[{"id":"pluvicto-plus-olaparib","kind":"pairing","name":"177Lu-PSMA-617 (Pluvicto) with olaparib","aka":[],"tldr":"An early trial gave the prostate cancer radiotherapy Pluvicto together with the tablet olaparib, on the idea that the pill makes the radiation harder for the cancer cell to repair. Most men's PSA fell, but this is still a small early-stage study, not proof it helps people live longer.","summary":"LuPARP (NCT03874884) is a phase 1 dose-escalation and dose-expansion trial run by Sandhu, Joshua, Emmett and colleagues (Peter MacCallum Cancer Centre and collaborators) combining 177Lu-PSMA-617 (7.4 GBq every 6 weeks, up to 6 cycles) with olaparib at doses from 50 mg to 300 mg twice daily, given on varying schedules relative to the radioligand infusion. The rationale is mechanistic: 177Lu-PSMA-617 causes single-strand DNA breaks that are normally repaired through PARP-dependent base-excision repair, and PARP inhibition is intended to convert these into lethal double-strand breaks, radiosensitising the tumour irrespective of BRCA or other homologous-recombination-repair status.\n\nAcross the 48 enrolled patients with mCRPC previously treated with an androgen-receptor pathway inhibitor and docetaxel, no dose-limiting toxicities were reported and the recommended phase 2 dose was set at olaparib 300 mg twice daily on days -4 to 18 of each 6-week cycle. In the overall cohort, the PSA50 response rate was 66% and PSA90 was 44%, with an objective response rate of 78% by RECIST v1.1 (comparable to, and in the PSA90 measure slightly higher than, the single-agent benchmarks from TheraP and VISION). Hematologic grade 3 toxicity was low (anaemia, neutropenia and thrombocytopenia each in the single digits of percent) and no patient discontinued for toxicity.\n\nThis is dose-finding, single-arm evidence in a heavily pre-treated population, not a randomised comparison, so it cannot show whether adding olaparib improves survival or response over 177Lu-PSMA-617 alone; a randomised phase 2 component was being planned as of the 2023 report. Trials of 225Ac-PSMA-I&T plus olaparib (e.g. NCT06909825) are testing the same radiosensitisation idea with an alpha emitter.","asOf":"2026-09-22","links":[{"label":"LuPARP phase 1 abstract (Sandhu et al., ASCO 2023, J Clin Oncol 41:5005)","url":"https://ascopubs.org/doi/10.1200/JCO.2023.41.16_suppl.5005"},{"label":"UroToday conference summary of LuPARP results and comparison with TheraP/VISION","url":"https://www.urotoday.com/conference-highlights/asco-2023/asco-2023-prostate-cancer/144916-asco-2023-luparp-phase-1-trial-of-177lu-psma-617-and-olaparib-in-patients-with-metastatic-castration-resistant-prostate-cancer-mcrpc.html"},{"label":"ClinicalTrials.gov: NCT03874884 (LuPARP)","url":"https://clinicaltrials.gov/study/NCT03874884"}],"tags":["prostate cancer","PARP inhibitor","early phase"],"related":["prostate-mcrpc","parp","radionuclide-parp-combination","sandhu-shahneen","louise-emmett","lu-177","ac-225"],"indications":[],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"a":"pluvicto","b":"olaparib","rationale":"177Lu-PSMA-617 causes single-strand DNA breaks that are normally repaired through PARP-dependent base-excision repair; adding a PARP inhibitor is intended to convert these into lethal double-strand breaks and radiosensitise the tumour.","evidence":"LuPARP phase 1 trial (NCT03874884, n=48 mCRPC): no dose-limiting toxicities, recommended phase 2 dose olaparib 300 mg BD days -4 to 18; PSA50 66%, PSA90 44%, RECIST objective response rate 78% (Sandhu et al., ASCO 2023).","pairingType":"combination"},{"id":"beta-psma-then-alpha-psma-rescue","kind":"pairing","name":"177Lu-PSMA-617 then 225Ac-PSMA rescue therapy","aka":[],"tldr":"When the standard radioactive prostate cancer treatment (177Lu-PSMA) stops working, some clinics switch to a more powerful alpha-particle version (225Ac-PSMA) as a rescue option. It can bring PSA down in about half of patients, but people who have already failed the beta treatment tend to respond less well and for a shorter time than those who have never had it.","summary":"225Ac-PSMA-617 or 225Ac-PSMA-I&T alpha-particle radioligand therapy is used, mainly outside the United States where actinium-225 is more accessible (for example in Germany), as salvage treatment for metastatic castration-resistant prostate cancer that has progressed after beta-emitting 177Lu-PSMA radioligand therapy (such as Pluvicto) plus prior androgen-receptor pathway inhibitors and taxane chemotherapy. Zacherl et al. (J Nucl Med 2021) reported the first dedicated series: of 14 patients treated with 225Ac-PSMA-I&T, 11 (79%) had previously received 177Lu-PSMA; 50% achieved a PSA decline of 50% or more, with median progression-free survival of 3.1 months and median overall survival of 7.7 months.\n\nA subsequent meta-analysis of retrospective 225Ac-PSMA-617 series (largely post-177Lu-PSMA patients) found pooled rates of 87% for any PSA decline and 66% for a PSA50 response, with pooled median overall survival of 12.5 months and progression-free survival of 9.1 months, and a molecular imaging response in 54% of patients — activity that the authors describe as clinically meaningful in a population that has exhausted other options, achieved with relatively low toxicity (xerostomia is the dominant, often dose-limiting, side effect; haematological toxicity is generally milder than with 177Lu-PSMA). A larger, more recent single-centre series (2025) similarly reported a median overall survival around 7 months in a mixed population, ranging up to 39 months in favourable cases.