Part XI · Hormone receptor-positive, HER2-negative disease · Chapter 64

Endocrine therapy and receptor degraders after progression

ESR1 mutation defeats oestrogen deprivation and not receptor degradation, which is why the degrader trials split where they do.

1 · Scope, and the sequence this chapter assumes

This chapter covers endocrine therapy for metastatic hormone receptor-positive, HER2-negative disease. It covers the two backbones, the acquired alteration that separates them, the oral receptor degraders, the first proteolysis-targeting chimera result, and the pathway inhibitors that are added to an endocrine partner.

Three things are deliberately left to neighbouring chapters. CDK4/6 inhibition is in CDK4/6 inhibition, combinations and sequencing, including which inhibitor to choose and whether to continue it. Conjugates and chemotherapy are in Conjugates and chemotherapy in later lines. The clinical framing of the four biomarker branches is in Endocrine resistance, and the presentations the sequence does not fit, which this chapter expands rather than repeats. Receptor biology is in Estrogen receptor signaling and endocrine resistance and agent pharmacology in Endocrine therapy.

The sequence assumed here is the common one. Most patients arrive having had an adjuvant aromatase inhibitor, then a first-line aromatase inhibitor with a CDK4/6 inhibitor. Almost every endocrine decision in this chapter is therefore made in a tumour already selected by oestrogen deprivation. That is not a detail of ordering. It determines which alterations are present and which drugs still have a target.

The tables are generated from the trial registry when the book is built. Five slices appear below: the whole field of endocrine therapy after progression, the first-line regimens, the oral degraders, the pathway combinations, and the trials still running. A filter is mechanical, so a wide one catches every trial whose fields match and not only the trials the section is about. Where a section makes a specific argument, its table is filtered on the question rather than on the drug class. A new readout enters the registry once and appears in every table whose filter matches it. The prose does not repeat a figure the table carries, except where the argument is about the figure itself.

2 · Aromatase inhibitors and fulvestrant as backbones

The backbones were chosen by a generation of randomised trials that no longer appear in any table. Anastrozole matched or beat tamoxifen as first-line therapy in postmenopausal women^1,2,3, and exemestane gave an early advantage in time to progression without a survival difference⁴. Tamoxifen still worked after first-line anastrozole⁵. Against megestrol acetate after tamoxifen, anastrozole and letrozole were at least as effective and avoided its weight gain^6,7. Higher doses of megestrol added nothing⁸, and the progestins compared with each other differed mainly in side effects⁹. A meta-analysis found improved survival with third-generation aromatase inhibitors against standard hormonal therapy¹⁰. Among the inhibitors, letrozole was more active than anastrozole second line in one trial¹¹, exemestane and anastrozole were similar in visceral disease¹², and anastrozole and letrozole were equally tolerated¹³. Fulvestrant was as effective as anastrozole after tamoxifen in the two registration trials^14,15. Oral estradiol is an option after aromatase inhibitor resistance, and 6 mg daily gave a clinical benefit rate similar to 30 mg with fewer serious adverse events¹⁶.

Premenopausal women were barely represented in that generation. Tamoxifen gives response rates comparable to oophorectomy in them, but by 1991 fewer than 400 premenopausal women had entered its phase II and III trials¹⁷. The two randomised comparisons with oophorectomy, 160 patients between them, could not establish equivalence.

Two backbones exist and they fail differently. Oestrogen deprivation removes the ligand, using an aromatase inhibitor with ovarian suppression where ovaries are functioning. Receptor-directed therapy leaves the ligand alone and acts on the protein. That distinction is the argument of this whole chapter, so it is worth stating before any trial.

Two tables follow and neither is confined to this section's question. The first is the wide one. It holds every registry trial with an endocrine component that enrolled after progression, whatever was added to the backbone or substituted into it, with the single-arm and exploratory studies left in. The second holds the first-line regimens, where an endocrine backbone stands in both arms and the comparison is about what joins it or replaces it. Read the arms column before the result column in both. The sections below take narrow slices of each.

Each section opens with the question its trials were built to answer, taken from the [Chapter Stories](stories.html) map. The story says what was being looked for and what the design cannot settle. The table says what else is in the cell. The prose argues the decision.

