On June 20, 2025 Orion’s collaboration partner Bayer reported that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency has recommended darolutamide, an oral androgen receptor inhibitor (ARi), plus androgen deprivation therapy (ADT) for marketing authorisation in the European Union (EU) for the treatment of patients with metastatic hormone-sensitive prostate cancer (mHSPC) (Press release, Orion, JUN 20, 2025, View Source [SID1234654026]). The CHMP recommendation is based on positive results from the pivotal Phase III ARANOTE trial which showed that darolutamide plus ADT significantly reduced the risk of radiological progression or death by 46% compared to placebo plus ADT (HR 0.54; 95% CI 0.41–0.71; P<0.0001) in patients with mHSPC. A final decision on marketing authorisation from the European Commission is anticipated in the coming months.

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The U.S. Food and Drug Administration (FDA) recently approved darolutamide in combination with ADT for mHSPC in June 2025, making it the first and only in the US and FDA-approved ARi for the treatment of patients with mHSPC, in combination with ADT, with or without chemotherapy. Darolutamide, under the brand name Nubeqa, is approved in over 85 countries for use with ADT and docetaxel in mHSPC, and with ADT alone in non-metastatic castration-resistant prostate cancer (nmCRPC) in patients who are at high risk of developing metastatic disease. Darolutamide is developed jointly by Orion and Bayer.

Prostate cancer is the second most common cancer and the fifth most common cause of cancer death in men worldwide. In 2022, an estimated 1.5 million men were diagnosed with prostate cancer, and about 397,000 died from the disease worldwide.1 In Europe, there were almost 474,000 estimated new cases of prostate cancer in 2022 with approximately 115,000 deaths. 2 Prostate cancer diagnoses are projected to increase to 2.9 million by 2040.3

About the ARANOTE trial

The ARANOTE trial is a randomized, double-blind, placebo-controlled Phase III study designed to assess the efficacy and safety of darolutamide plus ADT in patients with mHSPC. 669 patients were randomized 2:1 to receive 600mg of darolutamide twice daily or matching placebo in addition to ADT.

The primary endpoint of this study is rPFS, measured as time from randomization to date of first documented radiological progressive disease or death due to any cause, whichever occurs first. Secondary endpoints include overall survival (time to death from any cause), time to first castration resistant event, time to initiation of subsequent anti-cancer therapy, time to prostate-specific antigen (PSA) progression, PSA undetectable rates, time to pain progression, and safety assessments.

Results from the Phase III ARANOTE trial presented at ESMO (Free ESMO Whitepaper) 2024 and published in The Journal of Clinical Oncology showed that darolutamide plus ADT significantly reduced the risk of radiological progression or death by 46% compared to placebo plus ADT (HR 0.54; 95% CI 0.41–0.71; P<0.0001), in patients with mHSPC. Consistent benefits in radiological progression-free survival (rPFS) were observed across prespecified subgroups, including patients with high-volume (HR 0.60, 95% CI: 0.44-0.80) and low-volume (HR 0.30, 95% CI: 0.15-0.60) mHSPC. The incidence of adverse events in the treatment group with darolutamide plus ADT in the ARANOTE study was comparable to placebo plus ADT. Darolutamide plus ADT was generally well tolerated and showed lower discontinuation rates due to adverse events compared to placebo plus ADT.

About darolutamide

Darolutamide is an oral ARi with a unique chemical structure that binds with high affinity to the androgen receptor and exhibits a strong antagonistic effect against the androgen receptor inhibiting the receptor function and the growth of prostate cancer cells. Additionally, preclinical models and neuroimaging data in healthy humans, support darolutamide’s low potential for blood-brain barrier penetration.

Darolutamide (plus ADT or plus ADT and docetaxel) demonstrated a side effect profile, in both mHSPC registrational studies where the incidences of adverse events were roughly similar to the respective comparator arm. Darolutamide is a treatment option for doctors and patients, considering its tolerability and low risk of drug interaction.