\n\nImportantly, multiple groups note that patients who progressed on 177Lu-PSMA before starting 225Ac-PSMA have inferior outcomes compared with alpha-therapy-naive patients (a 2022 series found a 45% versus 50% PSA50 rate, and a 2021 Ezziddin group series used 225Ac-PSMA as an 'augmentation' added to, rather than purely after, 177Lu-PSMA cycles, reporting median PSA-progression-free survival of 9.1 months and overall survival of 14.8 months). 225Ac-PSMA remains investigational (not FDA- or EMA-approved) and randomised trials comparing it against other post-177Lu-PSMA options are still needed; it is generally reserved for salvage use in patients with adequate marrow reserve who have exhausted approved options.","asOf":"2026-09-22","links":[{"label":"Zacherl et al., first clinical results for 225Ac-PSMA-I&T in advanced mCRPC, J Nucl Med 2021;62:669-674","url":"https://jnm.snmjournals.org/content/64/10/1574"},{"label":"Meta-analysis of efficacy and safety of 225Ac-PSMA-617 targeted alpha therapy (PMC8852230)","url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC8852230/"},{"label":"Long-term safety and survival outcomes of 225Ac-PSMA (PMC11816130, 2025)","url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC11816130/"}],"tags":["prostate cancer","alpha therapy","salvage therapy"],"related":["prostate-mcrpc","targeted-alpha-therapy","psma","clemens-kratochwil","uwe-haberkorn","lu-177","ac-225"],"indications":[],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"a":"pluvicto","b":"ac225-psma","rationale":"Alpha particles deposit far more energy per track than beta particles and can still kill tumour cells that have become less responsive to 177Lu-PSMA, making 225Ac-PSMA a mechanistically plausible salvage option after beta-emitter progression.","evidence":"In a series of 14 patients (79% previously treated with 177Lu-PSMA), 225Ac-PSMA-I&T produced a PSA50 response in 50%, with median progression-free survival 3.1 months and overall survival 7.7 months (Zacherl et al., J Nucl Med 2021); a pooled meta-analysis of mostly post-177Lu-PSMA series found 66% PSA50 response and 12.5-month median overall survival, but response is consistently inferior to alpha-therapy-naive patients.","pairingType":"sequence"},{"id":"ga68-dotatate-then-lutathera","kind":"pairing","name":"68Ga-DOTATATE PET before Lutathera (177Lu-DOTATATE)","aka":[],"tldr":"Before starting the neuroendocrine tumour treatment Lutathera, patients get a somatostatin-receptor PET scan to confirm the tumour actually has the right target for the drug to lock onto. Lutathera's approval and use are built around this scan-first rule.","summary":"Lutathera (177Lu-dotatate) is FDA-approved for somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumours, and its own label states that eligibility in the pivotal programme required 'confirmed presence of somatostatin receptors on all lesions,' historically demonstrated with OctreoScan (111In-pentetreotide) uptake at least equal to normal liver, and now more commonly with PET agents such as 68Ga-DOTATATE, 68Ga-DOTATOC or 64Cu-DOTATATE, which have largely replaced OctreoScan because of higher sensitivity and better lesion detectability. Lesions with tracer uptake less than liver activity are considered somatostatin-receptor-negative and are not expected to respond to Lutathera; patients with significant somatostatin-receptor-negative (and, where available, FDG-positive) disease are generally excluded from treatment because such discordant lesions predict poor response to PRRT.\n\nThis is a drug-specific instance of the broader diagnostic-therapeutic 'theranostic' pairing between somatostatin-receptor PET and peptide receptor radionuclide therapy: the same molecular target (SSTR2) is imaged with a gallium-68- or copper-64-labelled diagnostic tracer and then treated with the lutetium-177-labelled therapeutic analogue, so the scan used for staging doubles as the biomarker test that selects patients for, and later monitors response to, Lutathera. SNMMI/EANM and society guidance recommend repeat somatostatin-receptor PET roughly 3-6 months after completing PRRT to assess response.\n\nEligibility based on receptor imaging (Krenning score equivalent, uptake greater than liver) sits alongside other selection criteria in the Lutathera label and NET treatment guidelines, including Ki-67 index, performance status, renal function and prior PRRT exposure. This record is specific to the Lutathera-DOTATATE PET pairing and is distinct from the generic sstr-pet-to-prrt technology-level pairing already in this graph, which covers somatostatin receptor PET's relationship to PRRT as a modality rather than the specific FDA-labelled drug requirement.","asOf":"2026-09-22","links":[{"label":"FDA label: Lutathera (lutetium Lu 177 dotatate), 2024 revision, eligibility criteria","url":"https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/208700Orig1s032lbl.pdf"},{"label":"SNMT practical considerations for 177Lu-DOTATATE programmes: SSTR imaging and patient selection","url":"https://tech.snmjournals.org/content/jnmt/early/2022/06/14/jnmt.122.263813.full.pdf"},{"label":"Clinical guide to PRRT with 177Lu-DOTATATE (PMC9737149)","url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC9737149/"}],"tags":["neuroendocrine tumours","theranostics","patient selection"],"related":["sstr2","neuroendocrine","sstr-pet","prrt","sstr-pet-to-prrt","richard-baum","ga-68","in-111","cu-64","lu-177"],"indications":[],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"a":"ga68-dotatate","b":"lutathera","rationale":"Lutathera targets the same somatostatin receptor (SSTR2) that 68Ga-DOTATATE PET images, so the diagnostic scan doubles as the biomarker test confirming a tumour expresses enough receptor to be worth treating, and later as the response-assessment tool.","evidence":"Lutathera's