Part XI · Hormone receptor-positive, HER2-negative disease · Chapter 66
Conjugates and chemotherapy in later lines
Why four conjugate trials against physician's choice chemotherapy still leave the order of giving them unmeasured.
1 · Scope, and the point at which endocrine therapy is exhausted
This chapter covers what happens after endocrine-based therapy stops working in metastatic hormone receptor-positive, HER2-negative disease. It covers the three antibody-drug conjugates with randomised evidence in this population, the sequencing problem they create, and the place single agent chemotherapy still holds.
The phrase endocrine exhausted is a clinical judgment and not a test result. It is worth being explicit about what it usually means in practice. A patient has progressed on an aromatase inhibitor with a CDK4/6 inhibitor, then on at least one further endocrine-based line chosen by biomarker, and no remaining endocrine option matches a detectable alteration. Or the disease is moving fast enough that waiting to find out is not safe.
Both halves of that definition are soft. The first depends on which alterations were tested for and when. The second depends on a judgment about tempo that no scan reports.
Advanced disease · HR+/HER2- · later
Choosing the next treatment after CDK4/6 inhibition fails
When should endocrine-directed treatment give way to chemotherapy or an antibody-drug conjugate?
Rationale
The convention is to hold cytotoxic treatment back while any endocrine option remains, because endocrine treatment is easier to live with. The convention assumes the remaining endocrine option still works. After a CDK4/6 inhibitor that is exactly what is in doubt. A conjugate was meant to move the threshold by delivering a cytotoxic payload only to cells carrying a surface antigen.
Experiment
Two trials randomised a CDK4/6 inhibitor with endocrine therapy against capecitabine in endocrine-resistant disease. Two more randomised a TROP2-directed conjugate against chemotherapy of the physician's choice, at different depths of prior chemotherapy. One asked whether adding a checkpoint inhibitor to such a conjugate helped. A single-arm study took a HER3-directed conjugate into disease that had had a CDK4/6 inhibitor and a line of chemotherapy. One ongoing trial moves the TROP2 conjugate ahead of the first chemotherapy line.
Finding
The two capecitabine trials disagree on progression-free survival. The disagreement follows their populations rather than their drugs. Neither of them produced an overall survival difference, which is the one thing they agree on. Both TROP2-directed conjugates lengthened progression-free survival against physician's choice chemotherapy. Only one of the two also lengthened overall survival. Adding a checkpoint inhibitor to a conjugate did not lengthen progression-free survival. The HER3-directed conjugate produced responses in a single arm.
Limitation
Neither capecitabine trial belongs to this position as it stands, because both gave a CDK4/6 inhibitor to patients who had never had one. They differ from each other in menopausal status and in how much of the population had had any treatment for metastatic disease, which is enough to explain the disagreement without invoking the drugs. Physician's choice names a different set of agents in each conjugate trial and in each country. The comparator is therefore not a fixed quantity across them. The two conjugate trials also sit at different depths of prior chemotherapy, which is the other reason their results are not interchangeable. A progression-free survival gain not followed by a gain in overall survival is a difference measured on imaging. The conjugate whose survival curves lay on top of each other is the warning this class has to answer. The checkpoint result that looks positive is a secondary analysis confined to the patients with evaluable tissue scoring PD-L1-positive. It is not significant.
Next question
If a conjugate beats chemotherapy after endocrine treatment has failed, does it belong ahead of the first chemotherapy line?
Where a section carries a clinical question from the [Chapter Stories](stories.html) map, that question opens it. The story says what was being looked for and what the design cannot settle. A table says what else is in the cell. The prose argues the decision.
Conjugate trials reaching this population.
The HER2-low trials are included because most of their patients had hormone receptor-positive disease.
Patients with hormone receptor-positive, HER2-negative metastatic breast cancer pretreated with endocrine therapy and zero or one chemotherapy regimen for metastatic disease, with no prior topoisomerase I inhibitor.
Sacituzumab govitecan plus pembrolizumab versus sacituzumab govitecan alone, randomised 1 to 1.
At 15.5 months median follow-up, sacituzumab govitecan plus pembrolizumab did not significantly improve progression-free survival compared with sacituzumab govitecan alone, median 8.4 versus 6.7 months, hazard ratio 0.76 (95% CI 0.48 to 1.19), P = 0.12.
Median overall survival was 20.0 versus 18.0 months (P = 0.18).
Patients with hormone receptor-positive, HER2-negative metastatic breast cancer who had previously progressed on CDK4/6 inhibitors and one line of chemotherapy.
Single arm of patritumab deruxtecan (HER3-DXd) 5.6 mg/kg intravenously every 3 weeks.
The study met its primary endpoint, with an overall response rate of 53.5% (90% CI 44.8 to 62.1).
not reported; overall response rate was the primary endpoint
hormone receptor-positive HER2-low or HER2-ultralow disease after one or more endocrine lines and no chemotherapy for metastatic disease; 713 HER2-low, 153 ultralow
trastuzumab deruxtecan vs physician's choice chemotherapy
median PFS 13.2 vs 8.1 months in HER2-low disease, HR 0.62
not yet reported, immature at the primary analysis
metastatic breast cancer in three cohorts by HER2 immunohistochemistry, 72 overexpressing, 74 HER2-low and 40 non-expressing; 177 in the full analysis set
trastuzumab deruxtecan, single arm in each cohort
response 70.6% in HER2-overexpressing, 37.5% in HER2-low and 29.7% in non-expressing disease
Secondary endpoint. At a median follow-up of 14.1 months, median overall survival was not reached in the HER2-overexpressing or HER2-low cohorts and was 11.6 months (95% CI 8.3 to 17.3) in the non-expressing cohort. Single arm in each cohort, so there is no comparison.
endocrine-resistant HR+/HER2-, all with prior endocrine therapy, a taxane and a CDK4/6 inhibitor, two to four prior chemotherapy regimens for metastatic disease
sacituzumab govitecan vs physician's choice chemotherapy
HER2-low metastatic disease after one or two chemotherapy lines; 494 of 557 hormone receptor positive
trastuzumab deruxtecan vs physician's choice chemotherapy
median PFS 10.1 vs 5.4 months in the hormone receptor-positive cohort, HR 0.51
median OS 23.9 vs 17.5 months in the hormone receptor-positive cohort, HR 0.64
Four of those rows are the same experiment. A conjugate was randomised against the physician's choice of single-agent chemotherapy in disease out of endocrine options, and each lengthened the time to progression. That is the only claim the table supports as a class. Everything else in it varies. None of the variation is between one conjugate and another.
