On March 25, 2025 Kezar Life Sciences, Inc. (Nasdaq: KZR), a clinical-stage biotechnology company developing novel small molecule therapeutics to treat unmet needs in immune-mediated diseases, reported positive topline results from the PORTOLA Phase 2a clinical trial evaluating zetomipzomib, a novel, first-in-class selective immunoproteasome inhibitor, in patients with autoimmune hepatitis (AIH) and reported fourth quarter and year end 2024 financial results (Press release, Kezar Life Sciences, MAR 25, 2025, View Source [SID1234651404]).
"We are pleased to announce these exciting results from the PORTOLA trial, the first successful randomized study in treatment-refractory AIH," said Chris Kirk, CEO and co-founder of Kezar. "We are encouraged by the safety and efficacy data in this difficult-to-treat patient population, specifically durable and steroid-sparing remissions experienced by patients treated with zetomipzomib. We are eager to work with the FDA Division of Hepatology and Nutrition to remove the partial clinical hold and align on an appropriate trial design to demonstrate the clinical benefit of zetomipzomib in AIH. I’d like to thank the team at Kezar, the physicians and staff at our clinical trial sites, and most importantly, the patients and their caregivers, for their participation, sacrifice and hard work."

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

"I am impressed by the totality of efficacy and safety data from the PORTOLA study," said Gideon Hirschfield, Chair of Autoimmune Liver Disease Research and Director of the Francis Family Liver Clinic, at the Toronto General Hospital. "Zetomipzomib represents a potent and targeted therapy for patients, and I believe these results will positively contribute to the design of a registrational trial of zetomipzomib in AIH, where patients are in need of better treatment options."
PORTOLA is a placebo-controlled, randomized, double-blind Phase 2a clinical trial evaluating the efficacy and safety of zetomipzomib in patients with AIH that are insufficiently responding to standard of care or

have relapsed from a previous CR. The trial enrolled 24 patients, randomized (2:1) to receive 60 mg of zetomipzomib or placebo in addition to background therapy for 24 weeks, with a protocol-suggested steroid taper. All patients were required to receive a starting daily steroid dose of 20-40 mg/day of prednisone (or budesonide equivalent) and physicians were encouraged to taper daily steroid usage to 5 mg/day consistent with AIH treatment guidelines established by the American Association for the Study of Liver Diseases (AASLD).
The primary efficacy endpoint of PORTOLA, which was not powered for efficacy, evaluated the proportion of patients who achieved a CR by Week 24, measured as normalization of alanine aminotransferase (ALT), aspartate aminotransferase (AST) and Immunoglobulin G (IgG) values (if elevated at baseline), with steroid dose levels not higher than baseline. A key secondary endpoint was the proportion of patients who achieved a CR by Week 24 with a steroid dose of 5 mg/day or less. The PORTOLA trial included a pre-specified subgroup analysis of patients who were on steroid-based therapy at the time of screening, which represents a patient population with unmet medical needs for a potential future registrational study. Additional exploratory endpoints included changes in histologic assessment of AIH as measured in biopsies taken within six months of screening and repeated at Week 24 of the trial.
Summary of Topline Results
PORTOLA enrolled 24 patients as the ITT population. Consistent with the AASLD treatment goals, zetomipzomib treatment resulted in higher rates of complete biochemical responses (CR) combined with reduction of steroid dosage to 5 mg/day or less, compared to placebo. In the ITT population:
•Without regard to steroid taper, 50.0% (8 of 16) of zetomipzomib patients achieved a CR, compared to 37.5% (3 of 8) of placebo patients.
•31.3% (5 of 16) of zetomipzomib patients achieved both a CR and steroid taper to 5 mg/day or less, compared to 12.5% (1 of 8) of placebo patients.
•18.8% (3 of 16) of zetomipzomib patients achieved both a CR and complete steroid withdrawal to zero mg/day, compared to 0% (0 of 8) of placebo patients.
•Median duration of response in zetomipzomib patients achieving a CR was 27.6 weeks (including the ongoing open-label extension), and no disease flares were reported in any zetomipzomib-treated patient achieving CR. Disease flares were defined as a sustained increase in ALT values to 25% above the CR value or 1.25-fold higher than the upper limit of normal for more than one week and requiring a restart or increase in steroid dose.
In the pre-specified subgroup analysis, 21 of the 24 patients entered the study on a steroid-based therapy at the time of screening. One patient in the placebo arm and two patients in the zetomipzomib arm were not receiving steroids at screening. All patients on study were required to initiate treatment with an initial prednisone dose of 20–40 mg/day. Of the 21 patients in this subgroup analysis:
•Median steroid use at screening was 20 mg/day for patients enrolled in the zetomipzomib arm, compared to 10 mg/day in the placebo arm, indicating that the zetomipzomib-treated arm was more refractory than the placebo arm.
•Without regard to steroid taper, 57.1% (8 of 14) of zetomipzomib patients achieved a CR, compared to 28.6% (2 of 7) of placebo patients.

