OpenOnco Handbook

Metastatic castration-resistant prostate cancer: biomarker and sequencing reasoning

draft hcp_learner en

Deterministic learning chapter over OpenOnco KB entities, synthetic cases, and source records.

Learning objectives

  1. Identify the germline / somatic HRR panel, prior-line history, and disease-burden inputs needed before mCRPC first-line treatment selection.
  2. Explain why ARPI continuation reasoning, BRCA/HRR routing to a PARP inhibitor, and Lu-177-PSMA / cabazitaxel options sit on a sequencing arc rather than a single 1L decision.
  3. Recognize emergency red flags — cord compression, marrow failure, transformation — that change the treatment timeline without changing the biomarker map.

At a glance

  • Castration resistance is defined by biochemical or radiographic progression on adequate testosterone suppression — prior ARPI use shapes every downstream choice.
  • Germline and tumor HRR panel (BRCA1, BRCA2, ATM, CHEK2, CDK12, PALB2) is treated as a treatment-defining test, not an optional add-on.
  • ARPI-naive mCRPC routes to abiraterone or enzalutamide; ARPI-resistant disease pulls PARP-inhibitor (BRCA-/HRR-driven) and Lu-177-PSMA reasoning into the conversation.
  • Docetaxel and cabazitaxel remain treatment-defining for chemotherapy-fit patients across lines; CARD established cabazitaxel after prior docetaxel + ARPI progression.
  • This chapter is an OpenOnco-authored learning aid, not official ESMO content or a CME-credit activity.

Diagnostic and biomarker minimum

Castration resistance is established by biochemical (PSA rise) or radiographic progression on adequate testosterone suppression. Before drafting any first-line mCRPC plan the chapter expects baseline PSA kinetics, conventional imaging plus PSMA-PET where access permits, baseline organ function, a documented prior-line history (ARPI exposure in mHSPC versus mCRPC matters), and germline + tumor HRR panel testing covering BRCA1, BRCA2, ATM, CHEK2, CDK12, and PALB2. The HRR panel is treatment-defining in this disease — not an optional add-on — because PARP-inhibitor routing depends on it.

Linked entities

DIS-PROSTATEProstate adenocarcinomadiseasesBIO-PSAProstate-specific antigenbiomarkersBIO-BRCA1-BRCA2-GERMLINEGermline BRCA1/BRCA2 mutationbiomarkersBIO-HRR-PANELHRR gene panel statusbiomarkersTEST-PSA-SERUMSerum PSAtestsTEST-PSMA-PETPSMA-PET/CT (Ga-68 or F-18)testsTEST-GERMLINE-BRCA-PANELGermline BRCA1/2 + HRR panel sequencingtests

Section sources

  • SRC-NCCN-PROSTATE-2025 NCCN Clinical Practice Guidelines — Prostate Cancer
  • SRC-ESMO-PROSTATE-2024 ESMO Clinical Practice Guideline on Prostate Cancer

First-line decision logic at mCRPC

OpenOnco splits the first-line mCRPC decision by prior ARPI exposure. ARPI-naive mCRPC routes to abiraterone or enzalutamide; ARPI-resistant disease pulls PARP-inhibitor reasoning into the canonical first option when a BRCA1/2 mutation (or, depending on the indication, a broader HRR alteration) is present. Patients without an actionable HRR alteration who have already received an ARPI move toward docetaxel chemotherapy at the next decision point. The transition from mHSPC to mCRPC is the moment when a fresh HRR result changes the algorithm — older germline-only tests should be repeated with tumor sequencing if the original result was negative.

Linked entities

ALGO-PROSTATE-MCRPC-1LALGO-PROSTATE-MCRPC-1LalgorithmsIND-PROSTATE-MCRPC-1L-ARPIIND-PROSTATE-MCRPC-1L-ARPIindicationsIND-PROSTATE-MCRPC-1L-PARPIIND-PROSTATE-MCRPC-1L-PARPIindicationsRF-PAN-BRCA-SOMATIC-PARPI-CANDIDATESomatic (tumor-only) BRCA1 or BRCA2 pathogenic variant identified on tumor NGS — pan-tumor PARPi-candidate signal. Disease applicability varies: ovarian (PAOLA-1, SOLO-1 — somatic BRCA pooled with germline in HRD-positive maintenance indication), mCRPC (PROfound cohort-A — olaparib mPFS 7.4 vs 3.6 mo, HR 0.34, somatic + germline pooled), pancreatic PDAC (POLO label is germline-only — somatic BRCA falls to off-label / NCCN "consider" tier), breast (OlympiAD / EMBRACA / OlympiA labels are germline-only — somatic BRCA breast remains investigational). Confirm somatic vs germline status via paired germline NGS before cascade-testing decisions (~40% of tumor-only "BRCA" calls are in fact germline per ASCO/CAP guidance). redflags

Section sources

  • SRC-PROFOUND-DEBONO-2020 Olaparib for Metastatic Castration-Resistant Prostate Cancer
  • SRC-NCCN-PROSTATE-2025 NCCN Clinical Practice Guidelines — Prostate Cancer

Second-line sequencing — taxanes, Lu-177-PSMA, and beyond

After progression on the first mCRPC line the chapter expects the learner to weigh cabazitaxel, Lu-177-PSMA, and radium-223 against each other. CARD established cabazitaxel after sequential ARPI + docetaxel exposure. Lu-177-PSMA requires PSMA-PET-positive disease and prior taxane / ARPI exposure per VISION. Radium-223 is reserved for symptomatic bone-predominant disease without visceral metastases (ALSYMPCA). The OpenOnco model surfaces all three as parallel options and uses red flags (visceral burden, transformation, marrow reserve) to narrow the choice.

