Imlunestrant regimens in ER+/HER2– breast bancer | Image Credit: 

Treatment with imlunestrant (Inluriyo) as single agent or in combination with abemaciclib (Verzenio) improved both progression-free survival (PFS) and overall survival (OS) vs standard-of-care (SOC) endocrine therapy in patients with previously treated estrogen receptor (ER)–positive, HER2-negative advanced breast cancer, according to updated data from the phase 3 EMBER-3 study (NCT04975308).

 showed that, at a median follow up of 27.6 months, patients with 

m) in the imlunestrant cohort (n = 138) achieved a median PFS of 5.5 months vs 3.8 months in the SOC group (n = 118; HR, 0.62; 95% CI, 0.47-0.82; 

 = .0007). Among all patients, the median PFS was 10.9 months with imlunestrant plus abemaciclib (n = 213) vs 5.5 months with imlunestrant alone (n = 213; HR, 0.59; 95% CI, 0.47-0.74; 

 <.0001). This PFS benefit for the combination was maintained regardless of 

m status. Also of note, among patients who had previously received a CDK4/6 inhibitor, the median PFS was 9.1 months with imlunestrant plus abemaciclib (n = 139) vs 3.7 months with imlunestrant alone (n = 140; HR, 0.53; 95% CI, 0.40-0.69; 

At 50% OS maturity, results showed that at a median follow-up of 29.5 months in patients with 

m, the median OS in the imlunestrant cohort was 34.5 months vs 23.1 months in the SOC group (HR, 0.60; 95% CI, 0.43-0.86; 

 = .0043). While not statistically significant, this 11.4-month numerical OS benefit was considered by the investigators to be clinically meaningful. This OS improvement was consistent with imlunestrant across all prespecified subgroups of patients with 

m. At 33% OS maturity, results showed that at a median follow-up of 27.1 months, the median OS was not reached with imlunestrant plus abemaciclib vs 34.4 months with imlunestrant alone (HR, 0.82; 95% CI, 0.59-1.16; 

The EMBER-3 update also included data showing a clinically meaningful improvement in time to chemotherapy (TTC) and PFS2 with the imlunestrant-based regimens.

m, the median TTC in the imlunestrant cohort was 15.6 months vs 10.2 months in the SOC group (HR, 0.66; 95% CI, 0.48-0.92). Among all patients, the median TTC was 27.8 months with imlunestrant plus abemaciclib vs 15.5 months with imlunestrant alone (HR, 0.78; 95% CI, 0.59-1.03).

m showed a median PFS2 of 19.2 months in the imlunestrant cohort vs 13.5 months in the SOC group (HR, 0.71; 95% CI, 0.53-0.95). Among all patients, the median PFS2 was 22.6 months with imlunestrant plus abemaciclib vs 18.5 months with imlunestrant alone (HR, 0.79; 95% CI, 0.61-1.02).

Overall response rates were higher with imlunestrant vs SOC and higher with imlunestrant/abemaciclib vs imlunestrant monotherapy, regardless of 

Safety data were consistent with previously reported outcomes for imlunestrant and abemaciclib with no new safety signals.

“Imlunestrant, as monotherapy or in combination with abemaciclib, provides an all-oral chemotherapy-free option after progression on endocrine therapy for patients with ER+, HER2– advanced breast cancer,” said lead study author Komal Jhaveri, MD, FACP, section head of the Endocrine Therapy Research Program Clinical, director of the Early Drug Development Service, and the Patricia and James Cayne Chair for Junior Faculty at Memorial Sloan Kettering Cancer Center in New York, New York.

Imlunestrant alone or combined with abemaciclib demonstrated significant PFS benefits compared with SOC endocrine therapy in ER+/HER2– breast cancer.

OS was numerically improved with the imlunestrant regimens vs SOC, but not statistically significant.

The median TTC with imlunestrant monotherapy was 15.6 months vs 10.2 months in the SOC arm (HR, 0.71; 95% CI, 0.53-0.95).

Between October 2021 and November 2023, the open-label phase 3 EMBER-3 trial enrolled patients with ER+, HER2– advanced breast cancer previously treated with aromatase inhibitors with/without CDK4/6 inhibitors.

Overall, 874 patients with a median age of 62 were randomized to imlunestrant monotherapy (n = 331), imlunestrant plus abemaciclib (n = 213), or SOC (n = 330; investigator’s choice of endocrine therapy: exemestane or fulvestrant). Imlunestrant was administered at 400 mg orally once daily and abemaciclib was administered at 150 mg orally twice daily. Treatment cycles were 28 days.