•35.7% (5 of 14) of patients on the zetomipzomib arm achieved a CR and steroid taper to 5 mg/day or less, compared to 0% (0 of 7) of placebo patients.
•21.4% (3 of 14) of patients on the zetomipzomib arm achieved a CR and complete steroid withdrawal to zero mg/day, compared to 0% (0 of 7) of placebo patients.
Safety
Treatment-emergent adverse events (TEAEs) were seen in all patients, with injection site reactions (ISRs) being the most commonly reported TEAE in both arms. Systemic injection reactions (SIRs), with onset occurring 8 to 24 hours post-dose and usually resolving within 48 hours, were all Grade 1 and Grade 2. SIRs are a protocol-defined set of specific adverse events (AEs) consisting of one or more of the following signs/symptoms: hypotension, tachycardia, nausea, vomiting, dizziness, headache, pyrexia, rigors and/or chills.
Three patients experienced treatment-emergent serious adverse events (SAEs): one in the placebo arm, a Grade 3 variceal bleeding with hematemesis and atrial fibrillation; and two in the zetomipzomib arm, a Grade 3 fever occurring after the Week 24 liver biopsy, and a Grade 3 influenza infection that fully resolved during study. All SAEs were considered unrelated to study treatment, and all three patients completed the double-blind treatment period. Infectious AEs were reported in 85.7% (6 of 7) of patients in the placebo arm and 56.3% (9 of 16) of patients in the zetomipzomib arm. One patient discontinued from the placebo arm for a UTI requiring antibiotic treatment prior to receiving a dose on study, and three patients discontinued on the zetomipzomib arm for a Grade 1 fatigue, Grade 2 hives and a Grade 2 AIH disease flare. The safety population (n=23) includes all patients who received at least one dose of study treatment:

Placebo Zetomipzomib
n=7 n=16
Adverse Events in Double-blind Treatment Period n (%) n (%)
Participants with at least 1 Treatment Emergent Adverse Event (TEAE) 7 (100.0) 16 (100.0)
Most common TEAE:
Injection Site Reaction (ISR) 4 (57.1) 15 (93.8)
Systemic Injection Reaction (SIR) 1 (14.3) 12 (75.0)
TEAE leading to study drug discontinuation 0 (0) 3 (18.8)
Grade 3 TEAE (no Grade 4 or 5 TEAEs reported) 1 (14.3)
3 (18.8)
Serious TEAE 1 (14.3) 2 (12.5)
Infectious TEAE 6 (85.7) 9 (56.3)
Grade ≥3 Infectious TEAE 0 (0) 1 (6.3)
Opportunistic Infections 0 (0) 0 (0)
Death 0 (0) 0 (0)

Financial Results
•Cash, cash equivalents and marketable securities totaled $132.2 million as of December 31, 2024, compared to $201.4 million as of December 31, 2023. The decrease was primarily attributable to cash used in operations to advance clinical-stage programs.
•Revenue decreased by $7.0 million in 2024 compared to 2023 due to the October 2023 upfront payment received under the collaboration and license agreement with Everest Medicines.