Linked entities

ALGO-PROSTATE-MCRPC-2LALGO-PROSTATE-MCRPC-2LalgorithmsIND-PROSTATE-MCRPC-2L-CABAZITAXELIND-PROSTATE-MCRPC-2L-CABAZITAXELindicationsIND-PROSTATE-MCRPC-2L-LU-PSMAIND-PROSTATE-MCRPC-2L-LU-PSMAindicationsIND-PROSTATE-MCRPC-2L-DOCETAXELIND-PROSTATE-MCRPC-2L-DOCETAXELindicationsRF-PROSTATE-TRANSFORMATION-PROGRESSIONSpinal cord compression OR rapid PSA doubling time (<3 months) OR new visceral metastases — emergency or aggressive-progression flag requiring urgent intervention or treatment intensification.redflags

Section sources

  • SRC-CARD-DE-BONO-2019 Olaparib for Metastatic Castration-Resistant Prostate Cancer
  • SRC-ALSYMPCA-PARKER-2013 Alpha Emitter Radium-223 and Survival in Metastatic Prostate Cancer
  • SRC-NCCN-PROSTATE-2025 NCCN Clinical Practice Guidelines — Prostate Cancer

Common traps

Do not treat regimen selection as the whole task. Cord compression is a neuro-oncologic emergency that interrupts sequencing decisions; AR-V7 detection in some assays suggests reduced ARPI sensitivity but does not replace the HRR-driven branch; transformation to neuroendocrine prostate cancer changes the chemotherapy backbone and prognosis; and germline BRCA mutations require cascade-testing counseling and contraception planning for younger partners. None of these change the immediate biomarker map but missing them changes the safety plan and the trajectory of care.

Linked entities

RF-PROSTATE-CORD-COMPRESSIONMetastatic prostate cancer with malignant epidural spinal cord compression (MESCC): new motor deficit, sensory level, cauda equina syndrome, severe back pain with vertebral metastasis — prostate is the most common solid tumor cause of MESCCredflagsRF-PROSTATE-AR-V7-ARSI-RESISTANCEAR-V7 (androgen receptor splice variant 7) detected in CTCs / ctDNA in mCRPC — predictive marker of ARSI (abiraterone, enzalutamide, apalutamide, darolutamide) failure. PROPHECY (Antonarakis 2019): AR-V7-positive on Epic CTC IHC associated with HR ~3 for inferior PFS/OS on ARSI vs AR-V7-negative; switch to taxane (docetaxel, cabazitaxel) recovers responses. INFORMATIONAL — FDA has NOT approved any therapy decision keyed on AR-V7; surfaces in MDT brief to flag patients in whom ARSI-after-ARSI is unlikely to work. redflagsRF-PROSTATE-TRANSFORMATION-PROGRESSIONSpinal cord compression OR rapid PSA doubling time (<3 months) OR new visceral metastases — emergency or aggressive-progression flag requiring urgent intervention or treatment intensification.redflagsBIO-AR-V7AR-V7biomarkers

Section sources

  • SRC-NCCN-PROSTATE-2025 NCCN Clinical Practice Guidelines — Prostate Cancer
  • SRC-ESMO-PROSTATE-2024 ESMO Clinical Practice Guideline on Prostate Cancer

Worked synthetic cases

  • patient_prostate_mcrpc_brca_olaparib_profound BRCA-mutant mCRPC routed to a PARP inhibitor (PROfound) - HRR-defined PARP-inhibitor routing, post-ARPI sequencing examples/patient_prostate_mcrpc_brca_olaparib_profound.json

Practice questions

0 of 3 answered · 0 correct

Answers, score, and reasoning tags are kept in your browser session only and clear when you close this tab. Multi-select questions require every correct option (and no extras) for a credit.

Question 1 type_a intro HQ-PROSTATE-MCRPC-1L-001

A patient with newly castration-resistant prostate cancer never received an ARPI during the mHSPC phase. PSMA-PET shows bone-predominant disease without visceral or nodal burden. HRR panel is wild-type. In the OpenOnco mCRPC first-line model, which track is the canonical default?

Question 2 type_a intermediate HQ-PROSTATE-MCRPC-1L-002

A patient with mCRPC has progressed on abiraterone given during the mHSPC phase. Tumor HRR panel shows a deleterious BRCA2 mutation; germline counseling confirms a pathogenic germline variant. He has no transformation features and good performance status. Which OpenOnco indication is the canonical first option at the current mCRPC line?

Question 3 type_k intermediate HQ-PROSTATE-MCRPC-1L-003

Which statements are true for OpenOnco mCRPC reasoning?