TulmiSTAR-01: A Two-part, Phase I Dose Escalation and Expansion Followed by a Randomized, Open-label Multicenter, Phase II Study to Assess the Safety and Efficacy of the Combination of Tulmimetostat (DZR123) and JSB462 (Luxdegalutamide) vs Standard of Care in Patients With Progressive Metastatic Castrate Resistant Prostate Cancer

This is a two-part, Phase I/II, open-label, global, multicenter study assessing the safety and efficacy of the combination of tulmimetostat (DZR123) and JSB462 (luxdegalutamide) versus standard of care in participants with progressive metastatic castrate resistant prostate cancer (mCRPC).

More details:

The Phase 1 study, comprised of Parts 1a and 1b, aims to assess the safety and tolerability of the combination of tulmimetostat and JSB462: 1. Part 1a is the parallel dose escalation that aims to determine the recommended dose(s) of tulmimetostat and JSB462, in combination, for further exploration. 2. Part 1b is the dose expansion/optimization that aims to determine the recommended dose of the combination for Phase II. The purpose of the Phase II study (Part 2) is to compare the combination of tulmimetostat with JSB462 in terms of the biochemical response as assessed by PSA50 compared to the standard of care (SoC) in adult men with progressive, taxane-naive mCRPC.

Overview

Tulmimetostat (CPI-0209; DZR123) is an oral, next‑generation inhibitor of the polycomb repressive complex 2 (PRC2) catalytic subunits EZH2 and EZH1. It is being evaluated in an ongoing first‑in‑human phase 1/2 study (NCT04104776) across advanced solid tumors and lymphomas, with dose‑optimization under the FDA’s Project Optimus framework. (novartis.com)

Mechanism of action

• Target: Dual EZH2/EZH1 inhibitor that reduces H3K27me3 and reprograms PRC2‑regulated gene expression. Compared with first‑generation EZH2 inhibitors, tulmimetostat shows improved potency and prolonged target residence time, enabling durable target coverage. (aacrjournals.org)
• Rationale: Tumors with ARID1A loss-of-function and certain BAP1‑deficient contexts exhibit dependence on PRC2 activity; preclinical models of ARID1A‑mutant bladder, ovarian clear cell, and endometrial cancers showed antitumor activity, and a blood‑based pharmacodynamic gene signature correlated with drug exposure in patients. (aacrjournals.org)

Efficacy

Phase 1/2, multi‑cohort (monotherapy) preliminary findings:

• ASCO 2023 (data cutoff Nov 8, 2022; n=62 treated, n=48 efficacy‑evaluable): confirmed responses observed in multiple cohorts. Notably, in peripheral T‑cell lymphoma (PTCL), 2 complete responses (CR) and 1 partial response (PR) among 7 evaluable patients; ovarian clear cell carcinoma (OCCC, ARID1A‑mutant) 1 PR/10; endometrial carcinoma (ARID1A‑mutant) 2 PR/5; mesothelioma (BAP1‑loss) 1 PR/12. These results met stage‑expansion criteria for OCCC, endometrial carcinoma, and mesothelioma cohorts. (ascopubs.org)

• ASCO 2024 (dose‑optimization update; data cutoff Oct 15, 2023; n=117 treated, n=111 efficacy‑evaluable): continued signals of antitumor activity across cohorts while exploring lower once‑daily doses (≤350 mg). Pharmacodynamic gene‑expression changes increased with dose and plateaued at higher exposures (≈225–375 mg). (ascopubs.org)

• ESMO 2024 (OCCC, ARID1A‑mutant; data cutoff Feb 18, 2024): randomized dose‑optimization showed confirmed PRs at 200 mg (3/10; ORR 30%), 300 mg (2/10; 20%), and 350 mg (1/14; ~7%); stable disease was frequent across arms. Similar pharmacodynamic effects were seen across doses. (oncologypro.esmo.org)

The study remains ongoing and recruiting; additional cohorts include urothelial and mCRPC (with an enzalutamide combination cohort). (novartis.com)

Safety

• Phase 1 (ASCO 2021): tulmimetostat was generally well tolerated up to 275 mg once daily with no dose‑limiting toxicities observed at that time; common adverse events (mostly grade 1–2) included fatigue, diarrhea, nausea, alopecia, anemia, and thrombocytopenia. Pharmacodynamic target engagement (global H3K27me3 reduction) was observed across dose levels. (ascopubs.org)

