By Lila Rouland | Published on November 18, 2025 | 3 min readMetastatic
castration-resistant prostate cancer (mCRPC) remains an
incurable disease
despite a decade of significant therapeutic progress. The clinical objective is
no longer limited to survival, but now also includes
quality of life (QoL) and
symptom control. The biological heterogeneity of mCRPC, marked by increasing
genomic complexity, calls for a
personalized approach based on
biomarkers to
guide therapeutic decisions. This review summarizes current treatments,
targeted innovations, and upcoming clinical challenges.
Standard
treatments and new targeted combinations: toward a biomarker-guided approach
Chemotherapy
remains a major component of treatment:
docetaxel, the standard first-line
therapy, prolongs overall survival (median OS: 19.2 vs 16.3 months, p <
0.004). If the disease progresses,
cabazitaxel also improves OS (15.1 vs 12.7
months) and provides benefits in pain control and PSA response. However,
significant hematologic toxicity may limit their use.
Androgen
receptor signaling inhibitors (ARSI) such as
enzalutamide and
abiraterone have
shown efficacy both before and after docetaxel. The
PREVAIL study demonstrated
a significant improvement in survival (32.4 vs 30.2 months) and radiographic
PFS (65% at 12 months). These agents are generally well tolerated but may cause
adverse effects such as
fatigue, hypertension, or metabolic disturbances.
Targeted
therapies are gaining importance with the rise of
precision oncology. About
20%
of mCRPC cases exhibit homologous recombination repair (HRR) defects, notably
BRCA1/2 mutations, which are sensitive to PARP inhibitors (PARPi). The
PROfound
trial showed improved PFS (7.4 vs 3.6 months, HR 0.34) and OS (18.5 vs 15.1
months) with
olaparib in patients harboring BRCA1/2 or ATM mutations.
Several
trials (PROpel, MAGNITUDE, TALAPRO-2) have evaluated
PARPi/ARSI combinations.
The PROpel study, conducted without prior biomolecular selection, demonstrated
improved PFS (24.8 vs 16.6 months) with olaparib + abiraterone, particularly in
BRCA-mutated patients (HR 0.29). However, toxicity (anemia, fatigue) remains a
limiting factor.
Toward more
personalized therapies: new targets, immunotherapy, and theranostics
The
PI3K/AKT/mTOR pathway, activated in cases of
PTEN loss (40–60% of mCRPC),
represents a promising target. The
IPATential150 trial showed a PFS benefit
with
ipatasertib + abiraterone in PTEN-negative patients (HR 0.65).
In
contrast,
immunotherapy has not yet shown significant benefit in this
population. The
KEYNOTE-199 and KEYLYNK-010 trials were negative in unselected
patients. Low
PD-L1 expression and a “cold” tumor microenvironment explain this
resistance.
Theranostic
approaches are rapidly advancing with
lutetium-177–PSMA. The
VISION trial
demonstrated improved PFS (8.7 vs 5.1 months) and QoL (FACT-P: 9.7 vs 2.4
months) with acceptable tolerance. The
PSMAfore trial, in the pre-taxane
setting, confirmed these results (rPFS: 12.0 vs 5.6 months, HR 0.43).
Toward biomarker-guided
therapeutic sequencing
The
treatment of mCRPC has evolved considerably with the integration of
PARP
inhibitors, AKT inhibitors, and
lutetium-177, alongside ARSI and taxanes.
However, the optimal sequencing and combination of these treatments remain to
be defined. Systematic integration of
genomic testing (HRR, PTEN, ctDNA) will
enable better
patient stratification and optimization of clinical outcomes
while preserving QoL.
Read next: Darolutamide: Will it redefine the initial treatment strategy in metastatic prostate cancer?
About the author – Lila RoulandDoctor of Oncology, specialized in Biotechnology and Management
