By Lila Rouland | Published on November 13, 2025 | 4 min readMetastatic
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.
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About the author – Lila RoulandDoctor of Oncology, specialized in Biotechnology and Management
