Roche has a rare breast cancer setback

Giredestrant fails, but the group hopes for better luck in earlier therapy lines.

Roche’s previous claims that its oral selective oestrogen degrader giredestrant could be best in class have come to nothing. The group disclosed during its first-quarter results today that the agent had failed the phase 2 Acelera trial in previously treated ER-positive Her2-negative breast cancer, handing the advantage back to Radius and Menarini, which have already scored with their rival project elacestrant.

However, Roche is clinging to a signal in a subgroup of patients – those with ESR1 mutations – saying this finding improves its confidence in giredestrant’s chances in first-line and adjuvant breast cancer, where phase 3 trials are ongoing.

Radius and Menarini’s decision to enrich its Emerald trial for ESR1 mutants now seems wise, while Sanofi’s recent failure with its oral Serd amcenestrant is increasingly looking like a consequence of targeting all comers.

And this issue could be relevant to both Astrazeneca and Lilly, which are also awaiting late-stage data on their contenders. At present, it is unclear whether either group has enriched their respective Serena-2 and Ember trials by ESR1 status.

Oral Serds in late-stage development for previously treated ER+ve/Her2-ve breast cancer
  Elacestrant Amcenestrant Giredestrant Camizestrant Imlunestrant
Company Radius Health/Menarini Sanofi Roche Astrazeneca Lilly
Registrational study Emerald Ameera-3 Acelera Serena-2 Ember-3
Prior CDK4/6 use Mandatory Mandatory for 80% Not mandatory Not mandatory Not mandatory
Enrichment for ESR1 mutation? Yes No No Unclear Unclear
Primary endpoint(s) PFS in all-comers PFS in all-comers (PFS in ESR1 mutants is secondary) PFS in all-comers (PFS in ESR1 mutants is secondary) PFS in all-comers PFS in all-comers (PFS in ESR1 mutants is secondary)
PFS in ESR1 mutants
Data All comers: 0.9mth benefit, HR=0.70 Failed primary endpoint Failed primary endpoint, signal seen in ESR1 mutants Ends Sep 2022 (previously Mar 2022) Ends Jun 2023 (previously Mar 2023)
ESR1 mutants: 1.9mth benefit, HR=0.55
Source: Evaluate Pharma &

ESR1 is thought to be a common resistance mechanism to aromatase inhibitors, the backbone of therapy, but has been associated with a benefit for new-generation Serds.

Roche’s Acelera trial, in second-line and later breast cancer, had a primary endpoint of progression-free survival in all comers. On this measure the study was a dud, but Bill Anderson, chief executive of the group’s pharma division, said during a conference call today that there was a numerical improvement here with giredestrant versus physician’s choice of endocrine therapy – which included Faslodex, an intramuscular Serd.

And this benefit was “more pronounced” in patients with baseline ESR1 mutations; stratifying PFS by ESR1 status was a secondary endpoint of Acelera. Because of this finding Mr Anderson described the result as “the best kind of negative study that you could have”.

Crucially, he reckons it should bode well for earlier lines of therapy, because “one would surmise that [these patients] should have a greater impact of endocrine blockade”. However, non-metastatic and front-line patients, for which Faslodex is not available, do not tend to have ESR1 mutations.

Giredestrant is in the Perservera study in first-line disease and the Lidera trial in the adjuvant setting.

With these trials not set to complete until April 2024 and December 2025 respectively, it will be some time until it becomes apparent whether Mr Anderson is right. In the meantime, whether another oral Serd can rival Radius and Menarini’s elacestrant looks likely to depend on how well Astra and Lilly have designed their trials.

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