Astra beats Roche twice in a day

Oral selective oestrogen receptor degraders, or Serds, had been looking like one of the more disappointing cancer classes of recent times. So Astrazeneca’s news of a win with its contender camizestrant in ER-positive, Her2-negative breast cancer today came as a surprise.

Not only that, but Astra scored a second victory, with its Akt inhibitor capivasertib coming up positive in the same breast cancer setting. Both results will come as a blow for Roche, whose own Akt inhibitor, ipatasertib, has effectively been written off; the Swiss group is one of two companies to have had setbacks with Serds.

Astra’s camizestrant news was particularly unexpected as Astra’s second-line study, Serena-2, had not deliberately enriched for patients with ESR1 mutations. These subjects had driven the benefit seen with Radius and Menarini’s elacestrant, the only other Serd to succeed so far.

The big question now is what proportion of ESR1 mutants were enrolled into Serena-2, and whether these were responsible for the positive PFS result. Astra previously said it expected 30-40% of patients to be ESR1-positive; for reference, 48% of patients in Menarini’s Emerald trial of elacestrant carried the mutation.

Astra has previously said that camizestrant could have clinical activity in patients with and without the mutation; still, Sanofi had also made a similar claim about amcenestrant, a project that flopped in both second and first-line disease and has now been scrapped.

Roche also flunked its second-line trial, and is pinning hopes on the front-line setting. Astra has its own first-line studies ongoing; the first to yield data will be Serena-6, which is focused on ESR1 mutants. It is unclear why this strategy might be needed here given that these mutations typically arise following endocrine therapy.

Even if this trial succeeds, the market will not be huge: ERS1 mutations are seen in less than 5% of first-line patients, Jefferies analysts estimate.

Other contenders in the space include Olema, which today reported more phase 1/2 data on its Serd/complete ER antagonist OP-1250; the group saw a 10% response rate among 57 heavily treated patients, a slip from 17% at an earlier update. A pivotal monotherapy trial in second/third-line disease is slated to start in mid-2023.

Arvinas plans to begin phase 3 monotherapy and combo studies of its Pfizer-partnered project, the ER-targeting protein degrader ARV-471, this year.

Akting up

Meanwhile, Astra’s apparent success with the Akt inhibitor capivasertib made it two wins in a day with a mechanism with which Roche had previously failed.

Still, the breast cancer settings here are not quite the same: capivasertib has scored in CAPItello-291, in ER-positive Her2-negative breast cancer (just like camizestrant), while Roche’s Akt inhibitor ipatasertib had failed two first-line triple-negative breast cancer studies and a third in front-line prostate cancer.

Again there are no hard data to go on, but Astra says capivasertib plus Faslodex beat Faslodex alone on the primary PFS endpoint in the second-line CAPItello-291 trial. OS analysis is immature but “encouraging”, and the PFS benefit has been seen in all-comers as well as in patients with various gene mutations, including PTEN alterations.

The last point is important given that Roche’s only late-stage success with ipatasertib had come in the Ipatential-150 trial in a subset of patients with PTEN-altered prostate cancer. Since there is no widespread screening for PTEN status, and Ipatential-150 failed in all-comers, the subgroup result represented a pyrrhic victory.

Notably, CAPItello-291 is the first pivotal capivasertib trial to read out, and puts the Astra project in pole position to become the first approved Akt inhibitor. Four other phase 3 studies are under way, one of which could read out next year.

Roche still has one remaining long shot, with the Ipatunity-150 trial in the first-line ER-positive, Her2-negative setting where ipatasertib already failed in Ipatunity-130. But even Roche does not seem to hold out much hope: Ipatunity-150 no longer appears in the group’s quarterly list of relevant clinical trials.