What alterations are targetable in metastatic castration-resistant prostate cancer?

Targetable Alterations in Metastatic Castration-Resistant Prostate Cancer

The most clinically validated targetable alterations in mCRPC are BRCA1/2 mutations (treated with PARP inhibitors), with emerging evidence for PTEN loss (AKT inhibitors), MSI-H/dMMR status (immune checkpoint inhibitors), and PSMA expression (radioligand therapy). 1

Primary Targetable Alterations with FDA-Approved Therapies

BRCA1/2 Mutations (Highest Priority)

• BRCA1/2 alterations (germline and/or somatic) are the most robustly validated targets in mCRPC, with PARP inhibitors demonstrating significant overall survival benefit (HR 0.69, medians: 19.1 vs 14.7 months). 1
• The benefit is predominantly observed in patients with BRCA alterations specifically, rather than broader DNA repair gene alterations. 1
• Rucaparib is FDA-approved for BRCA-mutated mCRPC after androgen receptor-directed therapy and taxane-based chemotherapy. 2
• Testing should be performed using NGS on tumor samples or plasma specimens to identify these mutations. 1

DNA Repair Gene Alterations Beyond BRCA

• DNA repair gene aberrations occur in 20-30% of mCRPC patients. 1
• PALB2, RAD50, RAD51, and BRIP1 mutations show promising but sparse data due to low frequency. 1
• ATM alterations were included in the PROfound trial but showed less benefit than BRCA alterations. 1

PTEN Loss

• PTEN alterations are found very frequently in mCRPC and represent an emerging therapeutic target. 1
• AKT inhibitors (ipatasertib) combined with abiraterone showed improvement in radiographic PFS in patients with PTEN loss in the IPATential 150 phase III trial, though not in the overall population. 1
• This represents a level of evidence that is promising but not yet as robust as BRCA-targeted therapy. 1

Targetable Alterations with Established Clinical Benefit

MSI-H/dMMR Status

• Mismatch repair gene mutations (MLH1, MSH2, MSH6, PMS2) lead to MSI-H when mutated. 1
• Immune checkpoint inhibitors (pembrolizumab, nivolumab) demonstrated effectiveness in multi-histology basket studies. 1
• However, in advanced prostate cancer specifically, ICIs have shown minimal activity despite success in other tumor types. 1

PSMA Expression

• PSMA-positive disease is targetable with lutetium-177 PSMA-617 radioligand therapy, which improved both radiographic PFS (HR 0.40, medians: 8.7 vs 3.4 months) and OS (HR 0.62, medians: 15.3 vs 11.3 months). 1
• This is indicated for patients pretreated with at least one taxane and one androgen receptor axis inhibitor. 1
• PSMA expression should be confirmed via imaging before initiating therapy. 3

Alterations Observed But Not Yet Validated in Prostate Cancer

Alterations Validated in Other Cancers

• NTRK fusions are targetable with TRK inhibitors across multiple tumor types, but data specific to prostate cancer are limited. 1
• KRAS, PIK3CA, BRAF V600E mutations, MDM2 and ERBB2 amplifications, and NRG1, ALK, RET, ROS1 fusions are classified at high levels in other tumors but have not shown significant impact in prostate cancer. 1

Clinical Implementation Algorithm

Testing Recommendations

1. Perform NGS on tumor samples or plasma to assess mutational status of at least BRCA1/2 in all mCRPC patients where PARP inhibitors are accessible. 1
2. Consider broader HRR gene panel testing (PALB2, RAD50, RAD51, BRIP1, ATM) for potential clinical trial enrollment. 1, 4
3. Assess PTEN status given emerging data with AKT inhibitors. 1
4. Evaluate MSI-H/dMMR status, though clinical benefit in prostate cancer is limited. 1
5. Confirm PSMA expression via imaging for radioligand therapy eligibility. 1, 3

Treatment Selection Based on Alterations

• For BRCA1/2 mutations: PARP inhibitor monotherapy (if ARPI-exposed) or PARP inhibitor + ARPI combination (if ARPI-naïve). 1, 4
• For PTEN loss: Consider AKT inhibitor + abiraterone combination based on phase III data. 1
• For PSMA-positive disease: 177Lu-PSMA-617 after progression on ARPI and taxane. 1, 3
• For patients without targetable alterations: Standard therapies including ARPI, chemotherapy (docetaxel, cabazitaxel), or radium-223 for bone-limited disease. 1, 3

Critical Pitfalls to Avoid

• Do not assume primary tumor profiling is sufficient; molecular drivers can change as disease progresses through treatments, requiring repeat testing at castration resistance. 1
• Do not discontinue ADT when adding targeted therapies; all novel agents are studied with concurrent ADT as backbone. 5, 3
• Do not extrapolate benefit from broader DNA repair gene alterations to all HRR mutations; the strongest evidence is specific to BRCA1/2. 1
• Do not rely on MSI-H status alone to predict ICI benefit in prostate cancer, as activity has been minimal despite success in other tumor types. 1