The first difference is where the patient was standing when she entered. Eligibility is written in units of prior chemotherapy rather than in units of biology. TROPiCS-02 required two to four previous chemotherapy regimens for metastatic disease. TROPION-Breast01 and DESTINY-Breast04 required one or two. DESTINY-Breast06 required none, and excluded anyone who had had chemotherapy for metastatic disease at all. Read down the population column and the four trials line up as a ladder. That ordering is an artefact of protocol writing rather than a tested sequence, and stacking the medians would compare populations rather than drugs. A hazard ratio from the shallowest of them describes a decision the deepest never tested.
The second difference is one of measurement. Two of the four required an assay result for the antibody's own target, and two required nothing of the kind. Trop-2 expression was never an entry criterion, so those trials enrolled whoever qualified on treatment history alone. The HER2-low trials enrolled on a staining category, which is a threshold on a continuous stain rather than a biological boundary HER2-low and ultralow reframed as a heterogeneity problem. A patient's eligibility moves with the assay in one pair of trials and not in the other.
The third difference is the endpoint. Only one of the four named overall survival a primary endpoint. That is the trial that failed it. Two of the others reported survival separately and one has not, because follow-up was short when the primary analysis was done. A blank survival cell and a tested negative survival result are different objects. The column cannot tell them apart.
The three remaining rows answer other questions and should not be read as further conjugate comparisons. SACI-IO HR+ randomised the addition of a checkpoint inhibitor to a conjugate rather than a conjugate against chemotherapy, and belongs to Unresolved questions and what reads out next. DAISY and ICARUS-BREAST01 are single-arm. One maps activity across the HER2 staining range, and the other carries the same payload class to a third antigen.
Two comparisons are missing. Neither can be supplied by longer follow-up. No row sets one conjugate against another. And no trial here randomised the decision that precedes everything in the table, which is whether to leave endocrine-based therapy at all. Every patient in every row had already been judged ready for a cytotoxic by the clinician who enrolled her.
The order within the class is therefore set by eligibility and habit rather than by evidence, and Sequencing conjugates and the cross-resistance problem is where that problem is worked through. Two trials that set a CDK4/6 inhibitor against capecitabine are sometimes quoted at this point and do not belong to it. Both gave the inhibitor to patients who had never had one, which is not the patient this chapter is about. They are argued in Single-agent chemotherapy and when it remains the right choice.
2 · Sacituzumab govitecan in hormone receptor-positive disease
TROPiCS-02 is where this drug's position rests. The reason is the depth of what it randomised. Every patient had received endocrine therapy, a taxane and a CDK4/6 inhibitor, together with two to four prior chemotherapy regimens for metastatic disease8. The control arm was the menu of single agents such a patient would otherwise have been given.
The result to hold is that survival moved and not only the time to progression6. Overall survival gains are rare this far into the disease, which is why the trial changed practice despite absolute medians measured in months. Set a patient's expectations from those medians rather than from the hazard ratio.
Trop-2 expression did not select the responders. The survival benefit was consistent across expression subgroups measured by immunohistochemistry6. That sits awkwardly beside the biomarker analysis of the same drug in triple-negative disease, where progression-free survival tracked a Trop-2 expression gradient9. The two findings are usually reported as if they conflict.
They may not. The triple-negative analysis graded progression-free survival across three expression bands in a subset of assessable patients, and it was exploratory9. The hormone receptor-positive analysis reported overall survival by subgroup6. Different endpoint, different population, different analysis plan. The safest reading is that Trop-2 staining has never been shown to identify a group that should not receive the drug, which is the only question a clinician needs answered.
The toxicity is predictable and is managed rather than avoided. Neutropenia and diarrhoea dominate, and both are payload effects rather than target effects Toxicity mechanisms, interstitial lung disease, ocular, and mucosal. UGT1A1 genotype affects SN-38 clearance and is worth knowing before the first dose in a patient with a suggestive history.
What the trial cannot support is the use most clinics now want. Its population had exhausted several cytotoxic lines, so nothing in it establishes the drug ahead of the first of them. That question is being asked prospectively and is taken up in Unresolved questions and what reads out next.
3 · Trastuzumab deruxtecan in HER2-low and HER2-ultralow disease
Two randomised trials moved this drug progressively earlier in the same population, and the second also moved the eligibility boundary. DESTINY-Breast04 enrolled patients with HER2-low disease after one or two prior chemotherapy lines, and the large majority had hormone receptor-positive disease7. DESTINY-Breast06 enrolled after endocrine-based therapy and before any chemotherapy for metastatic disease, and it added a HER2-ultralow cohort4.
They agree on the thing that matters. Against the physician's choice of chemotherapy, at two different depths of prior treatment, the conjugate delayed progression. Where they part is on survival. That is a difference of maturity rather than of effect. The earlier trial has reported survival with long follow-up10. The later one had too few events at its primary analysis to say anything, which is what a trial reads out when it is moved forward into a population that lives longer.
DAISY argues that the boundary is arbitrary from the other direction. It gave the same conjugate across three staining cohorts and confirmed responses occurred well above zero in immunohistochemistry 0 disease5. Within that cohort, response did not track the underlying ERBB2 transcript level either. Activity does not stop where the scoring category does. The study is single-arm, so it cannot say whether those patients would have done as well on chemotherapy, and the randomised ultralow evidence remains an exploratory cohort of one trial.
Caution
DESTINY-Breast06 is often read as showing that a conjugate should replace endocrine therapy once resistance appears. It shows something narrower. Its comparator was chemotherapy, and every patient enrolled had already been judged ready for chemotherapy. The trial therefore establishes that if the next line is cytotoxic, the conjugate is the better cytotoxic choice. It does not establish when to leave endocrine-based therapy, which is the decision that actually precedes it Endocrine therapy and receptor degraders after progression.
Interstitial lung disease is the toxicity that should shape the decision, because it is the one that can be fatal. Adjudicated interstitial lung disease or pneumonitis occurred in 11.3% of patients given the conjugate in DESTINY-Breast06 against 0.2% of those given chemotherapy4. In a patient with pre-existing lung disease, a low baseline oxygen saturation or prior thoracic radiotherapy, that asymmetry is a reason to think carefully about ordering. Surveillance and management are in Toxicity mechanisms, interstitial lung disease, ocular, and mucosal, and the difference between a grade 1 and a grade 5 event is mostly how early it was found.
4 · Datopotamab deruxtecan and the TROP2 question
TROPION-Breast01 carried two primary endpoints, progression-free survival and overall survival. It met the first and missed the second. The final survival analysis gave a hazard ratio for death of 1.01, with a confidence interval from 0.83 to 1.2211.
That combination is worth separating from the more common pattern of an unpowered secondary endpoint failing to confirm a progression-free survival result. Here survival was a stated primary endpoint that the trial was designed and powered to test. The trial answered its own question and the answer was no.
