Therapeutic Sequencing in Metastatic Castration-ResistantProstate Cancer (mCRPC)

Authored by Neal Shore, published on 2026-05-08 17:45:56.0

  1. mCRPC Diagnosis
    Progressive disease by PSA, radiographic, or clinical criteria despite castrate levels of testosterone (<50 ng/dL) achieved with ADT
    • Assess Key Patient and Disease Factors
      Disease volume (high vs low) Prior docetaxel for mHSPC? (de novo mCRPC vs post-docetaxel) Presence of actionable genomic alterations (HRR mutation, MSI-H/dMMR, TMB-H) Predominant disease site (visceral vs bone-predominant) Symptoms and pace of disease Patient comorbidities, preferences, and access
      • De novo mCRPC
        No prior docetaxel for mCRPC.
        • High-Volume Disease
          Visceral metastases and/or ≥4 bone lesions with ≥1 beyond vertebral bodies and pelvis.
          • Preferred Initial Treatment Options (High-Volume)
            ARPI (abiraterone or enzalutamide) + ADT (Category 1) ARPI (apalutamide) + ADT (Category 1) Docetaxel + ADT (Category 1)
            • If PSA or radiographic progression or intolerance
              • Subsequent Therapy After Progression on Prior Line
                Select next therapy based on prior treatments, mechanism of action, disease factors, prior toxicities, patient preference, and available options.
                • After ARPI (Abiraterone, Enzalutamide, Apalutamide, or Darolutamide)
                  Options (Choose one) Docetaxel + ADT (if not previously given) (Category 1) Radium-223 for symptomatic bone-predominant disease without visceral metastases (Category 1) PARP inhibitor if HRR mutation present and not previously used (Category 1) Clinical trial (Category 1)
                • After Docetaxel
                  Options (Choose one) ARPI not previously used (Category 1) Cabazitaxel + prednisone (Category 1) Radium-223 for symptomatic bone-predominant disease without visceral metastases (Category 1) PARP inhibitor if HRR mutation present and not previously used (Category 1) Clinical trial (Category 1)
                • After ARPI and Docetaxel
                  Options (Choose one) Cabazitaxel + prednisone (Category 1) Radium-223 for symptomatic bone-predominant disease without visceral metastases (Category 1) PARP inhibitor if HRR mutation present and not previously used (Category 1) 177Lu-PSMA-617 for PSMA-positive disease after ARPI and taxane therapy (Category 1) Clinical trial (Category 1)
                • After Cabazitaxel
                  Options (Choose one) 177Lu-PSMA-617 for PSMA-positive disease (Category 1) PARP inhibitor if HRR mutation present and not previously used (Category 1) Best supportive care or clinical trial (Category 1)
                • After 177Lu-PSMA-617
                  Options (Choose one) Clinical trial (Category 1) PARP inhibitor if HRR mutation present and not previously used (Category 1) Best supportive care
        • Low-Volume Disease
          No visceral metastases and < high-volume criteria.
          • Preferred Initial Treatment Options (Low-Volume)
            ARPI (abiraterone, enzalutamide, or apalutamide) + ADT (Category 1) Consider ASI + ADT (darolutamide) in select patients
            • If PSA or radiographic progression or intolerance
              • Subsequent Therapy After Progression on Prior Line
                Select next therapy based on prior treatments, mechanism of action, disease factors, prior toxicities, patient preference, and available options.
