton, MD:
I set expectations before treatment begins. Patients should understand that palbociclib is an oral anticancer therapy that requires scheduled dosing, laboratory monitoring, and communication with the care team. They should report fever or signs of infection, persistent or worsening diarrhea, painful mouth sores, increasing fatigue that interferes with daily activities, new or worsening cough or shortness of breath that could signal ILD, and any difficulty obtaining or consistently taking their medications.

For a patient who develops grade 3 neutropenia for the first time at the beginning of a cycle, palbociclib is generally held, the CBC is repeated within 1 week, and therapy is resumed at the same dose once the count recovers to grade 2 or lower, in the absence of febrile neutropenia or another clinical indication. If grade 3 neutropenia recurs on Day 1 of a subsequent cycle, I would hold palbociclib, repeat the CBC, and generally resume at the next lower dose after recovery. Continuing the full dose without interruption would not be appropriate, and routine granulocyte colony-stimulating factor is generally not necessary simply to preserve the original dose.

Nurses and pharmacists are essential for reviewing the dosing calendar, identifying interactions with strong CYP3A inhibitors and inducers, and counseling patients to avoid grapefruit products, reinforcing when blood counts are due (before starting, at the beginning of each cycle, on Day 15 of the first 2 cycles, and as clinically indicated), and making sure that patients know whom to contact between visits.

Your Thoughts
Are you incorporating palbociclib-based maintenance therapy into care for patients with HR-positive/HER2-positive metastatic breast cancer? What challenges have you encountered in the setting of first-line maintenance therapy for patients with HER2-positive MBC?