Recent clinical trials are reshaping the treatment landscape for metastatic prostate cancer, offering new hope for improved outcomes and quality of life. The ARANOTE, PEACE-3, and SPLASH trials have presented practice-changing data that could redefine treatment paradigms for both hormone-sensitive and castration-resistant prostate cancer. These studies, presented at major oncology conferences, introduce novel therapeutic strategies and combinations that address unmet needs in advanced prostate cancer management.
Darolutamide Plus ADT in Metastatic Hormone-Sensitive Prostate Cancer
The phase III ARANOTE trial evaluated the efficacy and safety of darolutamide in combination with androgen-deprivation therapy (ADT) for patients with metastatic hormone-sensitive prostate cancer (mHSPC). The study, involving 669 patients, demonstrated a significant improvement in radiological progression-free survival (rPFS) with the darolutamide plus ADT regimen compared to placebo plus ADT. Specifically, the combination reduced the risk of radiological progression or death by 46% (HR 0.54, 95% CI 0.41-0.71, P < 0.0001).
According to Fred Saad, MD, of the University of Montreal, the benefits were consistent across subgroups, including those with high- and low-volume disease. The trial also showed improvements in other secondary endpoints, such as time to castration-resistant prostate cancer (CRPC) and time to pain progression. Notably, the incidence of fatigue was lower in the darolutamide group (5.6%) compared to the placebo group (8.1%), and fewer patients discontinued treatment due to adverse events.
The ARANOTE trial's diverse patient population, including elderly, Asian, and Black individuals, strengthens the generalizability of its findings. The results suggest that darolutamide plus ADT could be an effective option for mHSPC patients, offering a balance of efficacy and tolerability.
Radium-223 and Enzalutamide Combination in Metastatic CRPC
The phase III PEACE-3 trial explored the combination of radium-223 with enzalutamide in patients with metastatic castration-resistant prostate cancer (mCRPC) and bone metastases. The trial demonstrated that this combination significantly improved radiographic progression-free survival and overall survival. This combination therapy may now be considered a first-line treatment option for mCRPC, with the important consideration that bone protective agents should be used to mitigate fracture risk, as observed in both the ERA-223 and PEACE-3 trials.
177Lu-PNT2002 as a Novel Radioligand Therapy
The phase III SPLASH trial investigated the use of 177Lu-PNT2002 in mCRPC patients who had progressed after treatment with an androgen receptor pathway inhibitor (ARPI). The trial demonstrated a significant radiographic progression-free survival benefit with 177Lu-PNT2002, along with a favorable safety profile. While overall survival data are still pending due to high crossover, the rPFS results suggest that 177Lu-PNT2002 may provide a new radioligand therapy option in the pre-chemotherapy mCRPC setting.
Implications for Clinical Practice
These trials collectively offer new strategies for managing metastatic prostate cancer. The ARANOTE trial supports the use of darolutamide plus ADT as a first-line option for mHSPC, while the PEACE-3 trial highlights the potential of combining radium-223 with enzalutamide in mCRPC. The SPLASH trial introduces 177Lu-PNT2002 as a promising radioligand therapy for mCRPC patients who have progressed on ARPIs.
These advances underscore the importance of personalized treatment approaches in prostate cancer, considering disease stage, prior therapies, and individual patient characteristics. As research continues, these and other novel strategies hold the potential to further improve outcomes and quality of life for men with metastatic prostate cancer.