•Research and development (R&D) expenses for the fourth quarter of 2024 decreased by $6.6 million to $16.0 million, compared to $22.6 million in the fourth quarter of 2023. Full year R&D expenses decreased by $20.0 million to $65.7 million in 2024, compared to $85.7 million in 2023. This decrease was primarily due to the Company’s strategic restructuring in October 2023 to prioritize its clinical-stage programs, reducing personnel-related costs and spending in its early-stage research activities, and a $5.0 million milestone payment made in 2023 under Kezar’s exclusive license agreement with Onyx Therapeutics. The decrease was partially offset by the increased clinical trial costs related to the PALIZADE and PORTOLA trials.
•General and administrative (G&A) expenses for the fourth quarter of 2024 decreased by $0.3 million to $5.5 million compared to $5.8 million in the fourth quarter of 2023. Full year G&A expenses decreased by $3.1 million to $23.4 million in 2024, compared to $26.5 million in 2023. The decrease was primarily due to a decrease in legal and professional service expenses and non-cash stock-based compensation.
•Restructuring and impairment charges decreased by $4.7 million to $1.5 million in 2024, compared to $6.2 million in 2023. The decrease was primarily related to one-time severance-related costs made in 2023 and higher impairment costs recognized in 2023 than 2024 on the right-of-use asset for the vacated floor in the leased office facility and certain equipment no longer utilized.
•Net loss for the fourth quarter of 2024 was $20.2 million, or $2.77 per basic and diluted common share, compared to a net loss of $32.3 million, or $4.44 per basic and diluted common share, for the fourth quarter of 2023. Net loss for 2024 was $83.7 million, or $11.49 per basic and diluted common share, compared to a net loss of $101.9 million, or $14.04 per basic and diluted common share in 2023. The weighted-average shares used to compute net loss per basic and diluted common share have been retroactively adjusted to reflect the one-for-ten reverse stock split completed on October 29, 2024.
•Total shares of common stock outstanding was 7.3 million shares as of December 31, 2024, after taking into effect the one-for-ten reverse stock split completed on October 29, 2024.
Conference Call and Webcast
Kezar Life Sciences will host a webcast and conference call today, March 25, 2025, at 8:00 a.m. ET to discuss topline results from the PORTOLA Phase 2a clinical trial. To access the live audio webcast with slides and dial-in information as needed, please register here: View Source
A live webcast of the event can also be found on the Kezar website at View Source A replay of the event will be available for 90 days following the presentation.

On March 25, 2025 Tempest Therapeutics, Inc. (Nasdaq: TPST), a clinical-stage biotechnology company developing first-in-classi targeted and immune-mediated therapeutics to fight cancer, reported that an abstract highlighting data supporting the immune component of amezalpat’s purported mechanism of action has been accepted for poster presentation at the 2025 American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting taking place April 25-30, 2025 in Chicago, IL (Press release, Tempest Therapeutics, MAR 25, 2025, View Source [SID1234651413]).

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

Poster presentation details:

Title: Amezalpat, a peroxisome proliferator-activated receptor alpha (PPARα) antagonist, inhibits suppressive macrophage development, activation and function
Abstract Number: 2171
Date & Time: Monday, April 28, 2025, 9:00 a.m. – 12:00 p.m. CT
Session Category: Immunology
Session Title: Interplay between Immune System and Radio-, Chemo- and Targeted Therapies 1
Location: Poster Section 35

On March 25, 2025 Exelixis, Inc. (Nasdaq: EXEL) reported that preclinical data will be presented for four pipeline molecules at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2025 taking place April 25-30 in Chicago, IL (Press release, Exelixis, MAR 25, 2025, View Source [SID1234651412]).

