# Metastatic castration-resistant prostate cancer

Source: https://nuclide.cc/indications/prostate-mcrpc/  
Nuclide record `prostate-mcrpc` (Indication). Data CC BY-NC 4.0, attribute "Data from Nuclide (nuclide.cc)"; commercial use needs a licence.

## TL;DR

Metastatic castration-resistant prostate cancer is disease that grows despite castrate testosterone. Sequenced treatments now include androgen receptor inhibitors, docetaxel and cabazitaxel, PARP inhibitors for men with BRCA-type mutations, the radioligand 177Lu-PSMA-617 and radium-223 for bone-predominant disease.

## Summary

Metastatic castration-resistant prostate cancer is defined by progression on scans or PSA, or new metastases, with castrate testosterone. Nearly every man reaches it from hormone-sensitive disease, and the treatment chosen depends on what he has already had. Men who have not had an androgen receptor pathway inhibitor receive abiraterone or enzalutamide; PROpel, TALAPRO-2 and MAGNITUDE showed that adding olaparib, talazoparib or niraparib helps men with BRCA and other homologous recombination repair mutations, and PROfound showed olaparib alone beats a second hormonal agent in these men. Docetaxel and then cabazitaxel remain the chemotherapies. VISION established 177Lu-PSMA-617 after chemotherapy and PSMAfore moved it before, for PSMA PET-positive disease; 177Lu-PSMA-I&T (SPLASH, ECLIPSE) follows the same path. Radium-223 lengthens life in symptomatic bone-predominant disease without visceral metastases (ALSYMPCA), sipuleucel-T is still approved for minimally symptomatic disease, and pembrolizumab is used for the rare mismatch repair-deficient tumour. Tumour and germline testing for HRR genes and mismatch repair is standard. Actinium-225 PSMA agents, the STEAP1 T-cell engager xaluritamig and the EZH2 inhibitor mevrometostat are in phase 3.

## Fields

- Kind: Indication
- Last checked: 2026-09-17
- Also known as: mCRPC; Metastatic CRPC; Castration-resistant metastatic prostate cancer; Hormone-refractory prostate cancer (older term)
- Tags: subtype-page
- Group: genitourinary
- Burden: The state in which nearly all prostate cancer deaths occur, about 400,000 a year worldwide; median survival from first treatment is now around three years, longer for men who have not had an androgen receptor inhibitor.
- Subtypes: mCRPC, androgen receptor pathway inhibitor-naive; mCRPC after an androgen receptor pathway inhibitor, chemotherapy-naive; mCRPC after taxane chemotherapy; HRR-mutant mCRPC (BRCA1, BRCA2, ATM and others; PARP inhibitors); PSMA PET-positive mCRPC (radioligand therapy); Bone-predominant mCRPC without visceral metastases (radium-223); Mismatch repair-deficient mCRPC (pembrolizumab)
- Biomarkers: Tumour and germline HRR genes (BRCA2 above all); PSMA PET uptake and FDG discordance; Mismatch repair deficiency and tumour mutational burden; PSA and alkaline phosphatase; Circulating tumour DNA (AR amplification, BRCA2 reversion); AR-V7 in circulating tumour cells (research)

## Standard of care

- First line, androgen receptor pathway inhibitor-naive: Abiraterone or enzalutamide; add olaparib, talazoparib or niraparib for HRR-mutant, above all BRCA-mutant, disease (PROpel, TALAPRO-2, MAGNITUDE). ([Abiraterone acetate](https://nuclide.cc/drugs/abiraterone/), [Enzalutamide](https://nuclide.cc/drugs/enzalutamide/), [Olaparib](https://nuclide.cc/drugs/olaparib/))
- After an androgen receptor pathway inhibitor: Docetaxel; olaparib or rucaparib for BRCA-mutant disease (PROfound); 177Lu-PSMA-617 for PSMA-positive disease before chemotherapy (PSMAfore); pembrolizumab for mismatch repair-deficient tumours. ([Docetaxel](https://nuclide.cc/drugs/docetaxel/), [Olaparib](https://nuclide.cc/drugs/olaparib/), [Lutetium-177 vipivotide tetraxetan](https://nuclide.cc/drugs/pluvicto/), [PSMAfore](https://nuclide.cc/trials/psmafore/), [Pembrolizumab](https://nuclide.cc/drugs/pembrolizumab/))
- After docetaxel: 177Lu-PSMA-617 (VISION), cabazitaxel, radium-223 for symptomatic bone-only disease (ALSYMPCA), or a PARP inhibitor if not yet used. ([Lutetium-177 vipivotide tetraxetan](https://nuclide.cc/drugs/pluvicto/), [VISION](https://nuclide.cc/trials/vision/), [Cabazitaxel](https://nuclide.cc/drugs/cabazitaxel/), [Radium-223 dichloride](https://nuclide.cc/drugs/radium-223/), [ALSYMPCA](https://nuclide.cc/trials/alsympca/), [TheraP (ANZUP 1603)](https://nuclide.cc/trials/therap/))
- Bone health: Denosumab or zoledronic acid to prevent skeletal events, with calcium and vitamin D; palliative radiotherapy to painful metastases.
- Phase 3 options: Actinium-225 PSMA radioligands, the STEAP1 T-cell engager xaluritamig, the EZH2 inhibitor mevrometostat and 177Lu-PSMA-I&T within trials. ([Actinium-225 PSMA agents](https://nuclide.cc/drugs/ac225-psma/), [177Lu-PSMA-I&T](https://nuclide.cc/drugs/lu177-psma-it/), [AlphaBreak (FPI-2265) & AcTION (225Ac-PSMA-617)](https://nuclide.cc/trials/alphabreak/), [SPLASH](https://nuclide.cc/trials/splash/), [ECLIPSE](https://nuclide.cc/trials/eclipse-psma/))