FDA label states eligibility required 'confirmed presence of somatostatin receptors on all lesions', historically shown by OctreoScan uptake at least equal to liver, now more often confirmed on 68Ga-DOTATATE PET; lesions with uptake below liver activity are considered SSTR-negative and unlikely to respond to PRRT.","pairingType":"diagnostic-therapeutic"},{"id":"prrt-then-alpha-net","kind":"pairing","name":"Beta PRRT → alpha PRRT","aka":[],"tldr":"When lutetium radioligand therapy stops working, alpha-emitting versions can still control the disease.","summary":"This sequence moves from beta-emitting lutetium-177 dotatate to an alpha-emitting radioligand, 212Pb-DOTAMTATE, when beta PRRT stops controlling a neuroendocrine tumour. Alpha particles deliver oxygen-independent clustered DNA damage that beta-resistant clones cannot repair, so the same somatostatin receptor target can be attacked again with a more destructive payload. The phase 2 ALPHAMEDIX-02 trial included a PRRT-exposed cohort in which disease control was maintained in most patients, and ACTION-1 is the randomised phase 3 test of 225Ac-DOTATATE after 177Lu. The pairing belongs to the wider topic of alpha versus beta emitters and targeted alpha therapy.","asOf":"2026-09-07","links":[{"label":"ClinicalTrials.gov NCT05153772: ALPHAMEDIX-02","url":"https://clinicaltrials.gov/study/NCT05153772"},{"label":"ClinicalTrials.gov NCT05477576: ACTION-1","url":"https://clinicaltrials.gov/study/NCT05477576"}],"tags":[],"related":["lu-177","ac-225","pb-212"],"indications":["neuroendocrine"],"sections":[],"technologies":["targeted-alpha-therapy"],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":["alpha-vs-beta"],"trials":["alphamedix-02","action-1"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"a":"lutathera","b":"alphamedix","rationale":"Alpha particles deliver oxygen-independent clustered DNA damage that beta-resistant clones cannot repair.","evidence":"Phase 2 (AlphaMedix); phase 3 pending (ACTION-1).","pairingType":"sequence"},{"id":"beta-then-alpha","kind":"pairing","name":"Beta radioligand → alpha radioligand","aka":[],"tldr":"After lutetium therapy stops working, an actinium version of the same drug can still produce responses.","summary":"This sequence pairing follows Radioligand therapy (beta emitters) with Targeted alpha therapy using the same targeting molecule: after lutetium stops working, an actinium version of the same drug can still produce responses. Alpha particles cause oxygen-independent clustered DNA damage that beta-resistant, hypoxic or small-volume disease cannot repair, as explained in the Alpha vs beta emitters entry. In Prostate cancer, Actinium-225 PSMA agents after Lutetium-177 vipivotide tetraxetan produced PSA responses in retrospective series, and phase 3 trials (AcTION, AlphaBreak) are ongoing. In Neuroendocrine tumours, Actinium-225 DOTATATE (RYZ101) is being tested in ACTION-1 after Lutetium-177 dotatate, so the evidence is retrospective and phase 1/2 with phase 3 pending.","asOf":"2026-09-04","links":[{"label":"ClinicalTrials.gov NCT06402331: AlphaBreak (FPI-2265) & AcTION (225Ac-PSMA-617)","url":"https://clinicaltrials.gov/study/NCT06402331"}],"tags":[],"related":["lu-177","ac-225"],"indications":["prostate","neuroendocrine"],"sections":[],"technologies":[],"targets":[],"drugs":["pluvicto","ac225-psma","lutathera","ryz101"],"companies":[],"institutions":[],"pathways":[],"terms":["alpha-vs-beta"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"a":"radioligand-therapy","b":"targeted-alpha-therapy","rationale":"Alpha particles cause oxygen-independent clustered DNA damage that beta-resistant, hypoxic, or small-volume disease cannot repair.","evidence":"Retrospective and phase 1/2; phase 3 pending.","pairingType":"sequence"},{"id":"docetaxel-then-lu177-psma","kind":"pairing","name":"Docetaxel (taxane chemotherapy) then 177Lu-PSMA-617","aka":[],"tldr":"In the trial that got 177Lu-PSMA-617 (Pluvicto) approved, everyone had already been treated with a taxane chemotherapy drug like docetaxel and with a hormone pill first. That is the treatment order the approval is based on, though a newer trial is now testing whether Pluvicto can be used earlier, before chemotherapy.","summary":"The pivotal VISION trial (NCT03511664; Sartor et al., NEJM 2021) that supported FDA and EMA approval of 177Lu-PSMA-617 (Pluvicto) enrolled adults with metastatic castration-resistant prostate cancer who had already progressed on at least one androgen-receptor pathway inhibitor (for example abiraterone or enzalutamide) and on one or two prior taxane-based chemotherapy regimens, typically docetaxel. Patients also had to have PSMA-positive disease on centrally read 68Ga-PSMA-11 PET-CT, with no qualifying PSMA-negative lesions. 177Lu-PSMA-617 (7.4 GBq every 6 weeks, up to 6 cycles) plus protocol-permitted standard care was compared with standard care alone; median overall survival was 15.3 months versus 11.3 months (hazard ratio 0.62, 95% CI 0.52-0.74, p<0.001).\n\nBecause prior taxane exposure was a trial entry requirement rather than a randomised comparison of sequencing strategies, VISION establishes an evidence-based treatment order — androgen-receptor pathway inhibitor, then taxane chemotherapy (commonly docetaxel), then 177Lu-PSMA-617 — rather than proving that giving the radioligand therapy after docetaxel is better than giving it before. Retrospective subgroup analyses of VISION found that survival benefit from 177Lu-PSMA-617 was preserved regardless of whether patients had received one or two prior taxane regimens, and regardless of the number of prior androgen-receptor pathway inhibitors.