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

"We are excited to share preclinical data from four of our pipeline molecules that constitute the next phase in our commitment to the discovery and development of innovative cancer treatments," said Dana T. Aftab, Ph.D., Executive Vice President, Discovery & Translational Research, and Chief Scientific Officer, Exelixis. "The results support the advancement into clinical development of these biotherapeutics and small molecules, as well as their potential to become best- and/or first-in-class therapies with differentiated clinical profiles."

Exelixis will present preclinical data for XL495 and XL309, small molecules that have demonstrated synthetic lethality in the context of certain genetic anomalies frequently found in some tumors. Preclinical data will also be presented for the PD-L1xNKG2A-targeting bispecific antibody XB628 and the tissue factor-targeting antibody-drug conjugate XB371. Initial details about the poster presentations can be found below. Full data will be presented at the AACR (Free AACR Whitepaper) Annual Meeting.

Abstract 1733: XL495 is a potent, selective, and orally bioavailable inhibitor of PKMYT1
Lead Author: Dana Gwinn, Ph.D.
Session Title: Kinase and Phosphatase Inhibitors 1
Monday, April 28, 2:00-5:00 p.m. CT
Preclinical results will be presented for XL495, a novel, potent small molecule inhibitor of PKMYT1. The inhibition of PKMYT1 is synthetically lethal in cells with genetic anomalies that lead to replication stress—a common occurrence in cancer cells but not in normal cells. Data from the analysis show XL495 has demonstrated the potential for anti-tumor activity alone and in combination with DNA-damaging agents. A phase 1 clinical study of XL495 in patients with locally advanced or metastatic solid tumors, both as monotherapy and in combination with select cytotoxic agents in tumor-specific indications, is underway.

Abstract 2936: Preclinical characterization of XB371, a novel anti-tissue factor antibody-drug conjugate
Lead Author: Kathy Gogas, Ph.D.
Session Title: Growth Factor Receptors and Other Surface Antigens as Targets for Therapy 1
Monday, April 28, 2:00-5:00 p.m. CT
This poster presentation will highlight preclinical data for XB371, an antibody-drug conjugate, constructed using Catalent’s SMARTag site-specific bioconjugation platform, that pairs a tissue factor-targeting antibody with a topoisomerase inhibitor payload using a novel cleavable linker. This design may offer the molecule broad applicability across tumor types and a clinically differentiated potential. Results to be presented support in vitro cell killing activity and in vivo efficacy, supporting the advancement of XB371 into clinical development. Exelixis is planning to submit an investigational new drug application to the U.S. Food and Drug Administration (FDA) for XB371 in 2025.

Abstract 5723: XL309 is a potent, selective, and orally bioavailable USP1 inhibitor active as monotherapy and in combination with PARP inhibitors or irinotecan
Lead Author: Alex Charruyer-Reinwald, Ph.D.
Session Title: PARP Inhibitors
Tuesday, April 29, 2:00-5:00 p.m. CT
Preclinical results will be presented for XL309, a potent and selective small molecule inhibitor of USP1, the inhibition of which is lethal in cells with BRCA 1/2 mutations. The findings demonstrate activity of XL309 alone or in combination with PARP or topoisomerase inhibitors. A phase 1 clinical study of XL309 as a monotherapy or in combination with olaparib in patients with advanced solid tumors is underway.

Abstract 6067: Preclinical evaluation of XB628: A novel PD-L1 x NKG2A bispecific antibody
Lead Author: Bee-Cheng Sim, Ph.D.
Session Title: Antibodies 3: Multi-Target Checkpoint Inhibitors and Immune Activators
Tuesday, April 29, 2:00-5:00 p.m. CT
Preclinical data on XB628, a first-in-class bispecific antibody that simultaneously targets PD-L1 and NKG2A, will be presented. Data from this analysis show that XB628 is efficacious in tumor cell killing in vitro and in vivo, supporting advancement of this molecule into clinical development. Earlier this month, the U.S. FDA cleared Exelixis’ Investigational New Drug application for XB628.