Three explanations have been offered and none has been excluded. Subsequent conjugate use was imbalanced, at 12.3% in the datopotamab arm against 24.0% in the chemotherapy arm, which would favour the control arm after progression11. Progression-free survival was assessed by blinded central review in an open-label trial, where the timing of scans and the decision to stop treatment are not blinded. Or the drug may delay progression in this setting without extending life.
The target itself does not resolve the question. Trop-2 is an address rather than a driver, chosen because it is differentially expressed on epithelium and not because tumours depend on it Antibody, linker, and payload design. Normal tissue expression is what limits the dose, which is why the dominant toxicities are mucosal and ocular rather than marrow-based. Two conjugates against the same antigen carrying the same payload class still differ in dominant toxicity. Linker chemistry and normal tissue handling separate them rather than the target Toxicity mechanisms, interstitial lung disease, ocular, and mucosal.
The practical consequence is a ranking argument rather than a prohibition. Where more than one conjugate is available and the disease is hormone receptor-positive, an agent that met a survival endpoint has a stronger claim than one that missed it. That inference crosses two trials with different entry criteria and different comparator menus. It should be labelled as such. Nobody has randomised the two drugs against each other, and no trial has selected patients for either one by Trop-2 staining.
5 · Sequencing conjugates and the cross-resistance problem
Advanced disease · HR+/HER2- · later
Antibody-drug conjugates after endocrine therapy
Does a second antibody-drug conjugate work after a first one has failed?
Rationale
The conjugates used here share a payload mechanism while differing in the antibody. If resistance is to the payload, changing the antibody buys nothing. If it is to the target, to its internalisation or to trafficking inside the cell, a different address might still work. Patients now arrive in later lines having already had a conjugate. The question has stopped being theoretical.
Experiment
A HER3-directed conjugate was given as a single arm after progression on CDK4/6 inhibition and a line of chemotherapy. Paired baseline and on-treatment biopsies were taken, to see how far the drug distributed inside the tumour and what the tumour did in response. A prospective study is now assigning a second conjugate after a first, in separate cohorts defined by which conjugate came before.
Finding
Redirecting the payload to a third antigen met its response endpoint in a population already treated with CDK4/6 inhibition and chemotherapy. The on-treatment tissue work associated efficacy with how far the conjugate distributed within the tumour and with an interferon response. At baseline the associations ran to where the receptor sat in the tissue and to the absence of an ESR1 mutation, with receptor level itself tracking only the progression endpoint.
Limitation
The HER3 study is single-arm. Its response rate has nothing to be read against and cannot rank HER3 delivery against another conjugate or against chemotherapy. That response is reported with a narrower confidence interval than the randomised trials beside it use, which is what a single-arm design of this kind specifies and not a sign of greater precision. The on-treatment biopsies come only from patients who stayed on the drug long enough to be rebiopsied. That is selection on the very outcome the biomarkers are being asked to explain. The authors state that every association is pending validation. The prospective sequencing study is still running. Its cohorts are non-comparative by design. It will report activity after a conjugate rather than the value of a sequence.
Next question
If the limit is the payload rather than the address, does adding checkpoint blockade to the conjugate make it work harder?
ICARUS-BREAST01TRADE-DXd
Three conjugates are now used in this population. They engage two antigens and they all carry a topoisomerase I inhibitor payload. That is the whole problem in one sentence.
A fourth antibody makes the point sharper rather than softer. ICARUS-BREAST01 took a HER3-directed conjugate into patients who had progressed on a CDK4/6 inhibitor and one line of chemotherapy, and met its response endpoint2. Its target is a third antigen. Its payload is the same deruxtecan class as two of the three agents already in use. Adding antigens does not add payload classes. Payload class is what the preclinical work in Mechanisms of conjugate resistance shows carrying cross-resistance.
That response rate has nothing to be read against. The study is single-arm, so it cannot rank HER3 delivery against another conjugate or against the chemotherapy those patients would otherwise have had. Its interval is reported at 90% rather than 95%, which is what a single-arm design of this kind specifies and not a sign of greater precision. Comparing it with the intervals in the randomised rows above is comparing two different constructions.
Its correlative work is the more interesting part. It also carries a selection problem worth naming. Baseline associations ran to where the receptor sat in the tissue and to the absence of an ESR1 mutation, while receptor level itself tracked only the progression endpoint2. The on-treatment associations ran to how far the conjugate distributed inside the tumour and to an interferon response. Those came from biopsies taken only in patients who stayed on the drug long enough to be rebiopsied. That is selection on the very outcome the biomarkers are being asked to explain. The authors state that all of it awaits validation.
The mechanistic case for expecting cross-resistance, and the preclinical work separating target loss from payload resistance and from transporter change, is set out in Payload class, cross-resistance, and sequencing between conjugates and Mechanisms of conjugate resistance. Three findings from there govern this section and are not repeated. Resistance can arise at any of six steps. Only the first of those steps is measured by any assay in clinical use. And payload class, rather than the conjugate as a unit, is what preclinical models show carrying the cross-resistance.
The clinical evidence for a second conjugate is a retrospective series of 85 patients who received two in sequence, described in Payload class, cross-resistance, and sequencing between conjugates12. It is consistent with partial rather than complete cross-resistance. It is also 85 patients treated off protocol, which is the best evidence available for a decision made many times a week. TRADE-DXd is the first prospective test and it has not reported. Its cohorts are defined by which conjugate came first and are non-comparative by design, so it will estimate how much activity survives a conjugate rather than rank one order against another.
What no trial in this chapter did is randomise the order of the same drugs. The design that answers a sequencing question randomises the position and then measures progression on the line after next, which is how SONIA settled the first-line CDK4/6 argument13. No conjugate trial and no chemotherapy trial in this disease has been built that way. Until one is, moving a drug earlier is demonstrated for the first segment of the sequence and assumed for the rest.
What follows for practice is a rationale and not a result, and the difference should be stated to patients. HER2-low or ultralow status determines whether trastuzumab deruxtecan is an option at all, so it is worth establishing before the conjugate decision rather than during it. Trials enrolled these agents at different depths of prior treatment, so the trial populations imply an ordering even though no trial compared orders. And a patient who progressed quickly on the first conjugate has, on the retrospective data, a poor prospect from the second.
Interplay
This is the clearest clinical instance of the ceiling argued in Where heterogeneity sets a ceiling on precision medicine. The decision is made on an antigen measurement taken from one block at one time, and that measurement answers only whether the antibody can bind. It says nothing about internalisation, lysosomal transport, efflux or repair capacity. A proportion of what is recorded here as conjugate failure is therefore allocation failure, and no improvement in the payload addresses it. Raising the ceiling requires a different kind of measurement rather than a better drug.