\n\nThis sequencing question is now being tested directly: the phase 3 PSMAfore trial (NCT04689828) enrolled taxane-naive patients progressing after one androgen-receptor pathway inhibitor and randomised them to 177Lu-PSMA-617 or to switching to a different androgen-receptor pathway inhibitor, explicitly to establish whether radioligand therapy can move earlier in the treatment sequence, ahead of chemotherapy, rather than only being used after it.","asOf":"2026-09-22","links":[{"label":"Sartor et al., VISION primary results, N Engl J Med 2021 (full text)","url":"https://www.nejm.org/doi/full/10.1056/NEJMoa2107322"},{"label":"JNM commentary on VISION eligibility criteria (prior taxane and ARPI requirements)","url":"https://jnm.snmjournals.org/content/63/6/823"},{"label":"PSMAfore design (taxane-naive, ARPI-progressed population), ASCO 2022","url":"https://ascopubs.org/doi/10.1200/JCO.2022.40.6_suppl.TPS211"}],"tags":["prostate cancer","treatment sequencing","radioligand therapy"],"related":["prostate-mcrpc","vision","psmafore","paper-vision-nejm-2021","michael-morris","oliver-sartor","ga-68","lu-177"],"indications":[],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"a":"docetaxel","b":"pluvicto","rationale":"The approval of 177Lu-PSMA-617 rests on a trial population defined by prior treatment order (hormone therapy, then taxane chemotherapy, then radioligand therapy), so this is the evidence-based sequence rather than a proven optimal one.","evidence":"VISION (n=831) required progression after at least one androgen-receptor pathway inhibitor and one or two taxane regimens (typically docetaxel) before enrolment; median overall survival with added 177Lu-PSMA-617 was 15.3 vs 11.3 months (HR 0.62, p<0.001) (Sartor et al., NEJM 2021). PSMAfore (NCT04689828) is testing whether the radioligand therapy can instead be used before taxane chemotherapy.","pairingType":"sequence"},{"id":"fdg-pet-response-adapted-therapy","kind":"pairing","name":"FDG PET then response-adapted chemotherapy","aka":[],"tldr":"In Hodgkin lymphoma, a PET scan taken partway through chemotherapy is used to decide whether to keep the same treatment, drop a harsh drug, or step up to something stronger. Trials show this scan-guided approach keeps most patients well without adding one particular lung-damaging drug.","summary":"RATHL (Response-Adapted Therapy in advanced Hodgkin Lymphoma; NCT00678327; Johnson et al., NEJM 2016) enrolled 1214 patients (1119 evaluable) with stage IIB-IV or bulky IIA classical Hodgkin lymphoma. All patients received two cycles of ABVD chemotherapy and then an interim FDG PET-CT scan (PET2). Patients with a negative PET2 (Deauville score 1-3; 83.7% of scanned patients) were randomised to continue ABVD or to drop bleomycin (AVD) for the remaining four cycles; those with a positive PET2 were escalated to BEACOPP-14 or escalated BEACOPP, with no randomisation in that arm.\n\nAt a median follow-up of 41 months, 3-year progression-free survival in PET2-negative patients was 85.7% with continued ABVD versus 84.4% with AVD (absolute difference 1.6 percentage points, within the prespecified non-inferiority margin), while overall survival was around 97% in both arms; the trial's practical conclusion was that bleomycin can be safely omitted after a negative interim scan, reducing pulmonary toxicity with an estimated treatment-failure risk of only 1.6%. PET2-positive patients who were escalated to BEACOPP reached a 3-year progression-free survival of 67.5%, which the investigators judged better than historical rates of continuing ABVD alone in PET2-positive disease (previously reported in the 15-45% range). Long-term follow-up (Blood 2022; JCO 2024) confirmed durability of both the de-escalation and escalation strategies.\n\nRATHL is the paradigm case for FDG-PET-guided, response-adapted treatment and sits alongside other PET2-adapted trials (Italian GITIL/FIL HD0607, US Intergroup S0816) that validated the same principle: interim FDG-PET response predicts outcome and can be used prospectively to tailor chemotherapy intensity. The same logic (imaging mid-treatment to decide whether to change systemic therapy) generalises to other FDG-avid cancers, for example the germ-cell tumour and lymphoma literature more broadly, though the specific numbers above are for classical Hodgkin lymphoma.","asOf":"2026-09-22","links":[{"label":"Johnson P, et al. RATHL: adapted treatment guided by interim PET-CT, N Engl J Med 2016;374:2419-2429","url":"https://thd.org.tr/thdData/userfiles/file/RATHL_Adapted_Treatment_Guided_by_Interim_PET-CT_Scan-2016_NEJM.pdf"},{"label":"PMC review of PET-adapted approaches to primary therapy for advanced Hodgkin lymphoma","url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC7268111/"},{"label":"Long-term follow-up of RATHL (Luminari et al., J Clin Oncol 2024)","url":"https://ascopubs.org/doi/10.1200/JCO.23.01177"}],"tags":["Hodgkin lymphoma","response-adapted therapy","FDG PET"],"related":["rathl","paper-rathl-interim-pet-adapted-abvd-advanced-hodgkin-nejm-2016","quantitative-imaging-biomarkers","pierre-vera"],"indications":[],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"a":"fdg-pet","b":"pet-adapted-therapy","rationale":"FDG uptake after two cycles of chemotherapy predicts long-term outcome in Hodgkin lymphoma, so an interim scan can be used prospectively to de-escalate treatment for good responders (reducing toxicity) or escalate it for poor responders (improving control).","evidence":"RATHL (n=1214, NCT00678327): in interim-PET-negative patients, 3-year progression-free survival was 85.7% with continued ABVD vs 84.4% after dropping bleomycin (AVD), supporting safe de-escalation; interim-PET-positive patients escalated to BEACOPP reached 67.5% 3-year progression-free