At the data cutoff date of August 18, 2025, 10.1% of patients overall remained on treatment. This included 10%, 5%, and 18%, of the single-agent imlunestrant, SOC, and imlunestrant plus abemaciclib, arms, respectively. When patients discontinued treatment, first subsequent anticancer treatments were similar across the treatment arms.

The primary endpoints were PFS per investigator assessment for single-agent imlunestrant vs SOC in all patients and in patients with ESR1m, as well as PFS for imlunestrant plus abemaciclib vs imlunestrant in all patientsOS was a secondary end point and exploratory end points included TTC and PSF2.

What are the next steps for imlunestrant?

Based on the primary PFS analysisof EMBER-3, the FDA approved single-agent imlunestrant in September 2025 for the treatment of patients with ER+/HER2– 

m advanced breast cancer with disease progression following at least 1 line of endocrine therapy.

Regarding next steps for imlunestrant, Jhaveri said the randomized, open-label, global, multicenter phase 3 EMBER-4 study (NCT05514054) has completed enrollment, accruing approximately 8000 patients with ER+/HER2– early breast cancer who have received 2 to 5 years of adjuvant endocrine therapy with or without a CDK4/6 inhibitor who are at increased risk of recurrence. Patients are being randomized in a 1:1 ratio to single-agent imlunestrant or SOC endocrine therapy of aromatase inhibitor or tamoxifen.

Jhaveri KL, Neven P, Casalnuovo M, et al. Imlunestrant with or without abemaciclib in advanced breast cancer (ABC): Updated efficacy results from the phase 3 EMBER-3 trial. Presented at: San Antonio Breast Cancer Conference; December 9-12, 2025; San Antonio, TX. GS3-08.

A study of imlunestrant, investigator’s choice of endocrine therapy, and imlunestrant plus abemaciclib in participants with ER+, HER2– advanced breast cancer (EMBER-3). ClinicalTrials.gov. Updated July 11, 2025. Accessed December 12, 2025. https://clinicaltrials.gov/study/NCT04975308

Food and Drug Administration. FDA approves imlunestrant for ER-positive, HER2-negative, ESR1-mutated advanced or metastatic breast cancer. U.S. Food & Drug Administration. Published September 25, 2025. Accessed December 12, 2025. https://tinyurl.com/mtsv3fpu

Articles

Imlunestrant, alone or with abemaciclib, demonstrated improved progression-free survival (PFS) and overall survival (OS) compared to standard endocrine therapy in ER-positive, HER2-negative advanced breast cancer, as shown in the EMBER-3 study. The combination therapy showed significant benefits in patients with ESR1 mutations and those previously treated with CDK4/6 inhibitors. The study also highlighted improvements in time to chemotherapy (TTC) and PFS2. Safety profiles were consistent with previous data. The FDA approved imlunestrant in September 2025, and the EMBER-4 study is underway to further evaluate its efficacy.

Imlunestrant alone or in combination with abemaciclib significantly improved PFS in ER-positive and HER2-negative breast cancer. 

Imlunestrant With/Without Abemaciclib Maintains PFS, OS Benefit in ER+/HER2– Breast Cancer

Breast Cancer | Image 
Credit: © peterschreiber.media 
- stock.adobe.com

Menopausal hormone replacement therapy (HRT) did not lead to adverse effects regarding the risk of developing breast cancer in women harboring 

 mutations who are at high risk for developing breast cancer or ovarian cancer, according to findings from an ongoing study.

Data were presented at the 2025 San Antonio Breast Cancer Symposium by Joanne Kotsopoulos, PhD, scientist at the Women’s College Hospital, professor at the University of Toronto, and Canada Research Chair in Hereditary Breast and Ovarian Cancer Prevention.

“We’re not really in a position to conduct a clinical trial of HRT, so instead we thought we’d take a more matched approach where we’d match women who did and did not initiate HRT after surgery,” said Kotsopoulos.

The cumulative incidence (CI) of breast cancer among 

 carriers by an any HRT use was significantly lower in patients who did use HRT compared to patients who did not (24.5% vs 42.9%).

“Use of any type of [HRT] was inversely associated with risk,” explained Kotsopoulos. “Then when we stratified by estrogen alone, which is used in women who don’t have uteruses, and then in the estrogen and progestin combination, used in women who do have a uterus, we see that the inverse association was limited to women who used [estrogen] alone. The patterns were similar whether we looked at 

A total of 676 matched pairs were included in the analysis. The number of patients exposed to any HRT use with either 

 variant was 87, and the number of unexposed patients was n 128 (HR, 0.48; 95% CI, 0.36–0.63, 

In patients with an estrogen-alone formulation, there was a statistically significant association with reduced mortality (HR, 0.37; 95% CI, 0.24–0.57, 

 <.0001). In patients with an estrogen plus progestin formulation, a statistically significant risk reduction was not observed (HR, 0.94; 95% CI, 0.54–1.63, 

Kotsopoulos noted that the number of patients with 

The research addresses a critical clinical challenge for women with a pathogenic variant in the 

 genes who have a history of breast cancer.

