At the June Pharmora Journal Club we discussed the follow up data for 3 ongoing studies in metastatic breast cancer, the primary results of which had been presented at an earlier conference.  

The follow up data focused on Progression-Free-Survival 2 (PFS2) and was hot off the press as it had been presented at ASCO 2026 earlier the same month.  

We discussed the reasoning for using PFS2 as an endpoint and its implementation into study design especially in the situation where it is not possible to use other measurements such as overall survival. For Pharmora, the value of the discussion was not only in understanding the individual studies, but in sharpening our approach to reviewing evidence. 

What is PFS2 and Why is it important?

The defined timeframe of PFS2 is the time from randomisation to first documented progression of disease (PD) on next-line therapy per investigator assessment or death due to any cause.  

In principle, PFS2 demonstrates whether benefit continues beyond first progression and into the next line of therapy. PFS2 could also provide a useful endpoint measurement where overall survival data are immature or difficult to interpret, for example in trials where patients crossover to the investigational product arm following PD on standard treatment.  

Study Findings

Pharmora looked at presentations of 3 trial studies and one analytical presentation:  

Dr David Cescon presented TB02, using first line Dato-DxD vs chemotherapy in patients with locally recurrent inoperable or metastatic triple-negative breast cancer.   

Dr Kevin Kalinsky presented ASCENT-04, looking at PFS2 and subsequent therapies in patients with previously untreated PD-L1+ metastatic triple negative breast cancer who were treated with Sacituzumab govitecan plus pembrolizumab. 

Dr Sara Tolaney presented ASCENT-03, discussing PFS2 in current trial patients with previously untreated metastatic triple negative breast cancer who were treated with only Sacituzumab. 

In all of the presentations discussed, PFS2 had been measured because overall survival could not be determined due to crossover. In each study the PFS2 was reported to have improved for the investigational product group. However, two studies did this as part of a post hoc analysis. Only one study had predefined PFS2 and included this as an endpoint in the initial trial design.   

Pharmora medics and scientists discussed the 3 studies and highlighted the important distinction between endpoints designed into a clinical trial from the beginning, compared with those added later. We noted that including additional post-hoc analyses can substantially affect the quality of the data and strength of interpretations. 

Endpoint Complexity

Following this, Pharmora looked at a presentation from Dr Meredith Regan, a statistician expert who examined the “Promises and Pitfalls of PFS2”.  

Dr Meredith M Regan suggested that PFS2 currently lacks uniform definition and that there was no standardised method of data collection. This makes PFS2 very difficult to compare between data sets and studies, impacting its value as an outcome measure. It was interesting to see some of the points we had raised, particularly with respect to the need for inclusion from the start of the trial, were also highlighted by this expert. 

We discussed how PFS2 can be affected by several factors: differences in data collection, subsequent therapy type, and crossover between arms; how it is impacted by PFS1 (in the context of continuing treatment through progression), and how censoring is handled when patients leave a study or have not yet progressed. 

In summary, PFS2 may help when overall survival data are immature or confounded, but it requires careful definition and cautious interpretation. 

We all left the journal club with a lot more understanding of the potential value and particular challenges with the PFS2 endpoint, ready to pass on our knowledge to our clients! 

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