6 · Single-agent chemotherapy and when it remains the right choice
Antibody-drug conjugates after endocrine therapy, continued
Once chemotherapy is reached, does the choice of agent matter?
Rationale
Two newer taxane formulations and an epothilone were developed to improve on weekly paclitaxel. The argument was that a different delivery vehicle, or a different tubulin-binding site, would raise response or lower toxicity. Each had promising single-arm data before the comparison was run.
Experiment
Three-arm randomisation of weekly nab-paclitaxel and weekly ixabepilone against weekly paclitaxel, each with bevacizumab, in chemotherapy-naive advanced disease.
Finding
Neither experimental agent improved progression-free survival and one was clearly worse. The oldest and cheapest arm was the best of the three.
Limitation
The comparison was made in chemotherapy-naive disease with a bevacizumab backbone, and the chapter that carries it is about later lines where the alternatives are conjugates rather than single agents. A negative result against paclitaxel does not establish how any of these agents performs after a conjugate has failed.
Next question
If single-agent chemotherapy has a settled answer, is the remaining question only when to stop reaching for a conjugate and use it?
CALGB 40502 / NCCTG N063H
Antibody-drug conjugates after endocrine therapy, continued
Once endocrine therapy is exhausted, does an antibody-drug conjugate beat the single-agent chemotherapy a clinic would otherwise give?
Rationale
The payload inside these conjugates is an ordinary cytotoxic. What the antibody changes is where that payload is delivered, not what it does to a dividing cell. The question was therefore whether a better address buys enough tumour exposure to beat giving the same class of drug systemically and accepting the toxicity that follows.
Experiment
Three randomised phase III trials gave a conjugate against physician's choice of single-agent chemotherapy in disease that was hormone receptor-positive and out of endocrine options. They do not all address the same antigen. They also set different requirements for how much chemotherapy a patient had to have had before entry. The control arm in each was drawn from the same short menu of single agents. That menu had been assembled by earlier trials that set those agents against physician's choice and against one another.
Finding
Each conjugate lengthened the time to progression against physician's choice chemotherapy. Overall survival did not follow in every case. In the trial that made progression-free survival and overall survival both primary, progression-free survival moved against chemotherapy. Overall survival did not.
Limitation
Physician's choice is a composite control rather than a drug. The trials that assembled that menu did not find its members interchangeable in the way the phrase implies. One of them showed a single agent lengthening overall survival against physician's choice in heavily pretreated disease. Another set one menu agent against another and separated them on neither co-primary endpoint. So the comparator is an average of agents whose relative merit was never settled, rather than the drug a particular clinician would have chosen for a particular patient. The three conjugate trials also demanded different amounts of prior chemotherapy before entry. They cannot be stacked into a sequence or read as a ranking. The dual-primary trial is the standing warning here, because it shows that a progression-free survival gain against chemotherapy in this setting does not convert into a survival gain on its own.
Next question
If the payload does the killing, does the antigen the antibody binds select anyone, or does it only have to be present?
Antibody-drug conjugates after endocrine therapy, continued
Should a conjugate replace the first chemotherapy rather than follow it?
Rationale
Every trial that established these drugs enrolled after chemotherapy had already been given. What they measured is the value of a conjugate at that point in the course. Moving it forward means giving a drug with its own distinctive toxicity to people who might have done well for a long time on one gentle cytotoxic. It also means giving it to people who might not have needed cytotoxic treatment at all yet.
Experiment
One phase III trial moved the HER2-directed conjugate ahead of any chemotherapy for metastatic disease in endocrine-pretreated patients, against physician's choice chemotherapy. Two TROP2 trials are doing the same in the first chemotherapy slot and have not reported. From the opposite direction, a randomised trial in aggressive disease compared endocrine therapy with a CDK4/6 inhibitor against combination chemotherapy, asking whether cytotoxic treatment was needed at that point at all.
Finding
The conjugate given before any chemotherapy lengthened time to progression against physician's choice chemotherapy, with overall survival immature at that analysis. Endocrine therapy with a CDK4/6 inhibitor outlasted combination chemotherapy in aggressive disease that would once have gone straight to cytotoxic treatment. Both results push conventional single-agent chemotherapy out of the slot it used to hold, from opposite directions.
Limitation
The control arm in the earlier-line conjugate trial is the same physician's-choice menu. Its overall survival was immature at the primary analysis. A longer time to first progression is currently the whole of the case for moving the drug forward. The aggressive-disease trial is phase II and premenopausal. It enrolled on a clinical judgement of aggressiveness rather than on a stated threshold. It therefore does not define who can safely be kept off chemotherapy. Most of all, no trial here randomised the order of the same drugs. The design that would answer that randomises the position and then measures progression on the line after next. That is how the first-line CDK4/6 question was settled. It is not how any conjugate in this position has been studied.
Next question
Does giving the conjugate earlier lengthen the whole sequence or only its first segment, and will any conjugate trial measure the second progression rather than the first?
Conjugates have displaced single-agent chemotherapy from several positions without abolishing it.
It remains the answer in four situations. The first is after conjugate exposure, where the remaining options are cytotoxic and the expectations are covered in Long-term disease control and the cost of staying on treatment. The second is where a conjugate is contraindicated, and a history of interstitial lung disease is the common example, given the pneumonitis rate in DESTINY-Breast064. The third is where access to a conjugate is not available, which is a real constraint in most of the world Global breast cancer care. The fourth is rapid progression requiring a response now, covered in Rapid progression and visceral crisis.
What belongs here beside those four is the evidence about choosing among the agents themselves.
Randomised chemotherapy comparisons reaching this population.
Adults with germline BRCA1 or BRCA2 mutated advanced HER2-negative breast cancer, ECOG 0 to 2, up to two previous chemotherapy lines for metastatic disease.
Veliparib plus carboplatin and paclitaxel versus placebo plus carboplatin and paclitaxel, randomised 2:1.
Median progression-free survival was 14.5 months with veliparib versus 12.6 months with placebo, hazard ratio 0.71 (95% CI 0.57 to 0.88), p=0.0016.
Final analysis, a secondary endpoint, gave median overall survival 32.4 months with veliparib versus 28.2 months with placebo, hazard ratio 0.916 (95% CI 0.736 to 1.140), P=0.434. Not significantly improved.
Postmenopausal patients with hormone receptor-positive, HER2-negative metastatic breast cancer resistant to aromatase inhibitors.
Palbociclib plus exemestane or fulvestrant versus capecitabine.