The standard medical guidance contraindicates the use of menopausal HRT for any woman with a personal history of breast cancer.

This issue is particularly important for 

 carriers due to 2 key factors: a tendency to develop breast cancer at an early age, and the common recommendation to undergo risk-reducing oophorectomy prior to natural menopause, which induces menopausal symptoms.

The study aimed to prospectively analyze the association between menopausal HRT use after a breast cancer diagnosis in 

 carriers and the subsequent risk of death.

The study was a prospective analysis conducted using data from a longitudinal study cohort.

 carriers with a confirmed diagnosis of breast cancer who had no history of other cancers and had not used menopausal HRT prior to their breast cancer diagnosis.

A matched-pair design was employed to control for confounding variables. Each menopausal HRT user was matched to a nonuser based on year of birth, age at breast cancer diagnosis, and treatments received. This resulted in a total study size of 676 matched pairs.

“To summarize, I think the overall conclusion is that we saw no adverse effect of [HRT] on 

 breast cancer risk. Estrogen alone was associated with a lower risk, irrespective of route and type. We saw no increased risks with the combination therapy,” said Kotsopoulos.

Kotsopoulos also acknowledged the limitations of the study, including small strata, not stratifying by tumor receptor status, and the need for a longer follow-up.

Kotsopoulos J. Menopausal hormone therapy and the risk of breast cancer in women with pathogenic variant in BRCA1 or BRCA2. Press briefing. San Antonio Breast Cancer Symposium. December 12, 2025.

2.Kotsopoulos J, Seca M, Lubinski J, et al. Menopausal hormone therapy after a diagnosis of breast cancer in women with a 

 pathogenic variant and risk of death. Published May 28, 2025. Accessed December 11, 2025. 

 43, 10506(2025). doi: 10.1200/JCO.2025.43.16_suppl.10506.

Menopausal hormone replacement therapy (HRT) does not increase breast cancer risk in women with BRCA1 or BRCA2 mutations, according to recent findings. The study, presented at the 2025 San Antonio Breast Cancer Symposium, used a matched-pair design to compare HRT users and non-users. Results showed a lower cumulative incidence of breast cancer in HRT users, particularly those using estrogen alone. The study highlights the potential safety of HRT in this high-risk group, although limitations such as small sample sizes and lack of tumor receptor status stratification were noted.

Menopausal hormone replacement therapy was not associated with an increased risk of breast cancer in women with BRCA mutations.

Menopausal HRT Does Not Influence Breast Cancer Risk in Women Harboring BRCA Variants

Frontline treatment with the combination of fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) and pertuzumab (Perjeta) was associated with better quality of life (QOL) and less gastrointestinal and skin and mucosal symptoms compared with a taxane, trastuzumab (Herceptin), and pertuzumab (THP) in patients with HER2-positive advanced or metastatic breast cancer, according to data from the phase 3 DESTINY-Breast09 trial (NCT04784715) that were presented during the 

Previous results showed that T-DXd plus pertuzumab demonstrated an improvement in progression-free survival.

In September 2025, the FDA granted priority review to the supplemental biologics license application of T-DXd for the first-line treatment of patients with unresectable or metastatic HER2-positive breast cancer.

In total, 383 patients received 5.4 mg/kg of T-DXd once every 3 weeks plus an 840 mg loading dose of pertuzumab followed by 420 mg once every 3 weeks. In the THP arm, 387 patients received a standard-of-care combination of the 3 drugs.

Compared with THP, T-DXd plus pertuzumab presents a distinct QOL profile. Patients receiving T-DXd plus pertuzumab more gastrointestinal symptoms, including nausea, vomiting, constipation, and appetite loss. This patient group also experienced fewer issues with skin and mucosal symptoms, nosebleeds, and extremity swelling.

Patients in both arms reported similar levels of pain control, fatigue, and overall treatment tolerability. Furthermore, the majority of patients on both treatments successfully maintained or improved their physical function throughout the study.

The PRO end points were time to deterioration in pain, proportion of patients experiencing deterioration in treatment-related symptoms, proportion of patients with maintained or improved physical function, and the overall adverse effect (AE) burden as reported by patients.

The impact on pain and physical function was largely similar between the investigational T-DXd plus pertuzumab arm and the THP arm.

The median time to deterioration in pain was not reached in either treatment arm. The statistical analysis showed a similar risk of pain deterioration for both groups (HR, 0.95; 95% CI, 0.74–1.21).

