SABCS 2022 preview – now Arvinas’s degrader takes a knock

With Menarini’s elacestrant likely to become the first US-approved oral Serd in February, attention has turned to what similarly acting competition it might face. One possible player, Arvinas’s Pfizer-partnered ARV-471, looks unlikely to become a threat, accidentally revealed data from next month’s San Antonio Breast Cancer Symposium suggest.

Results from ARV-471’s phase 2 expansion cohort briefly went up on the SABCS website yesterday, as a result of which Arvinas was forced to publish the entire study presentation today. The data show an alarming lack of efficacy for ARV-471, with a caveat, and mean that the big focus for followers of the Serd class will be Astrazeneca’s Serena-2 trial.

Astra’s Serd camizestrant was notable for having succeeded in Serena-2, and Astra has managed to get the data into SABCS as a late-breaker. This was the second Serd to succeed in a late-stage trial, bookending the failures of Sanofi’s amcenestrant and Roche’s giredestrant.

As such, SABCS will likely prompt much debate about the conflicting datasets, what they mean, and what might have influenced the differing results.

Valuation disconnect?

Against this background Arvinas, a relative latecomer, has worked hard to justify its $2bn-plus valuation, but judging by its SABCS dataset it has a tough task ahead. Its stock fell 16% yesterday when the abstract was revealed by accident, and this morning was off another 4%.

In a late-line ER-positive, Her2-negative breast cancer setting ARV-471 has only managed two partial remissions among 71 patients. The data, from the phase 1/2 Veritac trial, comprise two doses, and the lower one (200mg daily, the recommended phase 2 dose) accounts for just one response among 35 patients.

These remission data were only meant to have appeared in Arvinas’s SABCS presentation, due to be given on December 8. The abstract, intended to have comprised the only data revealed yesterday, instead focused on “clinical benefit rates” (CBRs), which additionally include cases of stable disease and are not considered a sign of a compound’s efficacy.

But these too caused some disappointment, since they showed the CBR in ESR1 wild-type patients to be meaningfully lower than in ESR1 mutants: 25% versus 47% respectively. Serds are thought to work especially well in ESR1 mutant disease, so a strong effect in patients without the mutation would have been a boon for Arvinas.

Menarini’s elacestrant probably owes much of its clinical success to the Emerald study having been enriched for this mutation. A big question for Astra’s Serena-2 data is how many patients had ESR1 mutations.

Another reason for the market’s disappointment with Arvinas was the median PFS of about 3.5 months for the 200mg ARV-471 dose, against sellside expectations of five months plus.

Stifel analysts said competitor Serds’ single-arm studies had shown five to six months’ mPFS, though importantly most of these biased recruitment towards patients without prior CDK4/6 inhibitor treatment. All 71 subjects in the Arvinas trial had progressed on these drugs.

The best mPFS with a Serd in a post CDK4/6 population seems to be the 6.5 months with Lilly’s imlunestrant, though curiously Lilly is now talking down this asset. SVB analysts recently noted Lilly’s tweaking of the imlunestrant pivotal study’s statistical analysis plan, and said management was unclear how much better oral Serds might be than Faslodex, Astra’s now off-patent intramuscularly delivered drug.

Another early Serd player, Olema, also has a SABCS poster, though this will be in combination with a CDK4/6 inhibitor. Monotherapy data for Olema’s contender, OP-1250, are due next year.

Olema has contended that OP-1250 is not only a degrader but also a complete ER antagonist; the latter mechanism is needed because no Serd degrades completely, the group’s chief executive, Sean Bohen, told last week’s Jefferies London healthcare conference. Mr Bohen called ARV-471 an incomplete degrader and an incomplete blocker.

Arvinas today revealed the design of the phase 3 monotherapy Veritac-2 trial, which will stratify for ERS1 mutation, and has co-primary PFS endpoints in all-comers and ESR1 mutants. Given the SABCS data it is hardly surprising to see the company hedging its bets this way.