survival, better than historical rates with unmodified ABVD (Johnson et al., NEJM 2016).","pairingType":"platform"},{"id":"prrt-plus-captem","kind":"pairing","name":"PRRT (177Lu-DOTATATE) with capecitabine and temozolomide (CAPTEM)","aka":[],"tldr":"For some pancreatic neuroendocrine tumours, doctors add two chemotherapy tablets (capecitabine and temozolomide) to the radioactive PRRT treatment. Trial data suggest the combination may control the pancreatic tumours for longer than either treatment alone, though it caused more blood-count side effects in one gut-tumour subgroup.","summary":"The Australasian Gastrointestinal Trials Group CONTROL NET study (Pavlakis et al.) is a randomised, open-label phase 2 trial that tested 177Lu-octreotate PRRT combined with capecitabine plus temozolomide (CAPTEM) against PRRT alone (midgut NET cohort) or CAPTEM alone (pancreatic NET, pNET, cohort). Chemoradionuclide therapy is given on the premise that temozolomide's DNA-alkylating damage is potentiated by concurrent radiation, an approach analogous to the CAPTEM regimen already used as chemotherapy alone in NETs.\n\nIn the pNET cohort, PRRT/CAPTEM produced a numerically longer median progression-free survival (not reached versus 14 months for CAPTEM alone) and a higher objective response rate (44% versus 28%, and in an earlier interim readout 67% versus 33%). In the midgut NET cohort the two regimens performed similarly on the 15-month progression-free survival endpoint (90% for PRRT/CAPTEM versus 92% for PRRT alone), with a numerically higher objective response rate for the combination (31-34% versus 15-23%) but at the cost of roughly double the grade 3/4 haematological toxicity (88% versus 46%).\n\nThe trial's own conclusion is that CAPTEM/PRRT activity in pNETs is durable enough to justify phase 3 testing, while in midgut NETs the extra toxicity did not appear matched by extra benefit. This is consistent with a wider literature (systematic review, PMC9790144) reporting CAPTEM alone achieves roughly 77% disease control across NET subtypes, most convincingly in pancreatic disease, and with retrospective comparisons finding broadly similar progression-free survival between PRRT and CAPTEM given sequentially rather than together.","asOf":"2026-09-22","links":[{"label":"AGITG CONTROL NET final results (Pavlakis et al., ASCO 2022, J Clin Oncol 40:4122)","url":"https://ascopubs.org/doi/10.1200/JCO.2022.40.16_suppl.4122"},{"label":"AGITG CONTROL NET midgut NET first results (ASCO 2020, J Clin Oncol 38:604)","url":"https://ascopubs.org/doi/10.1200/JCO.2020.38.4_suppl.604"},{"label":"JONS-online summary of CONTROL NET pancreatic and midgut results","url":"https://www.jons-online.com/special-issues-and-supplements/2020/2020-year-in-review-neuroendocrine-tumors/177lu-octreotate-prrt-temozolomide-capecitabine-in-pancreas-and-updated-midgut-nets"},{"label":"Systematic review of CAPTEM in advanced NENs (PMC9790144)","url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC9790144/"}],"tags":["neuroendocrine tumours","chemoradionuclide therapy"],"related":["pancreatic-net","neuroendocrine","temozolomide","prrt","jonathan-strosberg","lu-177"],"indications":[],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"a":"lutathera","b":"capecitabine","rationale":"Temozolomide's DNA-alkylating damage is thought to be potentiated by concurrent radiation from PRRT, so combining CAPTEM chemotherapy with PRRT ('chemoradionuclide therapy') may increase response over either given alone.","evidence":"AGITG CONTROL NET randomised phase 2 trial: in pancreatic NETs, PRRT/CAPTEM had a higher objective response rate than CAPTEM alone (44% vs 28%) and longer median PFS (not reached vs 14 months); in midgut NETs, 15-month PFS was similar (90% vs 92%) but grade 3/4 toxicity was roughly doubled with the combination (Pavlakis et al., ASCO 2022).","pairingType":"combination"},{"id":"psma-pet-to-rlt","kind":"pairing","name":"PSMA PET → PSMA radioligand therapy","aka":[],"tldr":"The scan shows whether the target is there; the treatment uses the same address. Only patients whose tumours light up are treated.","summary":"This diagnostic-therapeutic pairing links PSMA PET to Radioligand therapy (beta emitters) against PSMA in Prostate cancer: the scan shows whether the target is there, the treatment uses the same address, and only patients whose tumours light up are treated. Identical ligand chemistry means imaging biodistribution predicts therapeutic biodistribution and enables dosimetry. VISION and PSMAfore required PSMA PET positivity, so the pairing is embedded in phase 3 design and drug labels, and the standardised uptake value predicts response. The linked agents are Piflufolastat F-18 / Pylarify TruVu and Lutetium-177 vipivotide tetraxetan, and the pairing is the archetype of Theranostics now being copied for FAP, TROP2, HER2 and CAIX.","asOf":"2026-09-04","links":[{"label":"VISION: lutetium-177 PSMA-617 radioligand therapy extends survival in advanced prostate cancer (New England Journal of Medicine 2021)","url":"https://doi.org/10.1056/NEJMoa2107322"},{"label":"ClinicalTrials.gov NCT03392428: TheraP (ANZUP 1603)","url":"https://clinicaltrials.gov/study/NCT03392428"}],"tags":[],"related":["f-18","lu-177"],"indications":["prostate"],"sections":[],"technologies":[],"targets":["psma"],"drugs":["pylarify","pluvicto"],"companies":[],"institutions":[],"pathways":[],"terms":["theranostics"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"a":"psma-pet","b":"radioligand-therapy","rationale":"Identical ligand chemistry means imaging biodistribution predicts therapeutic biodistribution; also enables dosimetry.","evidence":"Embedded in phase 3 design and