A robust clinical development program is underway investigating darolutamide across various stages of prostate cancer. The program includes the Phase III ARASTEP trial evaluating darolutamide plus ADT compared to ADT alone in hormone-sensitive high-risk biochemical recurrence (BCR) prostate cancer, who have no evidence of metastatic disease by conventional imaging and a positive PSMA PET/CT at baseline. Furthermore, darolutamide is also being investigated by Bayer in the collaborative Phase III DASL-HiCaP (ANZUP1801) trial led by the Australian and New Zealand Urogenital and Prostate Cancer Trials Group (ANZUP). The study evaluates darolutamide as a treatment for localized prostate cancer in combination with radiotherapy.

About metastatic hormone-sensitive prostate cancer

At the time of diagnosis, most men have localized prostate cancer, meaning their cancer is confined to the prostate gland and can be treated with curative surgery or radiotherapy. mHSPC is a stage in the disease where the cancer has spread outside of the prostate to other parts of the body. Up to 10% of men will present with mHSPC when first diagnosed.4,5,6 For patients with mHSPC, ADT is the cornerstone of treatment, in combination with chemotherapy docetaxel and/or an androgen receptor inhibitor (ARi).

Despite treatment, most men with mHSPC will eventually progress to castration-resistant prostate cancer (CRPC), a condition with limited survival.

On June 20, 2025 Aptevo Therapeutics Inc. ("Aptevo" or the "Company") (Nasdaq:APVO), a clinical-stage biotechnology company focused on developing novel immuno-oncology therapeutics based on its proprietary ADAPTIR and ADAPTIR-FLEX platform technologies, reported the addition of preclinical candidate APVO455 to its growing portfolio of CD3-directed candidates built on the CRIS-7 derived CD3 binding domain-an approach demonstrating compelling potential across both hematologic and solid tumors (Press release, Aptevo Therapeutics, JUN 20, 2025, View Source [SID1234654025]).

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With this announcement, Aptevo now has a suite of three CD3-engaging molecules in development. All three share the same CRIS-7 derived binding domain with a low cytokine release profile. In addition, APVO455 and APVO442 contain CD3 binding domains that are optimized for targeting solid tumors. All three molecules are designed to drive tumor-specific immune activation while limiting systemic toxicity. The suite includes:

Mipletamig , a CD123 x CD3 bispecific currently in Phase 1b/2 for frontline AML, where 85% of evaluable frontline patients across two trials have achieved remission in combination with standard of care. No cytokine release syndrome (CRS) has been observed in the first two trial cohorts of the ongoing RAINIER trial

APVO442 , a PSMA x CD3 candidate targeting prostate cancer, currently in preclinical development

And now APVO455 , a Nectin-4 x CD3 bispecific developed to address multiple solid tumor types

"With APVO455, we are rounding out a purposefully designed CD3 product suite that reflects both scientific rigor and clinical learning," said Marvin White, President and CEO of Aptevo. "Compelling mipletamig clinical results, where we have treated more than 100 patients across three trials, give us confidence that CRIS-7 is a critical differentiator. Our molecules behave predictably, drive selective activation and are emerging from a shared design strategy grounded in real-world human data."

Mr. White continued, "Ultimately, this design choice has yielded a compelling safety profile in the clinic, as seen with mipletamig, and supports broader application across indications where tolerability remains a barrier to effective T-cell engagement."

About APVO455: Advancing Nectin-4 T-cell Targeting in Solid Tumors

APVO455 is a preclinical Nectin-4 x CD3 bispecific T-cell engager designed for tumors such as bladder, breast, NSCLC, and head and neck cancers, where Nectin-4 is highly expressed. Unlike other approaches that restrict activity to acidic tumor environments or rely on activated T-cells, APVO455 is designed to avoid binding to or triggering T-cell activation in the periphery and do so only in the presence of Nectin-4 positive tumor cells, offering the potential for a broader therapeutic window and more consistent immune activation.

Looking Ahead

APVO455 represents the third CD3 bispecific in Aptevo’s portfolio and the sixth overall drug candidate in active development. The Company anticipates further expanding its CD3 suite in the future.