Five reported trials address the backbone question itself, and none of them found a large effect. Substituting fulvestrant for an aromatase inhibitor, or adding it, buys months of progression-free time where it works at all. FALCON is the trial the decision rests on, because it is the double-blind randomised comparison against the drug a clinic would otherwise start⁵¹. Its final analysis reported no difference in overall survival between the two backbones⁵⁷.

FIRST asked the same drug question and is often quoted as though it agreed. It was a phase II trial whose primary endpoint was clinical benefit rate, and it did not meet it⁵⁶. A follow-up analysis reported median time to progression of 23.4 months with fulvestrant against 13.1 months with anastrozole⁵⁸. Its survival comparison was added by protocol amendment after the progression results were known⁵⁹. What separates FIRST from FALCON is phase, endpoint and analysis plan rather than the drug, which was the same drug in both.

The two addition trials disagree with each other, and the explanation is the population. SWOG S0226 added fulvestrant to anastrozole in previously untreated metastatic disease and lengthened progression-free survival⁵⁴. Its gain reached overall survival in a prespecified secondary comparison, and it held although crossover to fulvestrant at progression was encouraged⁶⁰. FACT added the same drug at first relapse after treatment of localised disease, in a population most of whom had already had adjuvant antioestrogen therapy, and gained nothing on either endpoint⁵³. The drug and the schedule matched. What differed was how much endocrine therapy the tumours had already been through. Both used the loading regimen followed by 250 mg monthly, which CONFIRM then showed was underdosing^43,61. The addition question has never been asked at the dose now prescribed.

The dose question is pharmacology rather than biology. The drug is given intramuscularly, reaches steady state slowly, and needs a day-14 loading dose in the first cycle. A patient who received the lower dose historically has not had an adequate trial of the drug.

The FALCON population has largely disappeared. Endocrine therapy-naive advanced disease now means de novo metastatic presentation without prior treatment, or relapse in a patient who never received endocrine therapy. A relapse after adjuvant tamoxifen does not qualify, because the trial excluded any previous endocrine therapy. Most patients presenting today carry adjuvant aromatase inhibitor exposure. The trial therefore settles the first endocrine choice, made at presentation or after a single line of chemotherapy for advanced disease. Almost every decision in this chapter is made at progression instead.

Everything else in the wide table is downstream of one fact about the second line. After a non-steroidal aromatase inhibitor, endocrine monotherapy of any kind performs poorly. EFECT could not separate fulvestrant from exemestane⁴⁴. SoFEA could separate neither fulvestrant with anastrozole from fulvestrant alone, nor fulvestrant from exemestane⁴¹. Both gave fulvestrant at 250 mg monthly after a loading regimen. That weak performance is not a historical curiosity, because it is the control arm almost every later trial in the table was measured against.

What has been added to that control arm falls into two groups. Where the partner carries a target of its own, the addition works. A CDK4/6 inhibitor did so in PALOMA-3 and DAWNA-1^40,33, and pathway inhibition did so in the trials argued in Endocrine therapy with PI3K, AKT and mTOR pathway inhibition. Where the partner was chosen on a mechanism with no companion marker, the record is consistently negative. Entinostat in E2112, venetoclax in VERONICA and fulvestrant added to an Aurora A kinase inhibitor in TBCRC 041 each returned their control arm's result^34,31,29. Study G200802 compared two doses of an androgen receptor agonist against each other, with no standard-therapy arm to be measured against at all²³.

Six rows are in that table for their backbone rather than for the question the trial asked. PEARL and Young-PEARL / KCSG-BR15-10 set an endocrine-based combination against capecitabine, which is the decision argued in Conjugates and chemotherapy in later lines^37,39. SUMMIT and SGNTUC-019 gave fulvestrant inside a HER2-directed regimen to disease carrying an activating HER2 mutation^28,20. Each reports an uncontrolled response rate from a basket cohort. Fulvestrant is the constant in both and not the variable. BioPER and TRINITI-1 are single-arm studies of what to do after a CDK4/6 inhibitor fails, and they appear because this table was asked for the exploratory trials as well^26,35. None of the six speaks to which backbone to start.