                • After ARPI (Abiraterone, Enzalutamide, Apalutamide, or Darolutamide)
                  Options (Choose one) Docetaxel + ADT (if not previously given) (Category 1) Radium-223 for symptomatic bone-predominant disease without visceral metastases (Category 1) PARP inhibitor if HRR mutation present and not previously used (Category 1) Clinical trial (Category 1)
                • After Docetaxel
                  Options (Choose one) ARPI not previously used (Category 1) Cabazitaxel + prednisone (Category 1) Radium-223 for symptomatic bone-predominant disease without visceral metastases (Category 1) PARP inhibitor if HRR mutation present and not previously used (Category 1) Clinical trial (Category 1)
                • After ARPI and Docetaxel
                  Options (Choose one) Cabazitaxel + prednisone (Category 1) Radium-223 for symptomatic bone-predominant disease without visceral metastases (Category 1) PARP inhibitor if HRR mutation present and not previously used (Category 1) 177Lu-PSMA-617 for PSMA-positive disease after ARPI and taxane therapy (Category 1) Clinical trial (Category 1)
                • After Cabazitaxel
                  Options (Choose one) 177Lu-PSMA-617 for PSMA-positive disease (Category 1) PARP inhibitor if HRR mutation present and not previously used (Category 1) Best supportive care or clinical trial (Category 1)
                • After 177Lu-PSMA-617
                  Options (Choose one) Clinical trial (Category 1) PARP inhibitor if HRR mutation present and not previously used (Category 1) Best supportive care
      • Post-Docetaxel mCRPC
        Docetaxel previously given for mHSPC or mCRPC.
        • Preferred Initial Treatment Options (Post-Docetaxel)
          ARPI not previously used (abiraterone, enzalutamide, apalutamide, or darolutamide) + ADT (Category 1) Sipuleucel-T in appropriate asymptomatic or minimally symptomatic patients (Category 2A) Radium-223 for symptomatic bone-predominant disease without visceral metastases (Category 1)
          • If PSA or radiographic progression or intolerance
            • Subsequent Therapy After Progression on Prior Line
              Select next therapy based on prior treatments, mechanism of action, disease factors, prior toxicities, patient preference, and available options.
              • After ARPI (Abiraterone, Enzalutamide, Apalutamide, or Darolutamide)
                Options (Choose one) Docetaxel + ADT (if not previously given) (Category 1) Radium-223 for symptomatic bone-predominant disease without visceral metastases (Category 1) PARP inhibitor if HRR mutation present and not previously used (Category 1) Clinical trial (Category 1)
              • After Docetaxel
                Options (Choose one) ARPI not previously used (Category 1) Cabazitaxel + prednisone (Category 1) Radium-223 for symptomatic bone-predominant disease without visceral metastases (Category 1) PARP inhibitor if HRR mutation present and not previously used (Category 1) Clinical trial (Category 1)
              • After ARPI and Docetaxel
                Options (Choose one) Cabazitaxel + prednisone (Category 1) Radium-223 for symptomatic bone-predominant disease without visceral metastases (Category 1) PARP inhibitor if HRR mutation present and not previously used (Category 1) 177Lu-PSMA-617 for PSMA-positive disease after ARPI and taxane therapy (Category 1) Clinical trial (Category 1)
              • After Cabazitaxel
                Options (Choose one) 177Lu-PSMA-617 for PSMA-positive disease (Category 1) PARP inhibitor if HRR mutation present and not previously used (Category 1) Best supportive care or clinical trial (Category 1)
              • After 177Lu-PSMA-617
                Options (Choose one) Clinical trial (Category 1) PARP inhibitor if HRR mutation present and not previously used (Category 1) Best supportive care
      • Consider Actionable Genomic Alterations at Any Point
        Review algorithm for Universal Germline Genetic Testing in Prostate Cancer
        • Preferred Targeted Options
          Use in any line when eligible HRR gene mutation (BRCA1/2, ATM, PALB2, etc.): PARP inhibitor (olaparib or rucaparib) + ADT (Category 1) MSI-H/dMMR or TMB-High: Pembrolizumab + ADT (Category 2A) NTRK fusion: Entrectinib or larotrectinib (Category 2A)
          • Continue ADT in All Cases
            Maintain continuous ADT throughout the mCRPC treatment course.
  2. Supportive Care Throughout
    Bone health (denosumab or zoledronic acid), pain management, management of treatment-related toxicities, cardiovascular risk assessment, and goals-of-care discussions.
tosprivacyNavigating therapeutic sequencing in the metastatic castration-resistant prostate cancer patient journey