{"entity":{"id":"prostate-mcrpc","kind":"indication","name":"Metastatic castration-resistant prostate cancer","aka":["mCRPC","Metastatic CRPC","Castration-resistant metastatic prostate cancer","Hormone-refractory prostate cancer (older term)"],"tldr":"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.","asOf":"2026-09-17","wikipedia":"https://en.wikipedia.org/wiki/Castration-resistant_prostate_cancer","links":[{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Castration-resistant_prostate_cancer"},{"label":"NCCN Guidelines: Prostate Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1459"}],"tags":["subtype-page"],"related":["prostate-mhspc","prostate-nmcrpc","prostate-nepc","prostate-bcr","lu-177","ac-225","ra-223"],"indications":[],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-vision-nejm-2021","paper-alsympca-radium-223-nejm-2013"],"journals":[],"dependsOn":[],"notes":[],"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)"],"standardOfCare":[{"setting":"First line, androgen receptor pathway inhibitor-naive","approach":"Abiraterone or enzalutamide; add olaparib, talazoparib or niraparib for HRR-mutant, above all BRCA-mutant, disease (PROpel, TALAPRO-2, MAGNITUDE).","refs":["abiraterone","enzalutamide","olaparib"],"guideline":{"version":"NCCN Guidelines: Prostate Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1459"}},{"setting":"After an androgen receptor pathway inhibitor","approach":"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.","refs":["docetaxel","olaparib","pluvicto","psmafore","pembrolizumab"],"guideline":{"version":"NCCN Guidelines: Prostate Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1459"}},{"setting":"After docetaxel","approach":"177Lu-PSMA-617 (VISION), cabazitaxel, radium-223 for symptomatic bone-only disease (ALSYMPCA), or a PARP inhibitor if not yet used.","refs":["pluvicto","vision","cabazitaxel","radium-223","alsympca","therap"],"guideline":{"version":"NCCN Guidelines: Prostate Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1459"}},{"setting":"Bone health","approach":"Denosumab or zoledronic acid to prevent skeletal events, with calcium and vitamin D; palliative radiotherapy to painful metastases.","refs":[],"guideline":{"version":"NCCN Guidelines: Prostate Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1459"}},{"setting":"Phase 3 options","approach":"Actinium-225 PSMA radioligands, the STEAP1 T-cell engager xaluritamig, the EZH2 inhibitor mevrometostat and 177Lu-PSMA-I&T within trials.","refs":["ac225-psma","lu177-psma-it","alphabreak","splash","eclipse-psma"]}],"stateOfArt":["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."],"history":[{"year":2004,"title":"TAX 327: docetaxel is the first drug to lengthen life in castration-resistant disease","refs":["docetaxel"]},{"year":2010,"title":"Cabazitaxel and sipuleucel-T approved","refs":["cabazitaxel"]},{"year":2011,"title":"Abiraterone approved after docetaxel","refs":["abiraterone"]},{"year":2012,"title":"Enzalutamide approved","refs":["enzalutamide"]},{"year":2013,"title":"ALSYMPCA: radium-223, the first alpha emitter","refs":["alsympca","radium-223"]},{"year":2020,"title":"PROfound: olaparib for HRR-mutant disease","refs":["olaparib"]},{"year":2021,"title":"VISION: 177Lu-PSMA-617 lengthens life","refs":["vision","pluvicto"]},{"year":2022,"title":"PROpel and MAGNITUDE: PARP inhibitor plus abiraterone","refs":[]},{"year":2023,"title":"PSMAfore and TALAPRO-2","refs":["psmafore"]},{"year":2025,"title":"ECLIPSE: 177Lu-PSMA-I&T meets its endpoint","refs":["eclipse-psma"]}],"pipeline":["ac225-psma","lu177-psma-it","fpi-2265"],"openProblems":["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."],"parent":"prostate"},"route":"/indications/prostate-mcrpc/","neighbours":{"indication":[{"id":"prostate-bcr","kind":"indication","name":"Biochemical recurrence of prostate cancer","route":"/indications/prostate-bcr/"},{"id":"prostate-mhspc","kind":"indication","name":"Metastatic