In cohort 2 median progression-free survival was 7.5 months with palbociclib plus fulvestrant versus 10.0 months with capecitabine, adjusted hazard ratio 1.13 (95% CI 0.85-1.50). In wild-type ESR1 patients it was 8.0 versus 10.6 months, adjusted hazard ratio 1.11 (95% CI 0.87-1.41). Palbociclib plus endocrine therapy was not superior.
Median overall survival in cohort 2 was 31.1 months with palbociclib plus fulvestrant versus 32.8 months with capecitabine, adjusted hazard ratio 1.10 (95% CI 0.81-1.50, p=0.550). In the wild-type ESR1 population it was 37.2 versus 34.8 months, adjusted hazard ratio 1.06 (95% CI 0.81-1.37, p=0.683).
Premenopausal women aged 19 years or older with hormone receptor-positive, HER2-negative metastatic breast cancer progressing on tamoxifen, performance status 0 to 2.
Palbociclib plus exemestane with leuprolide ovarian suppression versus capecitabine.
Median progression-free survival was 20.1 months with palbociclib plus exemestane and ovarian suppression versus 14.4 months with capecitabine, hazard ratio 0.659, one-sided p=0.0235.
In the 2025 analysis, median overall survival was 54.8 months with palbociclib plus endocrine therapy versus 57.8 months with capecitabine, hazard ratio 1.02, p=0.92. There was no overall survival difference.
Patients aged 18 years or older with chemotherapy-naive locally recurrent or metastatic breast cancer.
Weekly nab-paclitaxel or weekly ixabepilone versus weekly paclitaxel, each with bevacizumab.
Median progression-free survival was 11 months with paclitaxel, 9.3 months with nab-paclitaxel (hazard ratio 1.20, 95% CI 1.00 to 1.45, p=0.054) and 7.4 months with ixabepilone (hazard ratio 1.59, 95% CI 1.31 to 1.93, p<0.001). Neither experimental arm beat paclitaxel.
Overall survival results were concordant with progression-free survival, favouring neither experimental arm. No survival figures were given in the abstract.
two to five prior chemotherapy regimens including an anthracycline and a taxane
eribulin vs treatment of physician's choice
median OS 13.1 vs 10.6 months, HR 0.81
median OS 13.1 vs 10.6 months, HR 0.81
That table holds four questions rather than one. Reading it as a ranking of cytotoxics misreads all four. Two rows ask whether one named single agent beats another. One asks whether a single agent beats the menu a physician would otherwise have chosen from. Three ask whether endocrine therapy with a CDK4/6 inhibitor can be given instead of chemotherapy at all. One adds a PARP inhibitor to a chemotherapy backbone and belongs to the table below as much as to this one.
On the first question the answer is consistently negative. That is the finding to carry. Study 301 compared eribulin with capecitabine directly and separated them on neither co-primary endpoint19. CALGB 40502 / NCCTG N063H set nab-paclitaxel and ixabepilone against weekly paclitaxel as first chemotherapy for advanced disease, and neither experimental arm beat it18. The ixabepilone arm was clearly the worse of the two. Within the menu of single agents there is no demonstrated best drug. Choice is therefore driven by prior exposure, residual neuropathy, marrow reserve, renal and hepatic function, route and schedule. Those are patient variables, not trial variables. Capecitabine, eribulin, vinorelbine, gemcitabine and a weekly taxane are the working set, and agent detail is in Cytotoxic chemotherapy.
EMBRACE looks like an exception and is not one. It showed that a single cytotoxic agent can extend survival after several previous chemotherapy regimens20. That was not the expectation at the time. It remains the reason eribulin holds its position. The difference from Study 301 is design rather than drug. EMBRACE set eribulin against a composite of whatever the physician would otherwise have chosen, with overall survival as the sole primary endpoint, in a deeply pretreated population. Study 301 set it against one named agent, earlier in the disease, with two co-primary endpoints to satisfy. Beating an average of agents is not the same test as beating a particular one.
The substitution question divides on design too. Young-PEARL / KCSG-BR15-10 and PEARL both compared palbociclib with endocrine therapy against capecitabine, and they disagree on progression-free survival17,16. The populations are not the same. One enrolled premenopausal women progressing on tamoxifen and added ovarian suppression, at phase 2 with a one-sided test. The other enrolled postmenopausal women resistant to an aromatase inhibitor, at phase 3, with co-primary endpoints in a cohort and in an ESR1 wild-type subset. They agree on the endpoint that does not depend on a scan schedule. Neither showed an overall survival difference against capecitabine21,22. Substituting endocrine therapy with a CDK4/6 inhibitor for a cytotoxic changes how the time is spent rather than how much of it there is. That is the honest way to offer it. Both trials also enrolled patients who had never received a CDK4/6 inhibitor, which no longer describes anyone reaching a second line.
RIGHT Choice asks the same substitution question in aggressive disease, against combination rather than single-agent chemotherapy14. It is phase 2, its survival data are not yet reported, and its limits are discussed in Rapid progression and visceral crisis. It supports an older principle rather than replacing it. Combination chemotherapy raises response rate and toxicity together, while sequential single agents preserve function and allow more lines.
One group of patients should not reach that table at all. In germline carriers the physician's choice of chemotherapy was the comparator in two registration trials rather than the standard.
PARP inhibitor trials whose populations reach this chapter.
All enrolled HER2-negative disease, so hormone receptor-positive patients sit inside every row. Read the population column first. The entry criteria differ more between these trials than the drugs do.
Patients with pretreated advanced HER2-negative breast cancer, wild-type for BRCA1 and BRCA2, whose tumours carried a mutation in a homologous recombination pathway gene other than BRCA1 and BRCA2, enrolled alongside a parallel cohort of other solid tumours.
Single arm of open-label talazoparib monotherapy.
Four of the 13 patients with breast cancer had a RECIST partial response, an overall response rate of 31%, and three additional patients had stable disease of at least 6 months, a clinical benefit rate of 54%. All patients with germline PALB2 mutations had treatment-associated tumour regression.
not reported; the breast cancer cohort of 13 patients reported response and clinical benefit rates only
Adults with germline BRCA1 or BRCA2 mutated advanced HER2-negative breast cancer, ECOG 0 to 2, up to two previous chemotherapy lines for metastatic disease.
Veliparib plus carboplatin and paclitaxel versus placebo plus carboplatin and paclitaxel, randomised 2:1.
Median progression-free survival was 14.5 months with veliparib versus 12.6 months with placebo, hazard ratio 0.71 (95% CI 0.57 to 0.88), p=0.0016.
Final analysis, a secondary endpoint, gave median overall survival 32.4 months with veliparib versus 28.2 months with placebo, hazard ratio 0.916 (95% CI 0.736 to 1.140), P=0.434. Not significantly improved.