## State of the art

- PSMA PET and 177Lu-PSMA-617 make prostate cancer the model for theranostics.
- PARP inhibitors gave prostate cancer its first genotype-directed treatment.
- Survival in this once six-month setting is now measured in years, built from sequenced drugs rather than one breakthrough.

## Open problems

- The best sequence of radioligand, PARP inhibitor and chemotherapy is untested.
- Actinium-225 supply and the lack of alpha-emitter dosimetry.
- Lineage plasticity to neuroendocrine disease under androgen receptor blockade.
- Resistance to 177Lu-PSMA-617 in PSMA-low or FDG-discordant disease.

## Sources

- Wikipedia: https://en.wikipedia.org/wiki/Castration-resistant_prostate_cancer
- Wikipedia: https://en.wikipedia.org/wiki/Castration-resistant_prostate_cancer
- NCCN Guidelines: Prostate Cancer: https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1459

## Connected records

- indications: [Biochemical recurrence of prostate cancer](https://nuclide.cc/indications/prostate-bcr/), [Metastatic hormone-sensitive prostate cancer](https://nuclide.cc/indications/prostate-mhspc/), [Neuroendocrine and small-cell prostate cancer](https://nuclide.cc/indications/prostate-nepc/), [Non-metastatic castration-resistant prostate cancer](https://nuclide.cc/indications/prostate-nmcrpc/), [Prostate cancer](https://nuclide.cc/indications/prostate/)
- isotopes: [Actinium-225](https://nuclide.cc/isotopes/ac-225/), [Lutetium-177](https://nuclide.cc/isotopes/lu-177/), [Radium-223](https://nuclide.cc/isotopes/ra-223/)
- key papers: [225Ac-PSMA-617 for PSMA-targeted alpha-radiation therapy of metastatic castration-resistant prostate cancer](https://nuclide.cc/key-papers/paper-kratochwil-ac225-psma-jnm-2016/), [ALSYMPCA: alpha emitter radium-223 and survival in metastatic prostate cancer with bone metastases](https://nuclide.cc/key-papers/paper-alsympca-radium-223-nejm-2013/), [Appropriate use criteria for prostate-specific membrane antigen (PSMA) PET imaging](https://nuclide.cc/key-papers/paper-jadvar-snmmi-psma-auc-jnm-2022/), [LuPSMA trial: single-arm phase 2 study of 177Lu-PSMA-617 in metastatic castration-resistant prostate cancer](https://nuclide.cc/key-papers/paper-hofman-lupsma-lancet-oncol-2018/), [Phase I dose-escalation study of 225Ac-J591, a PSMA-targeting alpha-emitting antibody, in mCRPC](https://nuclide.cc/key-papers/paper-tagawa-ac225-j591-jco-2024/), [PSMAfore: 177Lu-PSMA-617 versus a change of androgen receptor pathway inhibitor in taxane-naive mCRPC](https://nuclide.cc/key-papers/paper-psmafore-lancet-2024/), [TheraP: [177Lu]Lu-PSMA-617 versus cabazitaxel in metastatic castration-resistant prostate cancer](https://nuclide.cc/key-papers/paper-therap-lancet-2021/), [VISION: lutetium-177 PSMA-617 radioligand therapy extends survival in advanced prostate cancer](https://nuclide.cc/key-papers/paper-vision-nejm-2021/)
- drugs: [177Lu-PSMA-I&T](https://nuclide.cc/drugs/lu177-psma-it/), [Abiraterone acetate](https://nuclide.cc/drugs/abiraterone/), [Actinium-225 PSMA agents](https://nuclide.cc/drugs/ac225-psma/), [Cabazitaxel](https://nuclide.cc/drugs/cabazitaxel/), [Copper-64 SAR-bisPSMA](https://nuclide.cc/drugs/cu-64-sar-bispsma/), [Docetaxel](https://nuclide.cc/drugs/docetaxel/), [Enzalutamide](https://nuclide.cc/drugs/enzalutamide/), [FPI-2265](https://nuclide.cc/drugs/fpi-2265/), [Lutetium-177 PNT2002](https://nuclide.cc/drugs/lu-177-pnt2002/), [Lutetium-177 rosopatamab tetraxetan](https://nuclide.cc/drugs/tlx-591/), [Lutetium-177 vipivotide tetraxetan](https://nuclide.cc/drugs/pluvicto/), [Olaparib](https://nuclide.cc/drugs/olaparib/), [Pembrolizumab](https://nuclide.cc/drugs/pembrolizumab/), [Radium-223 dichloride](https://nuclide.cc/drugs/radium-223/)