hormone-sensitive prostate cancer","route":"/indications/prostate-mhspc/"},{"id":"prostate-nepc","kind":"indication","name":"Neuroendocrine and small-cell prostate cancer","route":"/indications/prostate-nepc/"},{"id":"prostate-nmcrpc","kind":"indication","name":"Non-metastatic castration-resistant prostate cancer","route":"/indications/prostate-nmcrpc/"},{"id":"prostate","kind":"indication","name":"Prostate cancer","route":"/indications/prostate/"}],"isotope":[{"id":"ac-225","kind":"isotope","name":"Actinium-225","route":"/isotopes/ac-225/"},{"id":"lu-177","kind":"isotope","name":"Lutetium-177","route":"/isotopes/lu-177/"},{"id":"ra-223","kind":"isotope","name":"Radium-223","route":"/isotopes/ra-223/"}],"paper":[{"id":"paper-kratochwil-ac225-psma-jnm-2016","kind":"paper","name":"225Ac-PSMA-617 for PSMA-targeted alpha-radiation therapy of metastatic castration-resistant prostate cancer","route":"/key-papers/paper-kratochwil-ac225-psma-jnm-2016/"},{"id":"paper-alsympca-radium-223-nejm-2013","kind":"paper","name":"ALSYMPCA: alpha emitter radium-223 and survival in metastatic prostate cancer with bone metastases","route":"/key-papers/paper-alsympca-radium-223-nejm-2013/"},{"id":"paper-jadvar-snmmi-psma-auc-jnm-2022","kind":"paper","name":"Appropriate use criteria for prostate-specific membrane antigen (PSMA) PET imaging","route":"/key-papers/paper-jadvar-snmmi-psma-auc-jnm-2022/"},{"id":"paper-hofman-lupsma-lancet-oncol-2018","kind":"paper","name":"LuPSMA trial: single-arm phase 2 study of 177Lu-PSMA-617 in metastatic castration-resistant prostate cancer","route":"/key-papers/paper-hofman-lupsma-lancet-oncol-2018/"},{"id":"paper-tagawa-ac225-j591-jco-2024","kind":"paper","name":"Phase I dose-escalation study of 225Ac-J591, a PSMA-targeting alpha-emitting antibody, in mCRPC","route":"/key-papers/paper-tagawa-ac225-j591-jco-2024/"},{"id":"paper-psmafore-lancet-2024","kind":"paper","name":"PSMAfore: 177Lu-PSMA-617 versus a change of androgen receptor pathway inhibitor in taxane-naive mCRPC","route":"/key-papers/paper-psmafore-lancet-2024/"},{"id":"paper-therap-lancet-2021","kind":"paper","name":"TheraP: [177Lu]Lu-PSMA-617 versus cabazitaxel in metastatic castration-resistant prostate cancer","route":"/key-papers/paper-therap-lancet-2021/"},{"id":"paper-vision-nejm-2021","kind":"paper","name":"VISION: lutetium-177 PSMA-617 radioligand therapy extends survival in advanced prostate cancer","route":"/key-papers/paper-vision-nejm-2021/"}],"drug":[{"id":"lu177-psma-it","kind":"drug","name":"177Lu-PSMA-I&T","route":"/drugs/lu177-psma-it/"},{"id":"abiraterone","kind":"drug","name":"Abiraterone acetate","route":"/drugs/abiraterone/"},{"id":"ac225-psma","kind":"drug","name":"Actinium-225 PSMA agents","route":"/drugs/ac225-psma/"},{"id":"cabazitaxel","kind":"drug","name":"Cabazitaxel","route":"/drugs/cabazitaxel/"},{"id":"cu-64-sar-bispsma","kind":"drug","name":"Copper-64 SAR-bisPSMA","route":"/drugs/cu-64-sar-bispsma/"},{"id":"docetaxel","kind":"drug","name":"Docetaxel","route":"/drugs/docetaxel/"},{"id":"enzalutamide","kind":"drug","name":"Enzalutamide","route":"/drugs/enzalutamide/"},{"id":"fpi-2265","kind":"drug","name":"FPI-2265","route":"/drugs/fpi-2265/"},{"id":"lu-177-pnt2002","kind":"drug","name":"Lutetium-177 PNT2002","route":"/drugs/lu-177-pnt2002/"},{"id":"tlx-591","kind":"drug","name":"Lutetium-177 rosopatamab tetraxetan","route":"/drugs/tlx-591/"},{"id":"pluvicto","kind":"drug","name":"Lutetium-177 vipivotide tetraxetan","route":"/drugs/pluvicto/"},{"id":"olaparib","kind":"drug","name":"Olaparib","route":"/drugs/olaparib/"},{"id":"pembrolizumab","kind":"drug","name":"Pembrolizumab","route":"/drugs/pembrolizumab/"},{"id":"radium-223","kind":"drug","name":"Radium-223 dichloride","route":"/drugs/radium-223/"}],"trial":[{"id":"nct04868604","kind":"trial","name":"64Cu-SAR-bisPSMA and 67Cu-SAR-bisPSMA for Identification and Treatment of PSMA-expressing Metastatic Castrate Resistant Prostate Cancer (SECuRE)","route":"/trials/nct04868604/"},{"id":"nct07258407","kind":"trial","name":"A Clinical Trial Evaluating the Safety of TD001 In Patients With PSMA-Expressing Metastatic Prostate Cancer","route":"/trials/nct07258407/"},{"id":"nct05547061","kind":"trial","name":"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","route":"/trials/nct05547061/"},{"id":"nct06383052","kind":"trial","name":"A Phase 1/2 Study of 177Lu-NYM032 Injection in mCRPC","route":"/trials/nct06383052/"},{"id":"nct07226986","kind":"trial","name":"A Phase Ib/II Open-label Study of AMO959 With Lutetium (177Lu) Vipivotide Tetraxetan (AAA617) in Combination With ARPI in Adult Participants With PSMA","route":"/trials/nct07226986/"},{"id":"nct07311694","kind":"trial","name":"A Phase III Study Comparing HRS-4357 With Novel Androgen Receptor Pathway Inhibitors in Patients With Progressive, PSMA-Positive Metastatic Castration-Resistant Prostate Cancer","route":"/trials/nct07311694/"},{"id":"nct05658003","kind":"trial","name":"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","route":"/trials/nct05658003/"},{"id":"nct06990880","kind":"trial","name":"A Study of GSK5458514 Administered Alone or In Combination With Other Anti-Cancer Agents in Participants With Prostate Cancer","route":"/trials/nct06990880/"},{"id":"nct07047118","kind":"trial","name":"A Study of JSB462 (Luxdegalutamide) Plus Lutetium (177Lu) Vipivotide Tetraxetan in Patients With Metastatic Castration Resistant Prostate Cancer (mCRPC)","route":"/trials/nct07047118/"},{"id":"mcrpc","kind":"trial","name":"A Study of Pasritamig With or Without JNJ-87189401 Versus Placebo for Late Line Metastatic Castration-resistant Prostate Cancer (mCRPC)","route":"/trials/mcrpc/"},{"id":"nct07567521","kind":"trial","name":"A Study of TRC003 in the Treatment of Patients With Progressive PSMA-positive mCRPC","route":"/trials/nct07567521/"},{"id":"nct03972657","kind":"trial","name":"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","route":"/trials/nct03972657/"},{"id":"alphabreak","kind":"trial","name":"AlphaBreak (FPI-2265) & AcTION (225Ac-PSMA-617)","route":"/trials/alphabreak/"},{"id":"alsympca","kind":"trial","name":"ALSYMPCA","route":"/trials/alsympca/"},{"id":"nct06894511","kind":"trial","name":"An Open-label Study of Lutetium (177Lu) Vipivotide Tetraxetan (AAA617) in Combination With ARPI Versus AAA617 in PSMA Positive First-line mCRPC","route":"/trials/nct06894511/"},{"id":"nct05413850","kind":"trial","name":"Anti-tumour Activity of (177Lu) rhPSMA-10.1 Injection","route":"/trials/nct05413850/"},{"id":"nct07611110","kind":"trial","name":"AZD2265 Compared With Standard of Care in PSMA-positive Metastatic Castration-resistant Prostate Cancer (VECTRA-01)","route":"/trials/nct07611110/"},{"id":"eclipse-psma","kind":"trial","name":"ECLIPSE","route":"/trials/eclipse-psma/"},{"id":"enza-p","kind":"trial","name":"ENZA-p","route":"/trials/enza-p/"},{"id":"nct06909825","kind":"trial","name":"FPI-2265 (225Ac-PSMA-I&T) and Olaparib for Patients With Metastatic Castration-Resistant Prostate Cancer (mCRPC)","route":"/trials/nct06909825/"},{"id":"nct05682443","kind":"trial","name":"ONC-392 Plus Lutetium Lu 177 Vipivotide Tetraxetan in Patients With mCRPC","route":"/trials/nct05682443/"},{"id":"nct06780670","kind":"trial","name":"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","route":"/trials/nct06780670/"},{"id":"prince-trial","kind":"trial","name":"PRINCE","route":"/trials/prince-trial/"},{"id":"psmafore","kind":"trial","name":"PSMAfore","route":"/trials/psmafore/"},{"id":"splash","kind":"trial","name":"SPLASH","route":"/trials/splash/"},{"id":"nct06855277","kind":"trial","name":"Study Comparing AAA817+ARPI Versus Standard of Care in Adult Participants With PSMA-positive mCRPC","route":"/trials/nct06855277/"},{"id":"nct06004661","kind":"trial","name":"Study of Lutetium (177Lu) Vipivotide Tetraxetan in mCRPC Participants With Moderately and Severely Impaired and With Normal Renal