mCRPC in Men: What to Do When First-Line Therapy Has Failed
This protocol covers metastatic castration-resistant prostate cancer (mCRPC) in male patients with confirmed castrate testosterone levels and documented radiological or biochemical progression at the M1 stage, who have progressed after first-line mCRPC therapy, have had no prior androgen receptor pathway inhibitor (ARPI) use in the mCRPC setting, and have no known BRCA1/2 mutation.
Clinical Situation
Castrate testosterone below 50 ng/dL with radiological or biochemical progression confirmed at the metastatic (M1) stage. Male sex. No prior ARPI exposure during the mCRPC phase. No known BRCA1/2 mutation.
Previous Line — Failure Condition
First-line mCRPC treatment with abiraterone acetate, enzalutamide, or docetaxel — each given with ongoing androgen deprivation therapy — did not achieve the required goals: PSA decline ≥50%, sustained radiographic progression-free survival, and absence of new metastatic lesions.
Progression on that regimen is the clinical trigger that escalates management to the next step described here.
Treatment Approach (Partial)
Following progression on first-line mCRPC therapy, the evidence-based approach involves specific options across chemotherapy and targeted radionuclide therapy classes — the full sequencing algorithm and eligibility criteria are available in the structured protocol.
Key clinical goals: PSA decline ≥50% and radiographic progression-free survival.
References
Approved agents for the treatment of mCRPC in Europe are docetaxel, abiraterone/prednisolone (AAP), enzalutamide, cabazitaxel, olaparib, niraparib/AAP, talazoparib/enzalutamide, radium-223 and lutetium (177Lu) vipivotide tetraxetan.
The use of chemotherapy with docetaxel and subsequent cabazitaxel in the treatment sequence is recommended and should be applied early enough when the patient is still fit for chemotherapy.
Cabazitaxel more than doubled rPFS vs. another ARPI and reduced the risk of death by 36% vs. ARPI.
In two post-marketing randomised phase III trials, cabazitaxel was shown not to be superior to docetaxel in the first-line setting; in the second-line setting in terms of OS, 20 mg/m2 cabazitaxel was not inferior to 25 mg/m2, but less toxic.
177Lu-PSMA-617 plus SOC significantly prolonged both imaging-based PFS and OS, as compared with SOC alone.
Radium-223 significantly improved median OS by 3.6 months (HR: 0.70, p < 0.001) and was also associated with prolonged time to first skeletal event, improvement in pain scores and improvement in QoL.