On March 25, 2025 Veracyte, Inc. (Nasdaq: VCYT), a leading cancer diagnostics company, reported new data showing that its whole-genome sequencing (WGS)-based platform for minimal residual disease (MRD) testing detected cancer in patients treated for muscle-invasive bladder cancer (MIBC) with more accuracy than ddPCR-based blood testing and earlier compared to standard imaging (Press release, Veracyte, MAR 25, 2025, View Source [SID1234651411]). The findings, from the large, independent, multicenter, interventional TOMBOLA trial (NCT04138628), were shared in an oral presentation at the 40th Annual European Association of Urology Congress (EAU25) in Madrid by Iver Nordentoft, Ph.D., Aarhus University (Abstract A0162: "Comparison of ctDNA detection methods for monitoring minimal residual disease in patients with bladder cancer: Insights from the TOMBOLA Trial").

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

The new study involved 100 patients enrolled in the TOMBOLA trial who had MIBC and were undergoing standard-of-care neoadjuvant chemotherapy (NAC) and radical cystectomy (RC). Their blood samples were evaluated for circulating tumor DNA (ctDNA) using both ddPCR-based and Veracyte’s WGS-based MRD testing platform to detect disease recurrence. Patients also underwent imaging. At the 6-month milestone, in comparison to ddPCR, the Veracyte MRD testing platform had an equivalent and outstanding negative predictive value (95.9% Veracyte MRD vs. 96.2% ddPCR) for cancer recurrence, while having a higher specificity (88% Veracyte MRD vs. 62% ddPCR). Longer follow-up is required to determine the clinical impact of these results. The findings also showed that the Veracyte MRD testing platform detected cancer recurrence a median of 93 days sooner than imaging. In the ongoing trial, ctDNA-positive patients are treated with immunotherapy and followed for clinical response.

"Up to half of patients with muscle-invasive bladder cancer experience recurrence within two years of initial treatment, and using ctDNA status to guide oncological treatment would spare some patients from unnecessary treatments," said Lars Dyrskjøt Andersen, Ph.D., professor in the Department of Clinical Medicine and Department of Molecular Medicine at Aarhus University in Denmark and principal investigator of the TOMBOLA trial. "ctDNA testing using ddPCR has demonstrated promise for MRD detection, but it has inherent limitations that may impede its clinical use, particularly on a large scale. Our findings show that Veracyte’s whole-genome sequencing approach to MRD testing demonstrates high accuracy and may improve overall clinical utility, compared to ddPCR."

Veracyte’s MRD testing platform utilizes a combination of whole-genome sequencing and artificial intelligence (AI) to provide fast and accurate detection of residual cancer in a patient’s blood sample. This approach requires less blood and offers faster results, compared to ctDNA testing that uses bespoke panels, enabling earlier detection and improved outcomes. Veracyte’s MRD testing platform characterizes the complete set of cancer mutations in the tumor tissue sample and blood to establish a patient-specific, landmark genomic signature. It then uses whole-genome sequencing and AI to detect that signature in subsequent blood samples, indicating that cancer is present, and to track tumor progression throughout the patient’s treatment and follow-up care. Veracyte plans to launch its first MRD test in muscle-invasive bladder cancer in the first half of 2026, with other cancer indications to follow.

"The new data presented at EAU25 reinforce the power of the Veracyte Diagnostics Platform, which is at the core of all of our tests and will now enable us to expand into MRD testing in a clinically meaningful way," said Philip Febbo, M.D., Veracyte’s chief scientific officer and chief medical officer. "With our first MRD test in muscle-invasive bladder cancer, we are excited to expand our test offerings along the care continuum in urologic cancers where our Decipher tests are widely used and trusted by clinicians to help guide prognosis and treatment decisions."

