SERENA-4 may still hit, but will it matter?

Research evidence excerpt

SERENA-4 may still hit, but will it matter?

IdeaMExhibit 2: Implied HR estimates for SERENA-4

Trial persevERA (Roche) SERENA-4 (AstraZeneca)

HR Analysis Actuals Implied

Indication 1L ER+, HER2– LA/mBC 1L ER+, HER2– mBC

Trial size 992 1370

PFS Events 620

Event Rate 62.5%

Expected Events 856

Boundary for statistical significance HR 0.85; 2-sided p < 0.0456

SE (log HR) 0.068

Assumed alpha boundary (z) 2.00

Implied HR to achieve statistical significance 0.87

Source: Morgan Stanley Research estimates

persevERA read across to SERENA-4

Exhibit 3 shows why persevERA is not a one-for-one read-through to SERENA-

4. We see three key structural advantages for SERENA-4: (1) more statistical buffer,

with ~378 more patients; (2) enrichment for endocrine-sensitive recurrence, with

≥24m prior adjuvant ET and an added ≥12m since last adjuvant AI requirement for

prior-AI patients; and (3) stronger camizestrant-specific validation from SERENA-2 /

SERENA-6.

We view SERENA-4’s recurrent eligibility as supportive of the oral SERD thesis, with

recurrence after at least 24 months of adjuvant ET and, for prior AI-treated patients,

a requirement for at least 12 months since the last AI dose. This should enrich for

patients who remain endocrine-sensitive, but may have had enough prior endocrine

pressure for the ER pathway to start adapting, making deeper ER degradation more

differentiated than AI rechallenge. This view is directionally supported by

persevERA, where the >12 month TFI subgroup trended better than ITT, with HR

0.86 vs 0.89. However, SERENA-4 may still include two potentially dilutive groups.

In addition to de novo stage IV patients, tamoxifen-treated recurrence could also

dilute efficacy. SERENA-4 only requires a 2-week washout after tamoxifen, whereas