The first-line table has the same property and should be read the same way. PALOMA-1 / TRIO-18 and DAWNA-2 added a cell-cycle inhibitor to an aromatase inhibitor^52,49. SONIA asked when to give that inhibitor rather than whether⁴⁸. RIGHT Choice set endocrine therapy with ribociclib against combination chemotherapy in premenopausal disease selected for being aggressive⁴⁷. Those four belong to CDK4/6 inhibition, combinations and sequencing and Conjugates and chemotherapy in later lines. EGF30008 enrolled first-line patients regardless of HER2 status and found no progression-free survival gain in the centrally confirmed HER2-negative majority, which is the population of this chapter⁵⁵. PADA-1 and SERENA-6 changed the endocrine partner during first-line treatment on a plasma result, and are argued in Oral selective estrogen receptor degraders and their biomarker-defined benefit. INAVO120 is argued in Endocrine therapy with PI3K, AKT and mTOR pathway inhibition.

What neither table can show is the comparison the question now needs. Every reported backbone trial ran without a CDK4/6 inhibitor in either arm. They answer a question about endocrine monotherapy, in a position where monotherapy is no longer what is given. SERENA-4, persevERA and VERITAC-3 put an oral degrader against an aromatase inhibitor with palbociclib in both arms, which is the substitution question asked in the backbone actually used. None of the three has reported. Nor has any trial chosen the first-line backbone by ESR1 status, which is reasonable, because the alteration is rare before treatment.

The practical position is that the backbone is now chosen by two things. The first is what the tumour has already seen. The second is whether an ESR1 mutation is detectable.

3 · ESR1 mutation and what it changes

ESR1 mutation is acquired under aromatase inhibitor exposure and is rare in patients who have never received one. The evidence for that, including how prevalence differs between the adjuvant and metastatic settings, is set out in Endocrine therapy and the emergence of ESR1 alterations and is not repeated here.

Three consequences follow and they should be held separately.

The mechanism is ligand independence. A mutant receptor adopts an active conformation without oestrogen, so lowering oestrogen removes nothing that the tumour still needs. The receptor protein remains present and remains transcriptionally active. A drug that acts on the protein therefore still has a target.

The failure is specific. ESR1 mutation predicts failure of oestrogen deprivation, not failure of endocrine therapy as a class. This is the organising fact of the chapter and it is frequently misread. Patients whose disease carries the alteration are often described as endocrine-resistant and moved to chemotherapy, which discards the one branch where the mechanism and the available drugs line up.

The mutation describes a population rather than a tumour. It is subclonal and frequently polyclonal within a single patient. Its prevalence rises across successive endocrine lines Evolution across successive lines and the cost of each switch.

The measurement side is separable from all of that. Detection is a plasma assay, not a tissue assay. Archival primary tissue is usually negative because the selection had not yet happened, so a negative result on an old block carries no information. In plasma, sensitivity at low variant allele fractions is the limiting factor. Disease that sheds little DNA can give a false negative. The respective blind spots of tissue and plasma are developed in Liquid biopsy and longitudinal monitoring.

4 · Oral selective estrogen receptor degraders and their biomarker-defined benefit

Five randomised trials have tested an oral receptor degrader against endocrine monotherapy after progression. Two are phase III and three are phase II. Their headline results divide sharply, and reading that division as a ranking of the drugs is the mistake this section exists to prevent.

The divergence in that result column is design rather than chemistry. EMERALD and EMBER-3 prespecified the ESR1-mutant population as a primary analysis, which is why each can report a mutant result as a finding^30,19. EMERALD also lengthened progression-free survival in its whole population, against investigator's choice of endocrine therapy⁶². acelERA and AMEERA-3 prespecified progression-free survival by ESR1 mutation status only as a secondary endpoint, not as a primary analysis. SERENA-2 was a multi-dose study against fulvestrant, reported at a 90 percent confidence interval rather than the 95 percent convention of the phase III trials beside it, in postmenopausal women only²². It beat fulvestrant at both of the doses it carried forward, in a population not defined by mutation status. The populations differ as much as the designs. Prior CDK4/6 inhibition was required to enter EMERALD and was a stratification factor or nothing elsewhere.

EMERALD is the trial the decision rests on. Its comparator was the endocrine monotherapy that would otherwise have been given. Every patient in it had already had a CDK4/6 inhibitor. In patients with an ESR1 mutation whose prior endocrine therapy with a CDK4/6 inhibitor had lasted at least 12 months, the progression-free survival benefit was clinically meaningful and consistent across subgroups⁶³. The mutant analysis was written into the protocol rather than found in the data.