On June 20, 2025 SpringWorks Therapeutics, Inc. (Nasdaq: SWTX), a commercial-stage biopharmaceutical company focused on severe rare diseases and cancer, reported that the European Medicine Agency’s (EMA) Committee for Medicinal Products for Human Use (CHMP) has adopted a positive opinion recommending the approval of nirogacestat, an oral gamma secretase inhibitor, as monotherapy for the treatment of adults with progressing desmoid tumors who require systemic treatment (Press release, SpringWorks Therapeutics, JUN 20, 2025, View Source [SID1234654023]). The European Commission (EC) will review the CHMP opinion and is expected to make a final decision regarding the approval in the third quarter of 2025.

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"The positive opinion from the CHMP reflects the meaningful benefits nirogacestat can offer patients in Europe where currently there are no approved treatment options," said Saqib Islam, Chief Executive Officer of SpringWorks. "We look forward to the European Commission’s decision as we strive to bring nirogacestat to desmoid tumor patients globally."

Nirogacestat previously received Orphan Drug designation from the European Commission for the treatment of soft tissue sarcoma. The CHMP opinion was based on the Marketing Authorization Application (MAA) for nirogacestat, which centered on results from the Phase 3 DeFi trial that were published in The New England Journal of Medicine.1 In DeFi, nirogacestat met the primary endpoint of improving progression-free survival (PFS), demonstrating a 71% lower risk of disease progression compared to placebo. Nirogacestat demonstrated a significant improvement in objective response rate as well as early and sustained improvements in patient-reported outcomes (PROs), including pain, physical functioning and overall quality of life.

Nirogacestat exhibited a manageable safety and tolerability profile. The most common adverse reactions reported in patients receiving nirogacestat were diarrhea, ovarian toxicity, rash, nausea, fatigue, stomatitis, headache, abdominal pain, cough, alopecia, upper respiratory tract infection, and dyspnea.

"Desmoid tumors can have a profound impact on patients as well as their loved ones, and the positive CHMP opinion underscores the potential benefit of nirogacestat for these patients," Bernd Kasper, M.D., Ph.D., Professor, University of Heidelberg, Mannheim Cancer Center, Mannheim, Germany, and principal investigator of the DeFi trial. "It is very encouraging that a significant number of people taking nirogacestat experienced reductions in their tumor size and also rapid and sustained relief of their desmoid tumor symptoms, including pain."

Nirogacestat is approved in the U.S. for the treatment of adults with progressing desmoid tumors who require systemic treatment.

About the DeFi Trial
DeFi (NCT03785964) was a global, randomized (1:1), multicenter, double-blind, placebo-controlled pivotal Phase 3 trial that evaluated the efficacy, safety and tolerability of nirogacestat in adult patients with progressing desmoid tumors. The double-blind phase of the study randomized 142 patients (nirogacestat, n=70; placebo n=72) to receive 150 mg of nirogacestat or placebo twice daily. Key eligibility criteria included tumor progression by ≥20% as measured by Response Evaluation Criteria in Solid Tumors (RECIST 1.1) within 12 months prior to screening. The primary endpoint was progression-free survival (PFS), as assessed by blinded independent central review, or death by any cause. Secondary and exploratory endpoints included safety and tolerability measures, objective response rate (ORR), duration of response, changes in tumor volume assessed by magnetic resonance imaging (MRI), and changes in patient-reported outcomes (PROs). DeFi also included an open-label extension phase.

About Desmoid Tumors
Desmoid tumors are rare, aggressive, locally invasive tumors of the soft tissues that can be serious, debilitating, and, in rare cases when vital structures are impacted, life-threatening.2,3

Desmoid tumors are most commonly diagnosed in patients between the ages of 20 and 44 years, with a two-to-three times higher prevalence in females.4,5 It is estimated that there are 1,300-2,300 new desmoid tumor cases diagnosed per year in the European Union.6,7

Although desmoid tumors do not metastasize, they can be associated with recurrence rates of up to 77% after surgical resection.5,8 Desmoid tumor experts and treatment guidelines now recommend systemic therapies as first-line intervention for most tumor locations requiring treatment.9,10

About Nirogacestat

Nirogacestat is an oral, selective, small molecule gamma secretase inhibitor approved in the United States for the treatment of adult patients with progressing desmoid tumors who require systemic treatment. Nirogacestat is not approved for the treatment of any other indication in the United States, or for any indication in any other jurisdiction by any other health authority.