Patients aged 18 years or older, or 19 years or older in South Korea, with a germline BRCA1 or BRCA2 mutation and histologically confirmed progressive HER2-negative metastatic breast cancer and no more than two previous lines of chemotherapy for metastatic disease, enrolled at 14 centres in the UK, the USA, Israel, France, Switzerland and South Korea.
Single arm of olaparib 300 mg orally twice daily for four weeks, then olaparib 300 mg twice daily with durvalumab 1.5 g intravenously every four weeks until disease progression.
24 of 30 patients eligible for the activity analysis had disease control at 12 weeks, 80% (90% CI 64.3 to 90.9). Grade 3 or worse adverse events occurred in 11 of the 34 patients treated, 32%.
not reported; the primary endpoints were safety and tolerability and the disease control rate at 12 weeks
metastatic breast cancer with germline mutations in homologous recombination related genes other than BRCA1 and BRCA2 (cohort 1) or somatic mutations in those genes or in BRCA1/2 (cohort 2); 76% oestrogen receptor-positive HER2-negative
Single arm of olaparib 300 mg orally twice daily in two cohorts, cohort 1 germline mutations in homologous recombination genes other than BRCA1 and BRCA2, cohort 2 somatic mutations in those genes or in BRCA1 or BRCA2.
Objective response rate was 33% (90% CI 19% to 51%) in cohort 1 and 31% (90% CI 15% to 49%) in cohort 2. Confirmed responses occurred only with germline PALB2, response rate 82%, and with somatic BRCA1 or BRCA2, response rate 50%. Median progression-free survival was 13.3 months and 6.3 months in those two groups. No responses occurred with ATM or CHEK2 mutations alone.
Not reported. Overall survival was not an endpoint of this single-arm study.
germline BRCA1 or BRCA2 mutated HER2-negative advanced disease; 287 assigned talazoparib and 144 physician's choice chemotherapy
Talazoparib 1 mg once daily versus the physician's choice of single-agent chemotherapy, capecitabine, eribulin, gemcitabine or vinorelbine in continuous 21-day cycles, randomised 2:1.
Median progression-free survival was 8.6 months with talazoparib versus 5.6 months with chemotherapy, hazard ratio 0.54 (95% CI 0.41 to 0.71), P<0.001. Objective response rate was 62.6% versus 27.2%.
Final analysis gave median overall survival 19.3 months with talazoparib versus 19.5 months with chemotherapy, hazard ratio 0.848 (95% CI 0.670 to 1.073), P=0.17. Adjusting for subsequent PARP inhibitor and platinum use gave a hazard ratio of 0.756 (95% bootstrap CI 0.503 to 1.029).
germline BRCA1 or BRCA2 mutated HER2-negative metastatic disease with no more than two previous chemotherapy lines; 205 assigned olaparib and 97 standard therapy
Olaparib tablets 300 mg twice daily versus the physician's choice of single-agent chemotherapy, capecitabine, eribulin or vinorelbine in 21-day cycles, randomised 2:1.
Median progression-free survival was 7.0 months with olaparib versus 4.2 months with chemotherapy, hazard ratio 0.58 (95% CI 0.43 to 0.80), P<0.001. Response rate was 59.9% versus 28.8%.
Planned final analysis at 64% maturity gave median overall survival 19.3 months with olaparib versus 17.1 months with chemotherapy, hazard ratio 0.90 (95% CI 0.66 to 1.23), P=0.513. Not significantly improved.
The decision rests on OlympiAD and EMBRACA, because they randomised a PARP inhibitor against the thing the clinic would otherwise have done27,26. They agree twice over. Each lengthened progression-free survival against the physician's choice of chemotherapy, and neither improved overall survival at its final analysis28,29. A germline result therefore changes which class the next line comes from. It also changes how the line is tolerated. Neither trial showed that it changes how long the patient lives. What those two trials did and did not establish is read in full in PARP inhibition for germline carriers.
The other four rows differ from those two by design rather than by drug. The population column is where the difference sits. BROCADE3 gave a PARP inhibitor with a platinum doublet rather than in place of chemotherapy. Its question is therefore addition and not substitution, and its final analysis found no significant overall survival difference15,30. TBCRC 048 and Talazoparib Beyond BRCA moved eligibility off germline BRCA1 and BRCA2, both single-arm25,23. One took germline mutations in other homologous recombination genes in one cohort and somatic mutations, including somatic BRCA1 and BRCA2, in a second. The other took germline BRCA wild-type tumours carrying a mutation elsewhere in that pathway. MEDIOLA breast cohort added PD-L1 blockade to olaparib in a single arm, so nothing in it separates the contribution of the second drug from the first24.
Those two beyond-BRCA cohorts nonetheless agree on something the randomised trials never tested. Widening eligibility beyond germline BRCA1 and BRCA2 produces responses with some genes and none with others, with germline PALB2 the clearest of them25,23. A panel report naming any homologous recombination gene is not a PARP inhibitor indication. That agreement rests on two small uncontrolled cohorts. The randomised trial that would settle it does not exist.
Neither table holds the comparison a carrier in this chapter actually faces. No trial randomises a PARP inhibitor against a conjugate, in either order, and none of the conjugate trials stratified on germline status. The sequence is chosen on class reasoning and on tolerability.
In practice
Say what the line is for before starting it. Control of a symptom, protection of a threatened organ, and extension of time are different aims with different evidence behind them.
Choose the agent by what the patient can tolerate rather than by expected efficacy, because the comparative trials show no efficacy difference within the class.
Test for a germline BRCA1 or BRCA2 mutation before choosing the cytotoxic rather than after, since the result moves the patient into a different table.
Re-check performance status before each new line rather than at progression. A patient who has had three conjugates and two cytotoxics is a different physiological proposition from the trial populations above.
Ask about access explicitly. Conjugate availability is the binding constraint in most of the world, and single-agent chemotherapy is the realistic comparator there rather than the fallback Global breast cancer care.
Antibody-drug conjugates after endocrine therapy, continued
Does adding checkpoint blockade to a TROP2 conjugate improve on the conjugate alone?
Rationale
A topoisomerase payload kills in a way that releases tumour antigen and can draw immune cells into the tumour, which is the standard argument for putting a conjugate next to a checkpoint inhibitor. Hormone receptor-positive disease is the least immunogenic of the common subtypes. If a conjugate is what makes a tumour visible to the immune system, this is where an added effect should be easiest to attribute to the conjugate rather than to the tumour's own starting immunogenicity.