The two trials that missed carry more weight than their headline suggests, because the same split appears in them without having been powered for. In acelERA, of 232 patients evaluable for circulating tumour DNA, the 90 with a detectable ESR1 mutation had a hazard ratio for progression of 0.60, against 0.88 in the 142 without one²⁴. In AMEERA-3 the 120 of 280 patients carrying a baseline mutation had a hazard ratio of 0.9, in a trial whose overall hazard ratio sat slightly above one²⁵. Two failed trials reproduced the pattern of the two that succeeded, which is what makes it hard to explain as selective reporting.

The same dependence appears once more outside this table. VERITAC-2 set a receptor- degrading PROTAC against fulvestrant and concentrated its effect in the mutant patients²¹, and that trial is read properly in Targeted degradation and the first PROTAC result. Three mechanisms of receptor degradation, one dependence on mutation status. Together they establish that the mutation marks a treatable state rather than a general endocrine resistance.

The mutant and wild-type groups are set by an assay threshold and not by a boundary in the biology. Each trial called ESR1 status from plasma at its own limit of detection, in its own evaluable subset. A tumour called wild-type may carry a subclone below that limit, and a patient whose disease sheds little DNA may be called wild-type on volume rather than on genotype. Nothing in the table separates a true wild-type tumour from an undersampled one.

EMBER-3 carried a third arm, in which imlunestrant with abemaciclib beat imlunestrant alone¹⁹. That comparison admitted patients who had never received a CDK4/6 inhibitor. It is evidence that the combination is better than the single agent, and not evidence about continuing a CDK4/6 inhibitor beyond progression.

Every trial above randomised after the scan had changed. The harder question is whether to act on a rising mutation in a patient whose imaging is still reassuring. Two trials randomised at exactly that moment and they agree. PADA-1 monitored patients on a first-line aromatase inhibitor with palbociclib and, on a rising ESR1 mutation without progression, switched the endocrine partner to fulvestrant⁵⁰. SERENA-6 used the same trigger and switched to camizestrant while continuing the same CDK4/6 inhibitor^65,45. One degrader is parenteral and one is oral, one trial was open-label in a single country and the other was double-blind across twenty-three. The agreement therefore looks like a finding about the timing rather than about the molecule. The design argument, and its limits, are developed in Acting on evolution, intermittent dosing, adaptive therapy, pre-emptive switching.

What neither randomised is the comparison a clinic actually weighs. Both control arms continued an aromatase inhibitor already known at the molecular level to be failing, so the contrast is against something close to inert. Nobody has compared switching now with switching at radiological progression, which is the choice in front of the oncologist. The clock is the second problem. Progression-free survival here is measured from a randomisation triggered by an assay, so the starting point is set by a detection threshold on a ctDNA panel rather than by anything the patient experienced. Molecular progression is a laboratory convention as much as a biological event, and patients whose resistance takes a route that panel does not report never enter.

One result speaks past the first line. In SERENA-6 the switch also lengthened second progression-free survival, the key secondary endpoint, and the difference was statistically significant at its final analysis⁴⁵. The advantage therefore held through the next line of treatment, which is what a strategy trial has to show. Overall survival is not yet reported in either trial.

The arithmetic of that strategy is the part no table shows. PADA-1 monitored 1017 patients to randomise 172. SERENA-6 tested 3256 patients at least once, found 548 positive, and randomised 315⁴⁵. The rest were screened, tested every two to three months while well and responding, and never entered a trial result.

The precedent that should restrain enthusiasm is SWOG S0500. It changed treatment on a persistent circulating tumour cell count rather than on imaging, and survival did not improve⁶⁶. A blood marker can be prognostic without acting on it being therapeutic. That is why a progression-free survival result measured from a molecular randomisation needs a survival result behind it before it becomes a standard.

The strategy also has a service cost the progression curves do not show. It requires plasma testing every two to three months in patients who are well and responding. It then commits the service to changing treatment on a laboratory result while the imaging is unchanged. A clinic that cannot deliver the testing reliably should not adopt the strategy, because an irregularly tested patient gets the control arm with extra appointments.

5 · Targeted degradation and the first PROTAC result

A proteolysis-targeting chimera is a bifunctional molecule. One end binds the oestrogen receptor. The other recruits an E3 ubiquitin ligase. Bringing the two together marks the receptor for ubiquitination and proteasomal destruction. The molecule is then released and can act again, so the mechanism is catalytic rather than stoichiometric. A conventional degrader binds the receptor and destabilises the molecule it is bound to.

