What I’m presenting here at EAU this year is some data related to PSA response and outcomes in the ARANOTE study. So, very briefly, ARANOTE was a randomised phase III study looking at ADT alone versus ADT plus darolutamide in metastatic hormone-sensitive prostate cancer. We previously reported the results  of the study and published the results in JCO that showed that we were able to significantly improve radiographic progression free survival with the addition of darolutamide. So very significant clinically and statistically significant improvement in rPFS, time to mCRPC, time to PSA progression and, importantly, PSA response was more than three times higher with the addition of darolutamide compared to ADT alone – over 60% compared to less than 20% with ADT alone.

Now, what we looked at is the outcome of patients getting this PSA response. Clearly patients who get undetectable PSA, defined as less than 0.2, have much better outcomes in terms of rPFS and in terms of time to mCRPC and time to PSA progression, in the range of 80-90% reductions in the risk of progression when patients get this PSA of below 0.2.

Then we looked a little bit further and looked at whether high volume or low volume get these kinds of benefits. Yes, high volume and low volume do get better PSA responses and better outcomes but in the high volume it’s more in the range of 55% of patients get to below 0.2, low volume is over 80% get to below 0.2.

Then we looked at another level of detail, we looked at PSA entry into the study. The median PSA entry is the highest of all studies, in the range of 21 at PSA entry. What we looked at are patients coming in with the lower quartile – below 4.5 – compared to patients above the median of 21. Patients coming in with less than 4.5 had very significant likelihood of reaching below 0.2, so over 85%, and these patients did much better in terms of time to mCRPC and time to PSA progression. Patients with high volume also got very important results in terms of response to PSA with patients above 21 and they also benefitted to very similar degrees.

So really, regardless of PSA entry, you get much better results with darolutamide. Obviously if we can start them with lower PSAs, lower volume, that outcome is even better than patients who present unfortunately with higher volume, higher PSAs, where maybe we should be considering adding docetaxel, so a triplet approach, as opposed to a doublet approach in these higher risk patients.

What is the clinical significance of these results and what is next for this study?

The clinical significance of all of this is really that we can use a very simple, cheap biomarker called PSA to have a prognostic marker and response, in terms of PSA, is very prognostic in terms of how well patients are going to do. So that’s the good news.

It also helps us to maybe personalise how we follow patients. Patients who get these very strong PSA responses might not need to be followed as closely as those that don’t get to below 0.2. So this for the clinician and for the patients helps us to better personalise how we follow patients – frequency of imaging, frequency of visits. Now, the flip-side is what to do in patients who don’t get these very low PSA responses. That hasn’t been answered yet whether adding other therapies would make a difference is likely to be beneficial but we are still working on that sequential addition of therapies if patients haven’t started with the triplet approach from the beginning.