Is early therapeutic intensification the key to treating metastatic castration-sensitive prostate cancer?

Metastatic castration-sensitive prostate cancer (mCSPC) remains a major public health challenge for men worldwide. Historically, its management relied on androgen deprivation therapy (ADT) alone. However, advances in understanding the androgen receptor (AR) signaling pathway have profoundly changed therapeutic strategies. The early integration of chemotherapy (such as docetaxel) or androgen receptor signaling inhibitors (ARSi) has significantly improved overall survival, particularly in patients with high-volume disease. This review provides an updated overview of validated treatment strategies and emerging therapies.   Should treatment be intensified at diagnosis? The management of mCSPC is now based on combination regimens in which ADT is systematically associated with an intensification therapy. The CHAARTED and STAMPEDE trials demonstrated that early addition of docetaxel to ADT significantly prolongs overall survival in patients with high-volume disease. In contrast, the benefit for low-volume disease remains debated. The GETUG-AFU15 study did not show a clear advantage, but meta-analyses pooling data from these trials confirm the benefit of docetaxel in more aggressive disease forms. The second major shift comes from androgen-axis inhibitors such as abiraterone, enzalutamide, apalutamide, and darolutamide. The LATITUDE study showed that adding abiraterone to ADT in high-risk patients increased median survival to 53.3 months compared with 36.6 months for ADT alone. These results were confirmed in STAMPEDE, where overall survival reached 76.6 months. Enzalutamide (ENZAMET, ARCHES), apalutamide (TITAN), and darolutamide (ARASENS, ARANOTE) have each demonstrated improvements in progression-free survival with favorable safety profiles. Darolutamide, in particular, offers a lower risk of neurological toxicity due to its minimal blood–brain barrier penetration. Triple therapy combining ADT, an ARSi, and docetaxel is now an established option for patients with de novo, high-volume disease, with demonstrated benefits in the PEACE-1 and ARASENS trials. However, direct comparisons between triplet regimens and ARSi-based doublets are still ongoing. The therapeutic landscape is also evolving with the emergence of targeted strategies. PARP inhibitors such as niraparib and saruparib are being evaluated for patients with DNA repair gene mutations (BRCA1/2, ATM). Targeting the PTEN/PI3K/AKT pathway with capivasertib is also showing promise, as explored in the CAPItello-281 trial. In addition, radiotherapy directed at the primary tumor has shown overall survival benefits in patients with low metastatic burden, as demonstrated in the STAMPEDE and HORRAD trials. Metastasis-directed radiotherapy (SBRT), investigated in the STOMP and ORIOLE trials, has also been shown to prolong progression-free survival in patients with oligometastatic relapse. Finally, PSMA-targeted radioligand therapies, such as ^177Lu-PSMA-617, are generating strong interest for patients with high-volume disease, as seen in the ongoing UpFrontPSMA trial.   Has the era of personalized prostate oncology arrived? The management of mCSPC has entered a new era of intensified and personalized therapy. The combination of ADT with an ARSi, sometimes supplemented with docetaxel, now represents the standard backbone of treatment, especially for high-volume disease. Future perspectives focus on biomolecular stratification, improved treatment tolerability, and individualized therapeutic approaches. Significant challenges remain, including the direct comparison of doublet versus triplet regimens, the optimal selection of patients for local or targeted therapies, and the reduction of cumulative toxicity. Ongoing studies will refine the optimal strategies and further solidify the shift toward precision oncology, tailored to the genomic and clinical profile of each patient.