2025-11-18
How are new therapies transforming the management of metastatic castration-resistant prostate cancer?
Oncology
By Lila Rouland | Published on November 18, 2025 | 3 min read
Metastatic 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.
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.
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).
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.
About the author – Lila Rouland
With dual expertise in science and marketing, Lila brings her knowledge to the service of healthcare innovation. After five years in international academic research, she transitioned into medical and scientific communication within the pharmaceutical industry. Now working as a medical writer and content developer, she is committed to highlighting scientific knowledge and conveying it to healthcare professionals with clarity and relevance.
Metastatic 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 Rouland
Doctor of Oncology, specialized in Biotechnology and Management
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