Experiment
A randomised phase II trial gave a TROP2 conjugate with or without a checkpoint inhibitor, in disease pretreated with endocrine therapy and at most one chemotherapy regimen. Progression-free survival was the primary endpoint. The PD-L1-positive population was a key secondary one. A phase III trial is now testing the same addition with a different TROP2 conjugate, ahead of any chemotherapy, against physician's choice chemotherapy. Elsewhere in this subtype, checkpoint blockade has been given either in single-arm combinations, where the partner drug cannot be separated from the checkpoint inhibitor, or in populations selected for a high mutational burden.
Finding
Adding the checkpoint inhibitor did not improve progression-free survival over the conjugate alone in the population unselected for PD-L1. The PD-L1-positive subgroup pointed in the favourable direction without reaching significance. Elsewhere in this subtype, checkpoint blockade has produced responses only where the population was selected for a mutational phenotype.
Limitation
The PD-L1 result is a key secondary analysis, confined to the patients who had evaluable tissue and scored positive on it. It did not reach significance. Its own authors describe it as a trend for larger randomised trials to test rather than as a result. Eligibility also allowed entry with no chemotherapy at all for metastatic disease, and much of the enrolled population came in on that basis. The trial therefore sits earlier in the course than the line at which this conjugate is registered in this subtype. A single line label is covering a mixed population. The single-arm combination that sits beside it cannot establish what its checkpoint inhibitor added, as its authors say themselves, so it supplies no counterweight in either direction. The mutational-burden study selected on a threshold that its own correlative subgroup was too small to fix. It says that selection matters without saying where the line falls. The randomised comparison here is phase II and was not sized to exclude the size of effect a phase III would chase. The phase III now putting the same addition ahead of chemotherapy is the trial that will settle it.
Next question
If neither a partner drug nor a measured biomarker improves on the conjugate, does the remaining lever become where in the sequence the conjugate is given?
SACI-IO HR+MK-2870-010NIMBUSMEDIOLA breast cohort
The checkpoint question has now been asked properly once and answered negatively. SACI-IO HR+ randomised pembrolizumab with a Trop-2 conjugate against the conjugate alone, and progression-free survival did not improve in the population unselected for PD-L11. The PD-L1-positive analysis pointed the favourable way without reaching significance. It is a key secondary endpoint, restricted to the patients with evaluable tissue who scored positive on a combined positive score of at least 1. Its own authors present it as a trend for larger trials to test.
Its population is the part to read carefully. Entry allowed no chemotherapy at all for metastatic disease, and close to half the patients came in on that basis1. The trial therefore sits earlier in the disease than the line at which this conjugate is registered in this subtype. Its results therefore pool two different clinical situations, before and after chemotherapy for metastatic disease.
Nothing else in the subtype weighs against that result. MEDIOLA breast cohort combined a checkpoint inhibitor with olaparib in a single arm. Its authors say plainly that the design cannot show what the checkpoint inhibitor added24. NIMBUS produced responses only after selecting patients on tumour mutational burden. Its threshold subgroup is too small to fix where the cut-off should fall. Selection matters and nobody has measured where the line is.
SACI-IO HR+ also returned a useful null on measurement. Neither Trop-2 by immunohistochemistry, immunofluorescence or plasma epigenome-based assay, nor tumour-infiltrating lymphocytes, was associated with outcome, while a higher circulating tumour DNA fraction and PIK3CA mutations tracked worse progression-free survival1. Three ways of measuring the target all failed to select anyone, which is the same finding Sacituzumab govitecan in hormone receptor-positive disease reports from a different trial.
Conjugate trials in this population that have not reported.
Trial
Population
Experimental vs control
Primary endpoint
ASCENT-073 · 654 · awaited
endocrine-resistant HR+/HER2- disease with no previous chemotherapy for metastatic disease
sacituzumab govitecan vs physician's choice chemotherapy
progression-free survival by blinded independent central review
MK-2870-0103 · 1200 · ongoing
progression on one or more endocrine lines including a CDK4/6 inhibitor, chemotherapy candidates
sacituzumab tirumotecan alone or with pembrolizumab vs physician's choice chemotherapy
progression-free survival
TRADE-DXd2 · 357 · ongoing
HER2-low or HER2 immunohistochemistry 0 disease progressing on a previous antibody-drug conjugate, hormone receptor positive and negative cohorts
datopotamab deruxtecan or trastuzumab deruxtecan after previous conjugate exposure, non-comparative cohorts
objective response rate in the first and second conjugate cohorts
ASCENT-07 tests sacituzumab govitecan against chemotherapy in endocrine-resistant disease with no prior chemotherapy for metastatic disease. That is the slot DESTINY-Breast06 now occupies, so a positive result would create a genuine choice between two conjugates at one decision point, with no trial comparing them.
MK-2870-010 does two things at once. It brings a third Trop-2 conjugate into that same slot, carrying a topoisomerase I inhibitor payload again, so it extends this chapter's problem rather than solving it. It also carries a checkpoint-inhibitor arm, which makes it the phase 3 test of the addition that SACI-IO HR+ could not exclude at phase 2.
No trial randomises the choice between leaving endocrine-based therapy and continuing it, which is the decision that precedes everything in this chapter.
No assay in clinical use predicts which patient retains sensitivity after a topoisomerase I payload, and none of the running trials will produce one.
And no conjugate in this population carries a payload from a different class. Until one does, sequencing decisions will continue to rest on target expression, which answers one question out of six Mechanisms of conjugate resistance.