Function","route":"/trials/nct06004661/"},{"id":"nct05219500","kind":"trial","name":"Targeted Alpha Therapy With 225Actinium-Prostate Specific Membrane Antigen (PSMA)-I&T of Castration-resISTant Prostate Cancer (TATCIST).","route":"/trials/nct05219500/"},{"id":"nct06520345","kind":"trial","name":"The Study of 177Lu-TLX591 Plus SOC Versus SOC Alone in Patients With mCRPC (ProstACT Global)","route":"/trials/nct06520345/"},{"id":"therap","kind":"trial","name":"TheraP (ANZUP 1603)","route":"/trials/therap/"},{"id":"vision","kind":"trial","name":"VISION","route":"/trials/vision/"}],"term":[{"id":"flare-phenomenon","kind":"term","name":"Flare phenomenon","route":"/terms/flare-phenomenon/"},{"id":"psa-kinetics","kind":"term","name":"PSA kinetics: PSA doubling time and PSA density","route":"/terms/psa-kinetics/"},{"id":"psma-rads","kind":"term","name":"PSMA-RADS (PSMA reporting and data system)","route":"/terms/psma-rads/"},{"id":"salivary-gland-toxicity","kind":"term","name":"Salivary gland toxicity (xerostomia) from PSMA radioligand therapy","route":"/terms/salivary-gland-toxicity/"}],"person":[{"id":"chris-parker","kind":"person","name":"Chris C. Parker","route":"/people/chris-parker/"}],"company":[{"id":"advancell","kind":"company","name":"AdvanCell","route":"/companies/advancell/"},{"id":"cellbion","kind":"company","name":"CellBion","route":"/companies/cellbion/"},{"id":"full-life-technologies","kind":"company","name":"Full-Life Technologies","route":"/companies/full-life-technologies/"},{"id":"nuclidium","kind":"company","name":"Nuclidium","route":"/companies/nuclidium/"}],"opportunity":[{"id":"opp-grpr-psma-negative-prostate","kind":"opportunity","name":"GRPR imaging when the PSMA scan is negative","route":"/opportunities/opp-grpr-psma-negative-prostate/"}],"bottleneck":[{"id":"b-site-readiness-referral","kind":"bottleneck","name":"Site readiness and referral pathway delays","route":"/bottlenecks/b-site-readiness-referral/"}],"section":[{"id":"f-bone-targeted","kind":"section","name":"Bone-targeted radiopharmaceuticals","route":"/fronts/f-bone-targeted/"},{"id":"f-dosimetry","kind":"section","name":"Dosimetry","route":"/fronts/f-dosimetry/"},{"id":"f-radioligand-therapy","kind":"section","name":"Radioligand therapy","route":"/fronts/f-radioligand-therapy/"},{"id":"f-alpha-therapy","kind":"section","name":"Targeted alpha therapy","route":"/fronts/f-alpha-therapy/"}],"idea":[{"id":"idea-copper-theranostic-pair-standard","kind":"idea","name":"A single-molecule copper-64/copper-67 pair instead of switching ligands between scan and treatment","route":"/ideas/idea-copper-theranostic-pair-standard/"},{"id":"idea-rlt-plus-checkpoint-inhibitor","kind":"idea","name":"Adding a checkpoint inhibitor to PSMA radioligand therapy","route":"/ideas/idea-rlt-plus-checkpoint-inhibitor/"},{"id":"idea-rlt-plus-parp-inhibitor","kind":"idea","name":"Adding a PARP inhibitor to PSMA radioligand therapy","route":"/ideas/idea-rlt-plus-parp-inhibitor/"}],"pairing":[{"id":"pluvicto-plus-olaparib","kind":"pairing","name":"177Lu-PSMA-617 (Pluvicto) with olaparib","route":"/pairings/pluvicto-plus-olaparib/"},{"id":"beta-psma-then-alpha-psma-rescue","kind":"pairing","name":"177Lu-PSMA-617 then 225Ac-PSMA rescue therapy","route":"/pairings/beta-psma-then-alpha-psma-rescue/"},{"id":"docetaxel-then-lu177-psma","kind":"pairing","name":"Docetaxel (taxane chemotherapy) then 177Lu-PSMA-617","route":"/pairings/docetaxel-then-lu177-psma/"},{"id":"radium223-abiraterone-caution","kind":"pairing","name":"Radium-223 with abiraterone: a caution, not a combination","route":"/pairings/radium223-abiraterone-caution/"}],"roadmap":[{"id":"psma-theranostics-roadmap","kind":"roadmap","name":"PSMA theranostics roadmap: antigen discovery → PSMA PET → 177Lu-PSMA-617 → earlier lines and alpha","route":"/roadmaps/psma-theranostics-roadmap/"}],"target":[{"id":"tpbg-5t4","kind":"target","name":"5T4 (trophoblast glycoprotein)","route":"/targets/tpbg-5t4/"}]}}