labels.","pairingType":"diagnostic-therapeutic"},{"id":"tare-vs-sorafenib-caution","kind":"pairing","name":"Radioembolisation (TARE) compared with sorafenib in hepatocellular carcinoma","aka":[],"tldr":"Two large trials tested whether liver-directed radiation beads work better than the pill sorafenib for advanced liver cancer. Neither trial found the radiation beads extended life more than the pill, though patients had fewer side effects and better quality of life with the beads.","summary":"SARAH (SorAfenib versus Radioembolisation in Advanced Hepatocellular carcinoma; NCT01482442; Vilgrain et al., Lancet Oncology 2017) and SIRveNIB (SIRT versus sorafenib; NCT01135056; Chow et al., JCO 2018) were both open-label, randomised phase 3 trials designed to show superiority of yttrium-90 resin-microsphere radioembolisation (TARE/SIRT) over sorafenib 800 mg/day in locally advanced, unresectable hepatocellular carcinoma, with overall survival as the primary endpoint.\n\nSARAH randomised 467 patients (237 TARE, 222 sorafenib) across 25 French centres; median overall survival was 8.0 months with TARE versus 9.9 months with sorafenib (hazard ratio 1.15, 95% CI 0.94-1.41, p=0.18) — numerically worse, not better, with TARE, and the trial did not meet its superiority endpoint. SIRveNIB randomised 360 patients (182 TARE, 178 sorafenib) across 11 Asia-Pacific countries; median overall survival was 8.8 months with TARE versus 10.0 months with sorafenib (hazard ratio 1.1, 95% CI 0.9-1.4, p=0.36), again not meeting its superiority endpoint. In both trials tumour response rates were numerically higher with TARE, and grade 3 or worse adverse events and serious adverse events were significantly less frequent with TARE than with sorafenib (in SIRveNIB, grade ≥3 events in 27.7% versus 50.6% of treated patients).\n\nThe consistent message from both randomised trials is that TARE has not been shown to extend survival beyond sorafenib in this population, despite earlier retrospective and registry data suggesting a survival advantage for radioembolisation; the 2018 EASL practice guidelines subsequently did not recommend radioembolisation as a substitute for sorafenib in this setting. TARE's better tolerability and quality-of-life profile may still inform treatment choice for individual patients, but this is a caution against assuming imaging-guided intra-arterial radiotherapy is simply a 'better' alternative to systemic therapy on survival grounds alone.","asOf":"2026-09-22","links":[{"label":"Vilgrain et al., SARAH trial primary results, Lancet Oncol 2017 (PubMed)","url":"https://pubmed.ncbi.nlm.nih.gov/29107679/"},{"label":"Chow et al., SIRveNIB trial primary results, J Clin Oncol 2018 (PubMed)","url":"https://pubmed.ncbi.nlm.nih.gov/29498924/"},{"label":"PMC review comparing SARAH and SIRveNIB outcomes","url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC6295389/"}],"tags":["hepatocellular carcinoma","radioembolisation","negative trial"],"related":["hcc-intermediate","hcc","sarah-sirvenib","sirtex","y-90"],"indications":[],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"a":"radioembolisation-tare","b":"sorafenib","rationale":"Retrospective and registry data had suggested radioembolisation might match or beat sorafenib's survival benefit with a better safety profile, prompting two head-to-head randomised phase 3 trials designed to show TARE's superiority.","evidence":"SARAH (n=467): median overall survival 8.0 months (TARE) vs 9.9 months (sorafenib), HR 1.15, p=0.18. SIRveNIB (n=360): 8.8 vs 10.0 months, HR 1.1, p=0.36. Neither trial met its superiority endpoint, though grade ≥3 adverse events were less frequent with TARE (Vilgrain et al., Lancet Oncol 2017; Chow et al., JCO 2018).","pairingType":"caution"},{"id":"tare-plus-durvalumab-hcc","kind":"pairing","name":"Radioembolisation (TARE) with durvalumab in hepatocellular carcinoma","aka":[],"tldr":"Small early trials are giving liver-directed radiation beads (TARE) together with the immunotherapy drug durvalumab for liver cancer that cannot be operated on. Early results show high tumour shrinkage rates, but these are small studies and it is not yet proven that the combination helps people live longer than either treatment alone.","summary":"A phase I/IIa pilot trial (Aliseda et al., Clinical Cancer Research 2023) treated 24 patients with locally advanced, unresectable hepatocellular carcinoma (Child-Pugh score up to 7, BCLC stage B or non-metastatic BCLC-C) with yttrium-90 radioembolisation followed 7-14 days later by intravenous durvalumab 1500 mg every 4 weeks. At a median follow-up of 19 months, median time to progression was 15.2 months, 18-month overall survival was 58.3%, and the objective response rate by modified RECIST was 83.3% (29.2% complete response, 54.2% partial response). Toxicity was modest: 47.8% of patients had any-grade treatment-related adverse events and only 8.7% had grade 3 events (neutropenia, fever), with no treatment-related serious adverse events.\n\nThis single-arm signal has prompted larger prospective studies of TARE plus durvalumab-based regimens, including the phase II ROWAN study (NCT05063565, Boston Scientific-sponsored, TheraSphere followed by durvalumab plus a single dose of tremelimumab, the STRIDE regimen; enrolment of 100 patients completed August 2025, results expected 2027) and EMERALD-Y90 (NCT06040099, AstraZeneca-sponsored, TARE followed by durvalumab and bevacizumab, 58 patients enrolled). A retrospective National Cancer Database analysis of 1,664 patients cited by Boston Scientific also associated TARE plus immunotherapy with improved survival compared with immunotherapy alone, though retrospective comparisons of this kind cannot rule out selection bias.