VERITAC-2 tested that chemistry against fulvestrant in a randomised phase 3 trial. Its split is the teaching case of the chapter. Vepdegestrant significantly prolonged progression-free survival in the ESR1-mutant population. In the full randomised population it did not²¹.

The comparator is what makes this informative. Fulvestrant is itself a receptor degrader. The result is therefore degrader against degrader, so it cannot be explained by saying that degradation beats antagonism. Two readings remain and the trial does not separate them. Mutant disease may be more dependent on the amount of receptor protein present, so more complete degradation matters more. Or fulvestrant may simply perform worse against a mutant receptor, if its receptor engagement at the licensed intramuscular dose is incomplete. Both predict the observed split.

The wider point is the one to carry away. Two chemically distinct oral approaches to the receptor, the degraders of Oral selective estrogen receptor degraders and their biomarker-defined benefit and now the chimera, produce the same biomarker-defined split against the same comparator. What selects the responding patient is the resistance mechanism, not the chemistry used against it. A new molecule in this class should be expected to reproduce the split until a trial shows otherwise.

Two limits apply as they do to the whole class. No survival data exist. No trial has compared this agent with a CDK4/6 inhibitor combination at the same point in the sequence.

6 · Endocrine therapy with PI3K, AKT and mTOR pathway inhibition

One pathway, four levels of it, and seven trials that disagree about who should receive the drug more than they disagree about whether it works. Five of the seven are phase III. FAKTION is phase II and BYLieve is a single-arm cohort. Both are read as supporting evidence rather than as licensing trials.

The agreement in that table is broad and it is about direction. At every level of the pathway, adding the inhibitor to an endocrine partner lengthens progression-free survival against that partner alone. mTOR inhibition did it in 2012, alpha-selective PI3K inhibition and AKT inhibition did it next, and dual PI3K and mTOR inhibition did it most recently. Survival results are scarce. Two of the seven report a significant gain in overall survival, and one of those is a phase II.

The differences are about how the genotype entered the design, and that decides how much of each estimate is selection. SOLAR-1 enrolled two cohorts by tumour-tissue PIK3CA status. It powered the mutated cohort and reported the non-mutated one beside it, which is what lets the marker be called predictive here rather than prognostic^38,67. The methodology is worked through in Biomarker-selected, basket, umbrella, and platform trials. CAPItello-291 enrolled without selecting and made the pathway-altered patients a co-primary population²⁷. That is a weaker basis for a predictive claim, for a mechanical reason. The overall population contains the altered patients, so an overall effect is expected whenever the altered subgroup benefits. Separating the marker's predictive value needs the marker-negative analysis, which in that trial was not a primary endpoint. VIKTORIA-1 went further in the other direction and randomised the PIK3CA wild-type cohort separately, so its reported result belongs to wild-type disease alone and its mutant cohort has not yet reported¹⁸. BYLieve required the mutation for entry and had no control arm at all³². Its report also carries a published expression of concern⁶⁸.

The control arms differ as much as the designs, and that is the sentence the result column hides. Fulvestrant alone ran to a median of 2.0 months in VIKTORIA-1, against 3.6 months in CAPItello-291 and 5.7 months in the mutated cohort of SOLAR-1. The spread across those three control arms is as large as some of the treatment effects in the table, and it tracks how much prior therapy each population had been given. VIKTORIA-1 required progression on a CDK4/6 inhibitor with an aromatase inhibitor. Most of CAPItello-291 had had a CDK4/6 inhibitor. SOLAR-1 ran before that class was routine. A hazard ratio is a ratio to whatever the control arm did, so these numbers cannot be ranked against one another.

FAKTION and CAPItello-291 make the same point inside one drug. The phase II enrolled nobody who had received a CDK4/6 inhibitor. It reported a significant overall survival gain^36,69. The phase III enrolled a population most of whom had, and it has not reported overall survival at all. Same drug, same comparator, different population. The smaller and earlier trial is the one that looks better, which is the order to be suspicious of.

Measurement separates these trials as well. SOLAR-1 and BYLieve called the alteration on tumour tissue. Other trials accepted circulating tumour DNA, and the two do not identify the same patients. PTEN enters the AKT-pathway-altered group as loss of immunohistochemical staining rather than as a sequenced mutation. That one label therefore covers three assays and three thresholds.