In addition to the new data for Veracyte’s MRD testing platform, seven abstracts focused on the company’s Decipher Prostate and Decipher Bladder tests were presented at EAU25. More information can be found at the EAU25 website.

About Decipher Bladder

The Decipher Bladder Genomic Classifier is a 219-gene test, developed using RNA whole-transcriptome analysis and machine learning, that is designed for use in patients following bladder cancer diagnosis who face questions regarding treatment intensity. The test classifies bladder tumors into five molecular subtypes, each having distinct tumor biology and potential clinical implications. This information can help physicians and their patients better understand the degree of benefit that would likely be gained from neoadjuvant chemotherapy and/or the likelihood of harboring non-organ-confined disease at time of surgery, respectively. More information about the Decipher Bladder test can be found here.

About Decipher Prostate

The Decipher Prostate Genomic Classifier is a 22-gene test, developed using RNA whole-transcriptome analysis and machine learning, that helps inform treatment decisions for patients with prostate cancer. The test is performed on biopsy or surgically resected samples and provides an accurate risk of developing metastasis with standard treatment. Armed with this information, physicians can better personalize their patients’ care and may recommend less-intensive options for those at lower risk or earlier, more-intensive treatment for those at higher risk of metastasis. The Decipher Prostate test’s performance and clinical utility has been demonstrated in over 85 studies involving more than 200,000 patients. It is the only gene expression test to achieve "Level IB" evidence status and inclusion in the risk-stratification table in the most recent NCCN Guidelines* for prostate cancer. More information about the Decipher Prostate test can be found here.

On March 25, 2025 ORIC Pharmaceuticals, Inc. (Nasdaq: ORIC), a clinical stage oncology company focused on developing treatments that address mechanisms of therapeutic resistance, reported that a preclinical abstract highlighting the potential of ORIC-944, a potent and selective allosteric inhibitor of PRC2 to treat prostate cancer, has been accepted for poster presentation at the 2025 American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting taking place April 25-30, 2025 in Chicago, IL (Press release, ORIC Pharmaceuticals, MAR 25, 2025, View Source [SID1234651410]).

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

Poster presentation details:

Title: ORIC-944, a PRC2 inhibitor with best-in-class properties, restores luminal features and restricts adaptation in prostate cancer models, conferring synergy with AR pathway inhibitors
Abstract Number: 452
Date & Time: Sunday, April 27, 2025, 2:00 – 5:00 p.m. CT
Session Category: Experimental and Molecular Therapeutics
Session Title: Epigenetic Targets
Location: Poster Section 20

Abstract Highlights
ORIC-944 is a potent, highly selective, orally bioavailable, allosteric inhibitor of PRC2 that demonstrates best-in-class drug properties, including potency, solubility, and pharmacokinetics, with half-life supporting once daily dosing. In preclinical prostate cancer models, ORIC-944 demonstrated robust inhibition of PRC2, enhanced luminal cell state, and increased androgen receptor (AR) signaling. Analysis of chromatin revealed that ORIC-944 specifically restricts accessibility to lineage-associated transcription factors known to impart cellular plasticity in prostate cancer. This plasticity-restricted luminal state conferred by PRC2 inhibition is dependent on AR, leading to antitumor activity either in the hormone-depleted context or in the combination setting with an AR pathway inhibitor (ARPI). Together these data indicate that ORIC-944 reinforces a luminal cell state and, notably, restricts access to plasticity genes leading to a highly AR-dependent state in prostate models. This mechanism supports the observed preclinical synergy between PRC2 inhibition and ARPIs in both ARPI-sensitive and ARPI-resistant settings. These results position ORIC-944 as a potential best-in-class PRC2 inhibitor that blocks prostate tumor adaptation, restores luminal features, and sensitizes tumors to ARPIs. A phase 1b trial of ORIC-944 in combination with ARPIs is ongoing in metastatic prostate cancer (NCT05413421).