Proffered paper & mini oral session: Prostate cancer

Dr Tom Van den Mooter and Dr Michiel Strijbos from ZAS Hospital in Antwerp shared key takeaways from ESMO 2024 regarding prostate cancer. They highlighted several trials, noting that some were innovative while others yielded unexpected or even disappointing results, often due to choices of endpoints or crossover designs.

One standout study was a phase 1 trial involving a first-in-class dual AR ligand directed degrader and antagonist, which showed early signs of efficacy in heavily pretreated mCRPC patients. These patients had a high unmet need, having already undergone treatments like novel antihormonal agents and chemotherapy. Despite the study’s early stage and the absence of a comparator group, the ability to induce responses in such a challenging patient population was seen as encouraging. This drug, while still in its early stages of development, could potentially change the landscape of PCa treatment in the future, with upcoming phase 2 trials likely to provide more insight.

The PEACE 3 trial investigated the combination of Ra-223 and enzalutamide in patients with first-line mCRPC. Notably, these patients had not received prior treatment with ARPI in the hormone-sensitive setting, making them a relatively rare cohort in clinical practice. The trial demonstrated a significant improvement in both PFS and OS, which is remarkable given that Ra-223 is an older therapeutic agent.

In contrast, newer biological agents like Lu-PSMA were less encouraging. Trials such as SPLASH and UpFrontPSMA were criticized for their design and their choice of primary endpoints. 

The RAPSON trial compared Ra-223 to docetaxel in first-line mCRPC, with QoL as the primary endpoint. While the use of QoL in this setting is debatable, it was justified due to the importance of maintaining QoL in mCRPC patients. The trial confirmed a QoL benefit for Ra-223-treated patients during the treatment phase, though OS results are still pending. It is also important to note that patients in the RAPSON trial had prior ARPI treatment, which may impact future interpretations of the results.

Patient selection was a frequently debated topic at the congress, and it remains a critical issue in clinical trials and tumour boards. Identifying the right patient for a trial is essential, yet often overlooked. For example, high-volume patients differ from low-volume ones, and distinguishing between visceral versus bone-only metastases is important. Some trials were criticized for post-hoc subgroup analyses, such as the CONTACT-02 study in mCRPC with cabozantinib and atezolizumab, which was negative on its primary endpoint. However, discussions around possible activity in liver metastases—though not statistically significant—raised concerns about misuse of such analyses.

The ARANOTE trial randomised patients with mHSPC to receive either ADT alone or ADT plus darolutamide. While darolutamide had shown survival benefits with docetaxel in the ARASENS trial, its effect with ADT alone was previously unknown. The trial confirmed a benefit of darolutamide with ADT, though it raised ethical concerns, as by 2021, treatments like abiraterone and apalutamide had shown positive results. Additionally, many high-volume, de novo patients in ARANOTE could have been considered for triplet therapy rather than a singlet regimen. Nonetheless, the trial supports the use of darolutamide with ADT without the need for docetaxel.