INAVO120 is the trial to reason from in the first line. It selected twice, requiring a PIK3CA mutation and relapse during or within 12 months of adjuvant endocrine therapy, and it added the inhibitor to palbociclib with fulvestrant⁴⁶. It is the only phase III trial in this section with a significant survival benefit⁷⁰. Whether that belongs to the population, to the triplet or to the drug cannot be separated from a single trial. No arm isolates the pathway inhibitor from the cell-cycle drug.

BOLERO-2 predates biomarker selection entirely⁴². Everolimus with exemestane delayed progression in unselected patients and did not extend life⁷¹. It remains useful where sequencing is unavailable and the mechanism is otherwise unaddressed.

Two other mTOR trials bracket it. TAMRAD randomised 111 postmenopausal women with aromatase inhibitor-resistant disease to tamoxifen with or without everolimus⁷². Time to progression was 8.6 months against 4.5 months, with a hazard ratio of 0.54, and the hazard ratio for death was 0.45, although no formal comparison between the arms was planned. In aromatase inhibitor-naive disease, adding oral temsirolimus to first-line letrozole in 1,112 patients was stopped for futility at an interim analysis, with a hazard ratio for progression of 0.90⁷³. Whether that difference belongs to the population or to a different drug on an intermittent schedule cannot be separated.

Three things the table has no column for decide how this is used. Nothing here randomises pathway inhibition against a conjugate, or against continuing CDK4/6 blockade, at the same point in the sequence. Nothing compares two drugs of the same class, and INAVO121 is the first trial that will. And no column records delivered dose intensity, which is what hyperglycaemia, rash, stomatitis and diarrhoea actually determine.

Tolerability is what decides how much of that benefit a patient actually receives, and it differs in kind between the three approved options. SOLAR-1 established PIK3CA mutation as a predictive marker and also established why alpelisib is hard to give. Grade 3 or 4 hyperglycaemia occurred in 36.6% of patients against 0.7% on placebo³⁸. That rate is why the drug needs a glucose plan agreed before the first prescription rather than after the first abnormal reading.

Capivasertib is better tolerated and its toxicity is differently shaped. In CAPItello-291 grade 3 or higher rash occurred in 12.1% of patients against 0.3% on placebo, and diarrhoea in 9.3% against 0.3%²⁷. Rash is early and usually manageable. That is a different burden from a metabolic one carried for the length of a response.

Everolimus is limited by stomatitis, pneumonitis and metabolic toxicity rather than by any of those. Pathway biology is in PI3K, AKT, mTOR, and related networks and agent detail in Targeted therapy.

7 · Unresolved questions and what reads out next

Three trials ask the same question and it is the question that would rewrite this chapter. SERENA-4, VERITAC-3 and persevERA each test an oral receptor degrader against an aromatase inhibitor as the first-line backbone, with palbociclib in both arms. All three enrol without selecting for ESR1 mutation, which is the correct design, because the alteration is rare before treatment. A positive result would move the degraders from salvage to backbone. It would also make the pre-emptive switching strategy redundant, since there would be nothing to switch from.

CAPItello-292 asks whether AKT inhibition belongs alongside CDK4/6 blockade rather than after it, in a population unselected for the pathway alteration. evERA holds everolimus constant in both arms and varies the endocrine partner, so it asks a degrader question inside a pathway regimen rather than a pathway question. INAVO121 compares two PI3K-alpha inhibitors directly, and is the only trial in this area that will produce a within-class comparison. Within-class comparisons are what the field consistently lacks.

EvoPAR-Breast01 removes first-line CDK4/6 inhibition altogether in germline or somatic BRCA1, BRCA2 or PALB2 disease, replacing it with a PARP1-selective inhibitor and an oral degrader. It is the only trial listed here that takes the CDK4/6 inhibitor out, rather than changing the endocrine partner standing beside it.

Four questions have no trial attached to them and should be named. Nothing compares an oral degrader with a conjugate at the same decision point. Nothing randomises the order in which endocrine-based and conjugate therapy are given, which is the decision made in Conjugates and chemotherapy in later lines. No oral degrader has been compared with another, so the class will be ranked on cross-trial inspection unless that changes. And no oral degrader trial is powered for overall survival, so the class may reach routine use without a survival result at all.

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