When we were conceptualising the study in 2011, at that time intra-tumoural production of testosterone was already established as a valid target in men with progressive castration resistant prostate cancer. Soon after, abiraterone was approved in conjunction with prednisone for the treatment of patients with metastatic castration resistant prostate cancer. From the SWOG-9346 trial, which was actually conducted in men with metastatic hormone sensitive prostate cancer and was presented by Dr Maha Hussain in the 2013 ASCO Annual Meeting showing intermittent therapy with androgen deprivation therapy was not inferior to continuous androgen deprivation therapy, that trial also established that PSA at 7 months, so the better the PSA response at 7 months the higher was the overall survival benefit.

So if you put all these data together, which were abiraterone improving survival outcomes in the CRPC setting, better PSA responses in the hormone sensitive setting leading to improved overall survival and intra-tumoural production of testosterone leading to propagation or progression of prostate cancer despite androgen deprivation therapy. If we put all these things together it made sense to us to target intra-tumoural testosterone production in the hormone sensitive metastatic prostate cancer setting which we believed would improve PSA responses and survival outcomes. So we hypothesised that a combination of androgen deprivation therapy plus TAK-700 which is a CYP 17,20-lyase inhibitor and doesn’t require prednisone at the doses it was used in the trial will improve overall survival compared to standard androgen deprivation therapy with bicalutamide, which was considered standard at that point in time. So that was our hypothesis and the rationale for the study.

This was a large phase III randomised trial where 1,279 eligible men were randomised to ADT plus TAK-700 versus ADT plus bicalutamide. The primary endpoint was overall survival and secondary endpoints were progression free survival, PSA at 7 months, which is a known, validated surrogate for overall survival, and safety of the combination.

At the time of final analysis and after a median follow-up of 57 months the median overall survival with TAK-700 was 81 months versus 70 months with bicalutamide. However, an improvement of 11 months in the median overall survival with TAK-700 did not meet the pre-specified criteria for statistical significance. The median progression free survival was also significantly improved with TAK-700, in fact it was close to twice as high with TAK-700 compared to bicalutamide. PSA response rates were significantly higher with TAK-700.

So the results overall were very intriguing. We saw a significant improvement in PFS and PSA responses. We saw a clinically meaningful improvement in overall survival – almost a year, 12 months or 11 months to be more precise, improvement in overall survival with TAK-700 which did not meet the pre-defined criteria for statistical significance. So this was very interesting to us.

We looked back and saw that the median overall survival of the control arm was 70 months, which is great news for the patients, because it was 46 months in the SWOG-9346 trial presented by Dr Hussain in 2013, just eight years before. The same risk stratification, same number of patients with extensive risk disease. So really the same number of patients with extensive risk disease, similar criteria for risk stratification, similar patient population and you are seeing a jump from 46 months to 70 months in overall survival in patients who are receiving androgen deprivation therapy, standard ADT without intensification. So this was very intriguing to us.

We went back and did a post-hoc analysis of the receipt of subsequent life-prolonging therapy in the SWOG S1216 trial, especially in patients who were on the control arm. We noticed that 77% of patients on the SWOG S1216 control arm received subsequent life-prolonging therapy in the metastatic castration resistant prostate cancer setting which may have resulted in a median overall survival of 70 months which is the highest ever recorded median overall survival for patients on non-intensified ADTR among all the contemporary trials reported in the context of metastatic hormone sensitive prostate cancer.

As I said, compared to the median overall survival of men in the 9346 trial, or SWOG 9346 trial, there was a 24 months improvement in the median overall survival of men receiving non-intensified ADT. So I think this is overall very intriguing results, very thought-provoking results and very interesting results and great news for our patients.

The first news coming from this trial is really good news for our patients. That is the median overall survival on the ADT alone or non-intensified ADT arm has gone from 46 months in 2013, as reported in the SWOG 9346 trial by Dr Maha Hussain, to 70 months in 2021 as reported in 2021 by me in the 2021 ASCO Annual Meeting, that’s number one. Number two, the median overall survival in the TAK-700 arm was 80 months, again the highest ever reported median overall survival in the absolute terms in any contemporary trial. Another great piece of information for our patients, especially given what we also presented in the same ASCO meeting in 2021 that less than 30% of patients in the United States are receiving ADT intensification in metastatic castration sensitive or hormone sensitive prostate cancer. Based on these data that is unacceptable. The survival of our patients with newly diagnosed metastatic hormone sensitive prostate cancer is truly going to improve if these patients are offered ADT intensification therapy.

So that’s the second piece of data, the second piece of good news, that if our patients have access to ADT intensification for newly diagnosed hormone sensitive prostate cancer the survival will truly improve across the board. Number three, as we saw in the control arm of the S1216 trial, the median overall survival improved from 46 months to 70 months within a decade, less than a decade, likely because of access to treatment in the metastatic castration resistant prostate cancer setting. Thus, we can conclude that if our patients have access to both ADT intensification for hormone sensitive prostate cancer as well as newer drugs approved in the metastatic castration resistant prostate cancer setting over the last one decade, if they have access to those drugs we are going to see an unprecedented overall survival in our patients who are being newly diagnosed, who are being diagnosed who have a new metastatic prostate cancer tumour. So all great news for our patients.

Lastly, these results have profound implications on how we are going to design trials going forward in the next coming years because we have clearly shown the median overall survival of the control arm without ADT and the median overall survival with intensified treatment, intensified ADT with TAK-700. I think we will have to redo our maths if we are going to design clinical trials, and we are going to do that in the metastatic hormone sensitive prostate cancer setting. Obviously we need newer endpoints, faster endpoints and if you are going to wait for overall survival I don’t think it will be realistic anymore to even conceive these trials with overall survival as the primary endpoint. So those are the messages I have for my colleagues and my patients.