\n\nAs of September 2026 none of the randomised, adequately powered trials of TARE plus systemic immunotherapy in HCC has reported a definitive survival readout; the evidence base is early-phase and registry-level. Clinicians should treat the high response rates from the pilot study as hypothesis-generating rather than practice-changing pending ROWAN and EMERALD-Y90 results.","asOf":"2026-09-22","links":[{"label":"Aliseda et al., Y90-radioembolisation plus durvalumab phase I/IIa trial, Clin Cancer Res 2023;29:3650-3658","url":"https://pubmed.ncbi.nlm.nih.gov/37459133/"},{"label":"Boston Scientific TheraSphere systemic therapy combination evidence brochure","url":"https://www.bostonscientific.com/content/dam/bsc/us/pi/ir/ioe/therasphere/downloads/TheraSphere-Systemic-Brochure.pdf"},{"label":"ROWAN study (NCT05063565) enrolment-complete summary","url":"https://oncodaily.com/oncolibrary/immune-oncology/rowan-study-enrol-complet"},{"label":"ClinicalTrials.gov: NCT06040099 (EMERALD-Y90, TARE + durvalumab + bevacizumab)","url":"https://clinicaltrials.gov/study/NCT06040099"}],"tags":["hepatocellular carcinoma","radioembolisation","immunotherapy"],"related":["hcc","sirtex","boston-scientific","astrazeneca","nct05063565","nct06040099","y-90"],"indications":[],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"a":"radioembolisation-tare","b":"durvalumab","rationale":"Radiation from TARE can release tumour antigens and prime an immune response, providing a rationale for combining it with checkpoint blockade in unresectable hepatocellular carcinoma where systemic options are limited.","evidence":"Phase I/IIa pilot trial (n=24): objective response rate 83.3% by modified RECIST (29.2% complete response), 18-month overall survival 58.3%, low grade 3 toxicity (8.7%) (Aliseda et al., Clin Cancer Res 2023); larger randomised readouts (ROWAN, NCT05063565; EMERALD-Y90, NCT06040099) are pending as of September 2026.","pairingType":"combination"},{"id":"radium223-abiraterone-caution","kind":"pairing","name":"Radium-223 with abiraterone: a caution, not a combination","aka":[],"tldr":"Giving the bone-targeting radiotherapy radium-223 together with the hormone drug abiraterone does not help patients live longer and roughly doubles or triples the risk of a broken bone compared with abiraterone alone. This combination is no longer recommended.","summary":"ERA-223 was a randomised, double-blind, placebo-controlled phase 3 trial (Smith et al., sponsored by Bayer) in 806 men with asymptomatic or mildly symptomatic bone-predominant metastatic castration-resistant prostate cancer, comparing radium-223 plus abiraterone acetate/prednisone/prednisolone against placebo plus abiraterone acetate/prednisone/prednisolone. The trial was unblinded prematurely on 17 November 2017, before completion of follow-up, after an unplanned ad hoc analysis showed more fractures and more deaths in the radium-223 arm.\n\nAt the primary analysis (data cut-off 15 February 2018), the combination did not improve the primary endpoint of symptomatic skeletal-event-free survival: median 22.3 months with radium-223 versus 26.0 months with placebo (hazard ratio 1.122, 95% CI 0.917-1.374, p=0.26). Overall survival was numerically shorter with radium-223 (30.7 versus 33.3 months; 155 deaths [39%] versus 141 deaths [35%]) though the difference was not statistically significant. The starkest signal was fracture risk: any-grade fractures occurred in 29% of the radium-223 group versus 11% of the placebo group in the extended follow-up analysis (26% versus 10% during the on-treatment period). Independent central review confirmed 76 patients with at least one fracture in the combination arm versus 23 on placebo, with osteoporotic (fragility) fractures nearly tenfold more common (37 versus 4 patients). Fracture risk was substantially reduced, but not eliminated, by concurrent bone-health agents (bisphosphonates or denosumab): 15% versus 7% fracture incidence with and without radium-223 among bone-health-agent users, compared with much higher rates in patients not on a bone-health agent.\n\nOn the basis of ERA-223, the investigators explicitly do not recommend radium-223 in combination with abiraterone acetate plus prednisone/prednisolone, and the FDA and EMA revised prescribing information for radium-223 accordingly. This is one of the clearest examples in prostate-cancer radiopharmaceutical practice where two active, individually beneficial agents (radium-223 improved overall survival in ALSYMPCA; abiraterone improves survival in mCRPC) produce net harm when combined, and it is now standard teaching to avoid concurrent radium-223 and abiraterone outside a bone-health-agent-protected, closely monitored context.","asOf":"2026-09-22","links":[{"label":"Smith et al., ERA-223 primary results, Lancet Oncology 2019 (open-access PDF via UCLouvain)","url":"https://dial.uclouvain.be/pr/boreal/object/boreal:213463/datastream/PDF_02/view"},{"label":"ASCO Post summary of ERA-223 (fracture rate, OS)","url":"https://ascopost.com/issues/november-25-2018/treatment-with-radium-223-plus-abiraterone-not-advisable-in-metastatic-prostate-cancer/"},{"label":"PMC review discussing ERA-223 unblinding and fracture subtypes","url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC6642951/"}],"tags":["prostate cancer","safety signal","fractures"],"related":["prostate-mcrpc","bone-metastases","chris-parker","karim-fizazi","arpi","ra-223"],"indications":[],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"a":"radium-223","b":"abiraterone","rationale":"Both agents are individually beneficial in mCRPC (radium-223 improves survival in ALSYMPCA, abiraterone improves survival in mCRPC), so combining a bone-seeking alpha emitter