Post-Enzalutamide mCRPC: HRR/PARP, PSMA Radioligand, and Chemotherapy Sequencing

　　1.Reassessment after progression

　　Enzalutamide blocks androgen-receptor signaling.Rising PSA,radiographic progression,or worsening symptoms may indicate castration-resistant advancement.Do not simply switch to another anti-androgen;confirm ongoing castration,map bone and visceral disease,assess symptoms and performance status,and review prior treatment order.

　　For metastatic castration-resistant disease,obtain homologous recombination repair testing at minimum for BRCA1/2 and,as appropriate,ATM,PALB2,CHEK2 and other HRR genes.Add PSMA PET/CT to decide radioligand suitability.Molecular and imaging results together determine which mechanism to switch to.

　　2.HRR/BRCA abnormalities:PARP inhibitors

　　BRCA1/2 alterations have the strongest PARP-inhibitor evidence.Olaparib is an option after prior AR-pathway progression with HRR defects;PROfound showed better radiographic PFS than continuing another AR drug,with the largest benefit in BRCA subgroups.Rucaparib is positioned for BRCA-mutated disease after prior AR-targeted therapy.For non-BRCA HRR variants,decisions depend on the specific gene,prior chemotherapy,and tolerability rather than a uniform rule.

　　Monitor hemoglobin,leukocytes,platelets,nausea,fatigue,and renal function;persistent cytopenias or suspected myeloid disorder require hematology review and possible discontinuation.

　　3.PSMA-positive disease:lutetium-177

　　After enzalutamide or other AR drugs progress,patients with PSMA PET-avid lesions may be evaluated for lutetium-177 PSMA-617,also called vipivotide tetraxetan.It fits those who wish to delay taxanes,have homogeneous PSMA uptake,and lack high-risk mismatched visceral disease;VISION supports benefit after AR±taxane and PSMAfore supports earlier/chemo-delayed use.

　　Exclude or caution in low/negative PSMA uptake,extensive hepatic/peritoneal mismatch,severe myelosuppression,poor renal function,or goals inconsistent with radioligand therapy.Nuclear medicine and oncology should select candidates jointly.

　　4.No clear driver mutation:chemotherapy and other paths

　　If BRCA/HRR benefit is absent and PSMA is unsuitable,sequence by treatment history:

　　No prior chemotherapy or first mechanism switch after AR drugs:docetaxel if performance status allows;prefer chemotherapy sooner for symptomatic,rapid,or visceral-dominant progression.

　　Prior docetaxel progression:cabazitaxel for post-taxane control,especially when another AR switch is unlikely to help;CARD-type evidence favors it over switching AR drugs.

　　Symptomatic bone-only metastases without known visceral disease:evaluate radium-223 for skeletal events and pain.

　　Rare MSI-H/dMMR or high TMB markers:discuss immunotherapy in oncology;not a routine enzalutamide-resistance step.

　　Switching directly from enzalutamide to another AR-pathway agent often yields limited benefit because of cross-resistance;reserve it for cases where genomics,PSMA,chemotherapy tolerance,and progression rate all support that choice.