- trials: [64Cu-SAR-bisPSMA and 67Cu-SAR-bisPSMA for Identification and Treatment of PSMA-expressing Metastatic Castrate Resistant Prostate Cancer (SECuRE)](https://nuclide.cc/trials/nct04868604/), [A Clinical Trial Evaluating the Safety of TD001 In Patients With PSMA-Expressing Metastatic Prostate Cancer](https://nuclide.cc/trials/nct07258407/), [A Phase 1/2 Clinical Trial to Evaluate the Safety, Tolerability, Dosimetry, and Anti-tumor Activity of Ga-68-NGUL / Lu-177-DGUL in Patients With Metastatic Castration-resistant Prostate Cancer (mCRPC) Refractory to Standard Therapy](https://nuclide.cc/trials/nct05547061/), [A Phase 1/2 Study of 177Lu-NYM032 Injection in mCRPC](https://nuclide.cc/trials/nct06383052/), [A Phase Ib/II Open-label Study of AMO959 With Lutetium (177Lu) Vipivotide Tetraxetan (AAA617) in Combination With ARPI in Adult Participants With PSMA](https://nuclide.cc/trials/nct07226986/), [A Phase III Study Comparing HRS-4357 With Novel Androgen Receptor Pathway Inhibitors in Patients With Progressive, PSMA-Positive Metastatic Castration-Resistant Prostate Cancer](https://nuclide.cc/trials/nct07311694/), [A Study Evaluating [177Lu]Lu-PSMA-617 vs. a Change of Androgen Receptor-directed Therapy in Taxane Treatment Naive Chinese Male Patients With Progressive Metastatic Castrate Resistant Prostate Cancer](https://nuclide.cc/trials/nct05658003/), [A Study of GSK5458514 Administered Alone or In Combination With Other Anti-Cancer Agents in Participants With Prostate Cancer](https://nuclide.cc/trials/nct06990880/), [A Study of JSB462 (Luxdegalutamide) Plus Lutetium (177Lu) Vipivotide Tetraxetan in Patients With Metastatic Castration Resistant Prostate Cancer (mCRPC)](https://nuclide.cc/trials/nct07047118/), [A Study of Pasritamig With or Without JNJ-87189401 Versus Placebo for Late Line Metastatic Castration-resistant Prostate Cancer (mCRPC)](https://nuclide.cc/trials/mcrpc/), [A Study of TRC003 in the Treatment of Patients With Progressive PSMA-positive mCRPC](https://nuclide.cc/trials/nct07567521/), [A Trial to Find Out if REGN5678 (Nezastomig) is Safe and How Well it Works Alone or in Combination With Cemiplimab for Adult Participants With Metasta](https://nuclide.cc/trials/nct03972657/), [AlphaBreak (FPI-2265) & AcTION (225Ac-PSMA-617)](https://nuclide.cc/trials/alphabreak/), [ALSYMPCA](https://nuclide.cc/trials/alsympca/), [An Open-label Study of Lutetium (177Lu) Vipivotide Tetraxetan (AAA617) in Combination With ARPI Versus AAA617 in PSMA Positive First-line mCRPC](https://nuclide.cc/trials/nct06894511/), [Anti-tumour Activity of (177Lu) rhPSMA-10.1 Injection](https://nuclide.cc/trials/nct05413850/), [AZD2265 Compared With Standard of Care in PSMA-positive Metastatic Castration-resistant Prostate Cancer (VECTRA-01)](https://nuclide.cc/trials/nct07611110/), [ECLIPSE](https://nuclide.cc/trials/eclipse-psma/), [ENZA-p](https://nuclide.cc/trials/enza-p/), [FPI-2265 (225Ac-PSMA-I&T) and Olaparib for Patients With Metastatic Castration-Resistant Prostate Cancer (mCRPC)](https://nuclide.cc/trials/nct06909825/), [ONC-392 Plus Lutetium Lu 177 Vipivotide Tetraxetan in Patients With mCRPC](https://nuclide.cc/trials/nct05682443/), [Open-label Study Comparing AAA817 