• Phase 2 preliminary (ASCO 2023; 350 mg QD): most frequent treatment‑related adverse events (any grade/grade ≥3) were thrombocytopenia (51.6%/27.4%), diarrhea (45.2%/12.9%), nausea (37.1%/0%), anemia (30.6%/16.1%), fatigue (29.0%/0%), alopecia (25.8%/1.6%), vomiting (21.0%/0%), and neutropenia (17.7%/14.5%). Treatment‑emergent AEs led to dose modifications in 75.8%; discontinuation due to AEs in 8.1%. (ascopubs.org)

• Dose‑optimization update (ASCO 2024): safety profile consistent with EZH2‑class effects; dose modifications in 74.4%, serious AEs in 41.9%, and discontinuations due to AEs in 9.4%. Hematologic toxicities (thrombocytopenia, anemia) and diarrhea were the most common related events. (ascopubs.org)

Clinical development status

• Ongoing global phase 1/2 trial (NCT04104776) with monotherapy cohorts in ARID1A‑mutant solid tumors (urothelial/other, OCCC, endometrial), mesothelioma (BAP1‑loss), lymphoma (PTCL and EZH2‑mutant DLBCL), mCRPC, and a dose‑optimization schema for OCCC and endometrial cancer; includes an enzalutamide combination cohort in mCRPC. (novartis.com)

Further reading

• First‑in‑human phase 1 results (ASCO 2021 abstract). (ascopubs.org)
• Preliminary phase 2 results across cohorts (ASCO 2023 abstract). (ascopubs.org)
• Phase 2 dose‑optimization update (ASCO 2024 abstract). (ascopubs.org)
• OCCC randomized dose‑optimization data (ESMO 2024 poster 748P). (oncologypro.esmo.org)
• Mechanism and pharmacodynamics in preclinical and early clinical settings (peer‑reviewed, Cancer Research, 2024). (aacrjournals.org)
• Current trial listing and design overview (NCT04104776). (novartis.com)

Note: Reported clinical data are preliminary from conference abstracts and ongoing studies as of February–October 2024 cutoffs; peer‑reviewed clinical efficacy/safety publications have not yet been identified. (ascopubs.org)

Last updated: Oct 2025

Overview

Luxdegalutamide (JSB462; also known as ARV‑766) is an investigational, oral androgen receptor (AR) degrader being co-developed under a 2024 license agreement between Arvinas and Novartis for prostate cancer. Early human data come from a first‑in‑human phase 1/2 study in metastatic castration‑resistant prostate cancer (mCRPC); randomized phase 2 combination studies in prostate cancer began in 2025. (arvinas.com)

Mechanism of action

Luxdegalutamide is a proteolysis targeting chimera (PROTAC) that recruits the AR to an E3 ubiquitin ligase complex, leading to AR ubiquitination and proteasomal degradation. Preclinical work shows potent AR degradation (DC50 <1 nM in VCaP cells), activity against clinically relevant AR ligand‑binding domain (LBD) mutations (including L702H, H875Y, T878A), and tumor growth inhibition in xenograft models, including enzalutamide‑insensitive models. (aacrjournals.org)

Clinical development

• Monotherapy (phase 1/2, NCT05067140): Oral luxdegalutamide is being evaluated as monotherapy and with abiraterone in metastatic prostate cancer; Novartis lists this study internally as CJSB462A12101, linking ARV‑766 with JSB462/luxdegalutamide. (novartis.com)
• Combination trials (phase 2, 2025 start):
• mHSPC: luxdegalutamide (100 mg or 300 mg QD) + abiraterone vs standard ARPI (abiraterone or enzalutamide). NCT06991556. (novartis.com)
• PSMA‑positive mCRPC: luxdegalutamide (100 mg or 300 mg QD) + lutetium‑177 vipivotide tetraxetan vs lutetium‑177 vipivotide tetraxetan alone. NCT07047118. (novartis.com)

Efficacy

Phase 1/2 monotherapy (mCRPC; initial/updated meeting reports): - In the ASCO 2024 abstract (data cutoff Dec 15, 2023; n=103 treated), among PSA‑evaluable patients with AR LBD mutations (n=28), 50% achieved a ≥50% PSA decline (PSA50). Confirmed and unconfirmed RECIST partial responses were also observed. (ascopubs.org) - Company and independent conference coverage consistent with these findings reported PSA50 rates around 41–50% in AR LBD‑mutated tumors, including activity in L702H‑mutant disease. (ir.arvinas.com)

No randomized efficacy results have been reported yet; the ongoing phase 2 combination studies are designed to select doses and assess comparative activity in mHSPC and mCRPC. (novartis.com)

