Prostate cancer: new strategies are good, but without forgetting the role of radiotherapy

I read with great interest your article on the PROTEUS study, recently presented at the Asco, the American Congress of Clinical Oncology, and published in the New England Journal of Medicine. However, I feel it is necessary to propose some critical reflections: the hope is that the information provided - particularly on a subject as relevant and complex as the treatment of high-risk prostate cancer - is as complete, balanced and contextualised as possible.

Firstly, the article seems to suggest, albeit implicitly, that the results of the study may 'change the paradigm' of treatment for people with high-risk prostate cancer. This claim seems premature. The PROTEUS study, in fact, compares a strategy of systemic hormone intensification (apalutamide + ADT) in the perioperative setting with androgen deprivation therapy alone, but does not include an arm with radiotherapy, which today represents - together with surgery - one of the pillars of curative treatment in locally advanced or high-risk prostate cancer. This absence is not a minor methodological detail, but a substantial limitation: today, a significant proportion of patients are treated with radiotherapy combined with hormone therapy, an approach supported by robust long-term evidence in terms of biochemical control, metastasis-free survival and overall survival. Therefore, it is not possible, on the basis of the data presented, to establish a real superiority or even a comparative advantage over currently established radiotherapy strategies. To put it simply, it is as if one were to announce a great revolution in urban mobility on the basis of a study comparing a state-of-the-art drone with hitherto known helicopters, but neglecting the fact that in practice, in our cities, people move around by bicycle, car or scooter.

Secondly, the emphasis on the results - although interesting - deserves a more cautious reading. A pathological complete or near-complete response rate of less than 10%, although higher than control, must be interpreted with caution, especially considering that the true relevant clinical endpoint remains long-term overall survival, on which the study shows no impact. Similarly, the benefit in event-free and metastasis-free survival, although statistically significant, is not yet mature enough to redefine established standards. The advantage offered by this therapeutic strategy must also be assessed in the light of the adverse events reported in the study - which were far from negligible - for a proper balance between risks and benefits.

A further aspect completely absent from the article concerns economic sustainability. In the presence of already effective and established therapeutic alternatives, and not compared with the approach tested in the PROTEUS study, the introduction of new-generation drugs such as apalutamide in the perioperative phase inevitably entails a significant increase in treatment costs. In public healthcare systems such as ours, it is imperative that every therapeutic innovation is evaluated not only in terms of efficacy but also cost-effectiveness. Without a rigorous pharmacoeconomic analysis, the risk is that of proposing therapeutic models that are difficult to transfer into real practice because they are not sustainable on a large scale.

Finally, it seems necessary to emphasise that high-risk prostate cancer is an inherently multidisciplinary disease. Reducing the narrative to a comparison centred exclusively on surgery - however technologically advanced, including robotic surgery - risks offering a biased view. Indeed, it should be stressed that the trial results themselves show that a significant percentage of patients, due to the intrinsic nature of high-risk disease, required further postoperative treatment, including radiotherapy. The real challenge today is the optimal integration of surgery, radiation oncology and systemic treatments, selecting the most appropriate pathway for each patient.