On June 20, 2025 Ratio Therapeutics Inc. (Ratio), a pharmaceutical company employing innovative technologies to develop best-in-class radiopharmaceuticals for cancer treatment and monitoring, and TerraPower Isotopes, a subsidiary of TerraPower, a leading nuclear innovation company, reported they entered into a supply agreement for the medical radioisotope actinium-225 (Ac-225) (Press release, Ratio Therapeutics, JUN 20, 2025, View Source [SID1234654022]). Under the agreement, TerraPower Isotopes would supply Ratio with quantities of non-cGMP Ac-225 for use to incorporate into or use in the development of Ratio’s radiopharmaceuticals.

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Ac-225 plays a vital role in the development of next-generation radiopharmaceuticals, serving as a powerful alpha-emitting isotope used in targeted cancer therapies. For Ratio, access to a reliable supply of Ac-225 is essential to advancing its pipeline based on its proprietary Trillium and Macropa platforms. Together, these platforms enable the design and development of novel radiopharmaceuticals that can selectively target and eradicate cancer cells, offering a powerful and targeted approach to cancer treatment.

"Securing a reliable supply of Actinium-225 is a critical step in advancing our pipeline of targeted alpha therapies," said John Babich, Ph.D., President and Chief Scientific Officer of Ratio. "This agreement with TerraPower Isotopes strengthens our ability to scale production and advance our Trillium and Macropa platforms, which are purpose-built to fully harness the therapeutic potential of Actinium-225 in targeted alpha therapies."

"TerraPower Isotopes is committed to increasing the global supply of Actinium-225 to support cancer treatment research and development," said Scott Claunch, President of TerraPower Isotopes. "We’re proud to work with Ratio Therapeutics to help realize the full potential of Actinium-225 in radiopharmaceuticals. Once linked to a disease-targeting molecule, Actinium-225 labeled drug products can be precisely delivered to cancerous tissues, where they emit high-energy alpha particles capable of destroying tumor cells while sparing surrounding healthy tissue, making it a potentially transformative treatment option for patients."

On June 20, 2025 Ratio Therapeutics Inc. (Ratio), a pharmaceutical company employing innovative technologies to develop best-in-class radiopharmaceuticals for cancer treatment and monitoring, and TerraPower Isotopes, a subsidiary of TerraPower, a leading nuclear innovation company, reported they entered into a supply agreement for the medical radioisotope actinium-225 (Ac-225) (Press release, Ratio Therapeutics, JUN 20, 2025, View Source [SID1234654022]). Under the agreement, TerraPower Isotopes would supply Ratio with quantities of non-cGMP Ac-225 for use to incorporate into or use in the development of Ratio’s radiopharmaceuticals.

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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!

Ac-225 plays a vital role in the development of next-generation radiopharmaceuticals, serving as a powerful alpha-emitting isotope used in targeted cancer therapies. For Ratio, access to a reliable supply of Ac-225 is essential to advancing its pipeline based on its proprietary Trillium and Macropa platforms. Together, these platforms enable the design and development of novel radiopharmaceuticals that can selectively target and eradicate cancer cells, offering a powerful and targeted approach to cancer treatment.

"Securing a reliable supply of Actinium-225 is a critical step in advancing our pipeline of targeted alpha therapies," said John Babich, Ph.D., President and Chief Scientific Officer of Ratio. "This agreement with TerraPower Isotopes strengthens our ability to scale production and advance our Trillium and Macropa platforms, which are purpose-built to fully harness the therapeutic potential of Actinium-225 in targeted alpha therapies."

"TerraPower Isotopes is committed to increasing the global supply of Actinium-225 to support cancer treatment research and development," said Scott Claunch, President of TerraPower Isotopes. "We’re proud to work with Ratio Therapeutics to help realize the full potential of Actinium-225 in radiopharmaceuticals. Once linked to a disease-targeting molecule, Actinium-225 labeled drug products can be precisely delivered to cancerous tissues, where they emit high-energy alpha particles capable of destroying tumor cells while sparing surrounding healthy tissue, making it a potentially transformative treatment option for patients."