Versus Standard of Care in the Treatment of Previously Treated PSMA-positive mCRPC Adults Who Have Disease Progressed on or After [177Lu]Lu-PSMA Targeted Therapy](https://nuclide.cc/trials/nct06780670/), [PRINCE](https://nuclide.cc/trials/prince-trial/), [PSMAfore](https://nuclide.cc/trials/psmafore/), [SPLASH](https://nuclide.cc/trials/splash/), [Study Comparing AAA817+ARPI Versus Standard of Care in Adult Participants With PSMA-positive mCRPC](https://nuclide.cc/trials/nct06855277/), [Study of Lutetium (177Lu) Vipivotide Tetraxetan in mCRPC Participants With Moderately and Severely Impaired and With Normal Renal Function](https://nuclide.cc/trials/nct06004661/), [Targeted Alpha Therapy With 225Actinium-Prostate Specific Membrane Antigen (PSMA)-I&T of Castration-resISTant Prostate Cancer (TATCIST).](https://nuclide.cc/trials/nct05219500/), [The Study of 177Lu-TLX591 Plus SOC Versus SOC Alone in Patients With mCRPC (ProstACT Global)](https://nuclide.cc/trials/nct06520345/), [TheraP (ANZUP 1603)](https://nuclide.cc/trials/therap/), [VISION](https://nuclide.cc/trials/vision/)
- terms: [Flare phenomenon](https://nuclide.cc/terms/flare-phenomenon/), [PSA kinetics: PSA doubling time and PSA density](https://nuclide.cc/terms/psa-kinetics/), [PSMA-RADS (PSMA reporting and data system)](https://nuclide.cc/terms/psma-rads/), [Salivary gland toxicity (xerostomia) from PSMA radioligand therapy](https://nuclide.cc/terms/salivary-gland-toxicity/)
- people: [Chris C. Parker](https://nuclide.cc/people/chris-parker/)
- companies: [AdvanCell](https://nuclide.cc/companies/advancell/), [CellBion](https://nuclide.cc/companies/cellbion/), [Full-Life Technologies](https://nuclide.cc/companies/full-life-technologies/), [Nuclidium](https://nuclide.cc/companies/nuclidium/)
- opportunities: [GRPR imaging when the PSMA scan is negative](https://nuclide.cc/opportunities/opp-grpr-psma-negative-prostate/)
- bottlenecks: [Site readiness and referral pathway delays](https://nuclide.cc/bottlenecks/b-site-readiness-referral/)
- fronts: [Bone-targeted radiopharmaceuticals](https://nuclide.cc/fronts/f-bone-targeted/), [Dosimetry](https://nuclide.cc/fronts/f-dosimetry/), [Radioligand therapy](https://nuclide.cc/fronts/f-radioligand-therapy/), [Targeted alpha therapy](https://nuclide.cc/fronts/f-alpha-therapy/)
- ideas: [A single-molecule copper-64/copper-67 pair instead of switching ligands between scan and treatment](https://nuclide.cc/ideas/idea-copper-theranostic-pair-standard/), [Adding a checkpoint inhibitor to PSMA radioligand therapy](https://nuclide.cc/ideas/idea-rlt-plus-checkpoint-inhibitor/), [Adding a PARP inhibitor to PSMA radioligand therapy](https://nuclide.cc/ideas/idea-rlt-plus-parp-inhibitor/)
- pairings: [177Lu-PSMA-617 (Pluvicto) with olaparib](https://nuclide.cc/pairings/pluvicto-plus-olaparib/), [177Lu-PSMA-617 then 225Ac-PSMA rescue therapy](https://nuclide.cc/pairings/beta-psma-then-alpha-psma-rescue/), [Docetaxel (taxane chemotherapy) then 177Lu-PSMA-617](https://nuclide.cc/pairings/docetaxel-then-lu177-psma/), [Radium-223 with abiraterone: a caution, not a combination](https://nuclide.cc/pairings/radium223-abiraterone-caution/)
- roadmaps: [PSMA theranostics roadmap: antigen discovery → PSMA PET → 177Lu-PSMA-617 → earlier lines and alpha](https://nuclide.cc/roadmaps/psma-theranostics-roadmap/)
- targets: [5T4 (trophoblast glycoprotein)](https://nuclide.cc/targets/tpbg-5t4/)

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