with an androgen-receptor pathway inhibitor was hypothesised to add benefit; the trial testing this was stopped early for harm.","evidence":"ERA-223 phase 3 trial (n=806) was unblinded prematurely after excess fractures and deaths in the radium-223 arm: fractures occurred in 29% vs 11% of patients (radium-223 vs placebo, both plus abiraterone/prednisone), symptomatic skeletal-event-free survival was not improved (22.3 vs 26.0 months, HR 1.122, p=0.26), and overall survival was numerically shorter (30.7 vs 33.3 months) (Smith et al., Lancet Oncology 2019).","pairingType":"caution"},{"id":"rituximab-then-ibritumomab-tiuxetan","kind":"pairing","name":"Rituximab pretreatment before ibritumomab tiuxetan (Zevalin)","aka":[],"tldr":"Before giving the radioactive lymphoma treatment Zevalin, doctors first give a dose of the antibody drug rituximab. This clears out normal B-cells in the blood so the radioactivity goes to the lymphoma more precisely, and it is a mandatory step on the drug's official label, not an optional extra.","summary":"Ibritumomab tiuxetan (Zevalin), a yttrium-90-labelled anti-CD20 radioimmunotherapy, is administered only as part of a fixed two-step regimen defined in its FDA label and EMA product information. On day 1, patients receive rituximab 250 mg/m2 by intravenous infusion; seven to nine days later, a second rituximab infusion (250 mg/m2) is given, followed within four hours by the therapeutic yttrium-90 ibritumomab tiuxetan infusion, dosed at 0.4 mCi/kg (14.8 MBq/kg) for patients with platelet counts of 150,000/mm3 or more, or a reduced 0.3 mCi/kg (11.1 MBq/kg) for platelet counts of 100,000-149,000/mm3, with a maximum activity cap of 32 mCi regardless of body weight.\n\nThe pharmacological rationale, stated explicitly in the EMA summary of product characteristics, is that rituximab pretreatment clears circulating and marginal-zone CD20-positive B-cells, which would otherwise act as a radioactivity 'sink' and reduce the fraction of the yttrium-90 dose reaching lymphoma cells; the rituximab dose used in the Zevalin regimen is deliberately lower than the dose used when rituximab is given as monotherapy. Zevalin is approved for relapsed or refractory low-grade or follicular B-cell non-Hodgkin lymphoma, and as consolidation after first-line induction chemotherapy in previously untreated follicular lymphoma (the latter still requiring the same rituximab-then-Zevalin sequence).\n\nBecause rituximab must be ordered and administered separately from the Zevalin kit, this is one of the clearest examples of a mandated, label-level drug sequence in radiopharmaceutical practice: Zevalin cannot be lawfully administered without preceding rituximab, and the labels carry boxed warnings for infusion reactions (during the rituximab step) and for prolonged, severe cytopenias following the radiolabelled step.","asOf":"2026-09-22","links":[{"label":"FDA label: Zevalin (ibritumomab tiuxetan), 2018 revision","url":"https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/125019s227lbl.pdf"},{"label":"EMA product information: Zevalin (rituximab pretreatment rationale and dosing)","url":"https://ec.europa.eu/health/documents/community-register/2020/20200211147169/anx_147169_en.pdf"}],"tags":["lymphoma","radioimmunotherapy","mandatory sequence"],"related":["cd20","dlbcl","follicular-lymphoma","radioimmunotherapy","y-90"],"indications":[],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"a":"rituximab","b":"ibritumomab-tiuxetan","rationale":"Rituximab pretreatment clears circulating and marginal-zone CD20-positive B-cells that would otherwise compete for binding, so the radiolabelled antibody given afterwards delivers more of its radiation dose specifically to lymphoma cells.","evidence":"The FDA label and EMA SmPC for Zevalin mandate a fixed two-step regimen: rituximab 250 mg/m2 on day 1, then a second rituximab 250 mg/m2 infusion on day 7-9 followed within 4 hours by yttrium-90 ibritumomab tiuxetan at 0.4 mCi/kg (or 0.3 mCi/kg if platelets 100,000-149,000/mm3), capped at 32 mCi total.","pairingType":"sequence"},{"id":"sstr-pet-to-prrt","kind":"pairing","name":"SSTR PET → PRRT","aka":[],"tldr":"SSTR PET followed by PRRT is the original theranostic pair: the scan with the diagnostic isotope decides who gets the same molecule with the therapeutic isotope.","summary":"This diagnostic-therapeutic pairing links somatostatin receptor PET, using gallium-68 or copper-64 DOTATATE, to peptide receptor radionuclide therapy with lutetium-177 dotatate or 177Lu-edotreotide in neuroendocrine tumours. Because the imaging and therapeutic agents share identical peptide chemistry, the biodistribution seen on the scan predicts where the therapy will be delivered, which is the founding logic of theranostics. Every pivotal PRRT trial, including NETTER-1, NETTER-2 and COMPETE, required SSTR-avid disease on imaging, and both the intensity of uptake, graded on the Krenning scale, and the absence of FDG-avid lesions lacking SSTR predict benefit. The same template was later copied by PSMA theranostics in prostate cancer.","asOf":"2026-09-07","links":[{"label":"ClinicalTrials.gov NCT03049189: COMPETE","url":"https://clinicaltrials.gov/study/NCT03049189"}],"tags":[],"related":["ga-68","cu-64","lu-177"],"indications":["neuroendocrine"],"sections":[],"technologies":[],"targets":["sstr2"],"drugs":["lutathera","itm-11"],"companies":[],"institutions":[],"pathways":[],"terms":["theranostics"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"a":"sstr-pet","b":"prrt","rationale":"Identical peptide chemistry means imaging biodistribution predicts therapy delivery.","evidence":"Embedded in all pivotal PRRT trials.","pairingType":"diagnostic-therapeutic"}]