References
All 30 references
Garrido-Castro AC, Kim SE, Li T, et al. SACI-IO HR+: a randomized phase II trial of sacituzumab govitecan with or without pembrolizumab in patients with metastatic hormone receptor-positive/HER2-negative breast cancer. Ann Oncol 2026. PMID 42323161
Pistilli B, Mosele F, Corcos N, et al. Patritumab deruxtecan in HR+/HER2- advanced breast cancer: a phase 2 trial. Nat Med 2025 31:3492-3503. PMID 40908353
Bardia A, Jhaveri K, Im SA, et al. Datopotamab deruxtecan versus chemotherapy in previously treated inoperable/metastatic hormone receptor-positive human epidermal growth factor receptor 2-negative breast cancer: primary results from TROPION-Breast01. J Clin Oncol 2025 43:285-296. PMID 39265124
Bardia A, Hu X, Dent R, et al. Trastuzumab deruxtecan after endocrine therapy in metastatic breast cancer. N Engl J Med 2024 391:2110-2122. PMID 39282896
Mosele F, Deluche E, Lusque A, et al. Trastuzumab deruxtecan in metastatic breast cancer with variable HER2 expression: the phase 2 DAISY trial. Nat Med 2023 29:2110-2120. PMID 37488289
Rugo HS, Bardia A, Marme F, et al. Overall survival with sacituzumab govitecan in hormone receptor-positive and human epidermal growth factor receptor 2-negative metastatic breast cancer (TROPiCS-02): a randomised, open-label, multicentre, phase 3 trial. Lancet 2023 402:1423-1433. PMID 37633306
Modi S, Jacot W, Yamashita T, et al. Trastuzumab deruxtecan in previously treated HER2-low advanced breast cancer. N Engl J Med 2022 387:9-20. PMID 35665782
Rugo HS, Bardia A, Marme F, et al. Sacituzumab govitecan in hormone receptor-positive/human epidermal growth factor receptor 2-negative metastatic breast cancer. J Clin Oncol 2022 40:3365-3376. PMID 36027558
Bardia A, Tolaney SM, Punie K, et al. Biomarker analyses in the phase III ASCENT study of sacituzumab govitecan versus chemotherapy in patients with metastatic triple-negative breast cancer. Ann Oncol 2021 32:1148-1156. PMID 34116144
Modi S, et al. Trastuzumab deruxtecan in HER2-low metastatic breast cancer: long-term survival analysis of the randomized, phase 3 DESTINY-Breast04 trial. Nat Med 2025 31:4205-4213. PMID 41062831
Pistilli B, Jhaveri K, Im SA, et al. Datopotamab deruxtecan versus chemotherapy in previously treated inoperable/metastatic hormone receptor-positive, HER2-negative breast cancer: final overall survival analysis of the phase III TROPION-Breast01 study. Ann Oncol 2026 37:663-674. PMID 41448362
Mai N, Klar Lieberman MM, Ferraro E, et al. Sequential antibody-drug conjugate therapy in patients with metastatic breast cancer treated with sacituzumab govitecan and trastuzumab deruxtecan. JCO Precis Oncol 2025 9:e2400898. PMID 40440568
Sonke GS, van Ommen-Nijhof A, Wortelboer N, et al. Early versus deferred use of CDK4/6 inhibitors in advanced breast cancer. Nature 2024 636:474-480. PMID 39604725
Lu YS, Mahidin EIBM, Azim H, et al. Final results of RIGHT Choice: ribociclib plus endocrine therapy versus combination chemotherapy in premenopausal women with clinically aggressive hormone receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer. J Clin Oncol 2024 42:2812-2821. PMID 38771995
Diéras V, et al. Veliparib with carboplatin and paclitaxel in BRCA-mutated advanced breast cancer (BROCADE3): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol 2020 21:1269-1282. PMID 32861273
Martin M, et al. Palbociclib in combination with endocrine therapy versus capecitabine in hormonal receptor-positive, human epidermal growth factor 2-negative, aromatase inhibitor-resistant metastatic breast cancer: a phase III randomised controlled trial-PEARL. Ann Oncol 2020 32:488-499. PMID 33385521
Park YH, et al. Palbociclib plus exemestane with gonadotropin-releasing hormone agonist versus capecitabine in premenopausal women with hormone receptor-positive, HER2-negative metastatic breast cancer (KCSG-BR15-10): a multicentre, open-label, randomised, phase 2 trial. Lancet Oncol 2019 20:1750-1759. PMID 31668850
Rugo HS, et al. Randomized Phase III Trial of Paclitaxel Once Per Week Compared With Nanoparticle Albumin-Bound Nab-Paclitaxel Once Per Week or Ixabepilone With Bevacizumab As First-Line Chemotherapy for Locally Recurrent or Metastatic Breast Cancer: CALGB 40502/NCCTG N063H (Alliance). J Clin Oncol 2015 33:2361-9. PMID 26056183
Kaufman PA, Awada A, Twelves C, et al. Phase III open-label randomized study of eribulin mesylate versus capecitabine in patients with locally advanced or metastatic breast cancer previously treated with an anthracycline and a taxane. J Clin Oncol 2015 33:594-601. PMID 25605862
Cortes J, O'Shaughnessy J, Loesch D, et al. Eribulin monotherapy versus treatment of physician's choice in patients with metastatic breast cancer (EMBRACE): a phase 3 open-label randomised study. Lancet 2011 377:914-923. PMID 21376385
Ahn HK, et al. Palbociclib plus endocrine therapy versus capecitabine in premenopausal women with hormone receptor-positive, HER2-negative metastatic breast cancer (Young-PEARL): overall survival analysis of a randomised, open-label, phase 2 study. Lancet Oncol 2025 26:343-354. PMID 39978378
Martín M, et al. Overall survival with palbociclib plus endocrine therapy versus capecitabine in postmenopausal patients with hormone receptor-positive, HER2-negative metastatic breast cancer in the PEARL study. Eur J Cancer 2022 168:12-24. PMID 35429901
Gruber JJ, Afghahi A, Timms K, et al. A phase II study of talazoparib monotherapy in patients with wild-type BRCA1 and BRCA2 with a mutation in other homologous recombination genes. Nat Cancer 2022 3:1181-1191. PMID 36253484
Domchek SM, Postel-Vinay S, Im SA, et al. Olaparib and durvalumab in patients with germline BRCA-mutated metastatic breast cancer (MEDIOLA): an open-label, multicentre, phase 1/2, basket study. Lancet Oncol 2020 21:1155-1164. PMID 32771088
Tung NM, Robson ME, Ventz S, et al. TBCRC 048: phase II study of olaparib for metastatic breast cancer and mutations in homologous recombination-related genes. J Clin Oncol 2020 38:4274-4282. PMID 33119476
Litton JK, Rugo HS, Ettl J, et al. Talazoparib in patients with advanced breast cancer and a germline BRCA mutation. N Engl J Med 2018 379:753-763. PMID 30110579
Robson M, Im SA, Senkus E, et al. Olaparib for metastatic breast cancer in patients with a germline BRCA mutation. N Engl J Med 2017 377:523-533. PMID 28578601
Robson ME, et al. OlympiAD final overall survival and tolerability results: Olaparib versus chemotherapy treatment of physician's choice in patients with a germline BRCA mutation and HER2-negative metastatic breast cancer. Ann Oncol 2019 30:558-566. PMID 30689707
Litton JK, et al. Talazoparib versus chemotherapy in patients with germline BRCA1/2-mutated HER2-negative advanced breast cancer: final overall survival results from the EMBRACA trial. Ann Oncol 2020 31:1526-1535. PMID 32828825
Diéras V, Han HS, Wildiers H, et al. Veliparib with carboplatin and paclitaxel in BRCA-mutated advanced breast cancer (BROCADE3): Final overall survival results from a randomized phase 3 trial. Eur J Cancer 2024 200:113580. PMID 38309017