Safety

Phase 1/2 monotherapy (mCRPC; ASCO 2024 abstract): - No dose‑limiting toxicities; maximum tolerated dose not reached (20–500 mg QD tested).
- Treatment‑related adverse events (any grade ≥10%): fatigue (36%; grade 3 in 3%), nausea (19%; 1%), diarrhea (15%; 1%), alopecia (14%), increased creatinine (13%), decreased appetite (11%); no grade 4 TRAEs reported. Dose reductions in 7% and discontinuations in 10% across 103 patients. (ascopubs.org)

Additional interim communications have highlighted generally favorable tolerability compared with first‑generation AR degraders; full peer‑reviewed safety datasets are pending. (ir.arvinas.com)

Further reading

• ASCO 2024 meeting abstract (phase 1/2 initial results): ARV‑766 (luxdegalutamide) in mCRPC. (ascopubs.org)
• AACR 2023 discovery abstract: Preclinical characterization of ARV‑766 as an AR‑degrading PROTAC. (aacrjournals.org)
• Novartis trial listings confirming JSB462 = luxdegalutamide and outlining ongoing phase 2 combinations in mHSPC (NCT06991556) and PSMA‑positive mCRPC (NCT07047118). (novartis.com)
• Novartis listing of the phase 1/2 monotherapy study (NCT05067140; internal code CJSB462A12101). (novartis.com)

Notes: As of October 7, 2025, there are no published, peer‑reviewed full manuscripts of human efficacy results for luxdegalutamide; available human data are from meeting abstracts and company/meeting summaries. Randomized phase 2 studies are ongoing. (ascopubs.org)

Last updated: Oct 2025

Key Inclusion Criteria:

* Participant is an adult man ≥ 18 years of age.

* Participant must have histologically and/or cytologically confirmed adenocarcinoma of the prostate without neuroendocrine or small cell features (current or prior biopsy of the prostate and/or metastatic site).

* Participant must have ≥ 1 metastatic lesion that is present on screening/baseline CT, MRI, or bone scan imaging obtained ≤ 28 days prior to start of treatment (Part 1a dose escalation) or randomization (Part 1b dose expansion and Part 2).

* Participant must have progressive mCRPC.

* Participant must have a castrate level of serum/plasma testosterone (\< 50 ng/dL or \< 1.7 nmol/L).

* Prior ARPI therapy:

* Part 1a and 1b only: must have progressed on at least one prior second generation ARPI (abiraterone, enzalutamide, darolutamide, or apalutamide).

* Part 2 only: must have progressed on one prior second generation ARPI (abiraterone, enzalutamide, darolutamide, or apalutamide).

* Prior chemotherapy:

* Part 1a dose escalation only: may have received ≤ 2 prior lines of chemotherapy in CRPC setting. Note: Prior chemotherapy is permitted in the HSPC setting.

* Part 1b dose expansion/optimization only: may have received up to one prior line of chemotherapy in CRPC setting. Note: Prior chemotherapy is permitted in the HSPC setting.

* Part 2 only: Participants must be taxane-naïve in mCRPC setting; prior chemotherapy permitted in HSPC setting only

Key Exclusion Criteria:

* Previous treatment with any PRC2 inhibitor, including but not limited to EZH2 inhibitors, EZH2/1 inhibitors, or embryonic ectoderm development (EED) inhibitors.

* Previous treatment with a protein degrader compound that targets the AR.

* Known hypersensitivity or contraindication to any of the study treatment components or its excipients or to drugs of similar chemical classes.

* Treatment with any investigational agent within 28 days (or 5 half-lives, whichever is longer) prior to study entry.

* Previous treatment with radioligand therapy in the mCRPC setting, except in Part 1a where participants may have received RLT in mCRPC setting.

* Participants with evidence of mCRPC or biochemical recurrence / PSA only disease or asymptomatic prostate cancer without known metastatic disease and with no requirement for therapy and with normal PSA for ≥ 1 year prior to study entry.

* Participants with a history of CNS metastases must have received therapy (surgery, radiotherapy, gamma knife) and be neurologically stable, asymptomatic, and not receiving corticosteroids for the purpose of maintaining neurologic integrity. Those with leptomeningeal disease are eligible if those areas have been treated, are stable, and no neurological impairment is present. For those with parenchymal CNS metastasis (or a history of CNS metastasis), baseline and subsequent radiological imaging must include evaluation of the brain with MRI (preferred) or CT with contrast.

Other protocol-defined inclusion/exclusion criteria may apply.