A high percentage of patients in both arms maintained or improved their physical function. At cycle 2, 82.9% of patients in the T-DXd plus pertuzumab arm (n = 328) maintained or improved physical function vs 82.4% of patients in the THP arm (n = 341). At cycle 27 (18.7 months), 75.4% of patients in the T-DXd plus pertuzumab arm (n = 187) maintained or improved their physical function vs 77.7% of patients in the THP arm (n = 166).

The primary differences in patient experience emerged in the specific types of AEs reported. Patients in the T-DXd plus pertuzumab arm experienced a worsening of gastrointestinal issues, specifically nausea/vomiting (49.1% vs 30.2%). Conversely, patients in this arm reported less deterioration in skin and mucosal symptoms, including nosebleeds and extremity swelling (22.9% vs 33.5% at cycle 2; 37.4% vs 41.8% at cycle 27). Deterioration in fatigue was comparable between both arms at cycles 2 (41.2% vs 41.9%) and 27 (38.0% vs 35.5%), recognized as 2 key time points in the study. A similar overall of treatment between the regimens was reported.

The patient-reported outcomes from the DESTINY-Breast09 trial provide crucial context to the primary efficacy and safety results. The data concludes that T-DXd plus pertuzumab offers durable pain control and allows for the maintenance of physical function, outcomes that are comparable to the standard-of-care THP regimen.

“Patients reported T-DXd and [THP] as similarly tolerable over time,” Mothaffar F. Rimawi, MD, of the Dan L. Duncan Comprehensive Cancer Center and Baylor College of Medicine in Houston, Texas, concluded during the presentation. “The risk of clinically meaningful deterioration was similar, although data are still immature at this interim analysis.”

Rimawi M, Loibl S, Jiang Z, et al. Trastuzumab deruxtecan (T-DXd) + pertuzumab vs taxane + trastuzumab + pertuzumab (THP) for first-line treatment of patients with HER2+ advanced/metastatic breast cancer: patient-reported outcomes from the DESTINY-Breast09 study. Presentation RF6-07. San Antonio Breast Cancer Symposium. December 10, 2025.

Rimawi M, Loibl S, Jiang Z, et al. Trastuzumab deruxtecan (T-DXd) + pertuzumab (P) vs taxane + trastuzumab + pertuzumab (THP) for first-line (1L) treatment of patients (pts) with HER2-positive (HER2+) advanced/metastatic breast cancer (a/mBC): patient-reported outcomes (PROs) from the DESTINY-Breast09 study. Presented at the San Antonio Breast Cancer Symposium. December 10, 2025. https://tinyurl.com/28xrar89

The combination of fam-trastuzumab deruxtecan-nxki (T-DXd) and pertuzumab shows promise as a frontline treatment for HER2-positive advanced or metastatic breast cancer, offering better quality of life and fewer skin and mucosal symptoms compared to the standard taxane, trastuzumab, and pertuzumab regimen. Both treatment arms demonstrated similar pain control and physical function maintenance. However, T-DXd plus pertuzumab was associated with more gastrointestinal symptoms. The FDA has granted priority review for T-DXd in this setting, highlighting its potential as a first-line treatment option.

Frontline treatment with T-DXd plus pertuzumab improved QOL vs THP in patients with HER2-positive advanced or metastatic breast cancer.

Trastuzumab Deruxtecan Plus Pertuzumab Does Not Worsen QOL in HER2+ Metastatic Breast Cancer

Pelabresib plus ruxolitinib in myelofibrosis: 

Pelabresib (CPI-0610) in combination with ruxolitinib (Jakafi) was clinically superior compared with ruxolitinib alone for the treatment of patients with JAK inhibitor–naive myelofibrosis, according to data from the phase 3 MANIFEST-2 trial (NCT04603495) presented during the 

The pelabresib plus ruxolitinib combination demonstrated deep and durable improvements across primary and secondary efficacy end points compared to ruxolitinib monotherapy.

In patients who were evaluable at week 96, combination therapy was associated with least a 35% reduction in spleen volume (SVR35) in 91.5% of patients (n = 97 of 106) vs 57.5% (65/113) with ruxolitinib plus placebo, indicating a sustained benefit from previous evaluation at week 24. At week 24, the SVR35 was 82.9% (n = 141 of 170) with the combination vs 41.8% (76/182) with placebo plus ruxolitinib. The median duration of spleen response was not reached in the combination arm vs 138.3 weeks in the placebo arm (HR, 0.692; 95% CI, 0.454-1.056).

In the intent-to-treat population, SVR35 was maintained at week 96 by 45.3% (n = 97 of 214) in the pelabresib plus ruxolitinib arm vs 30.1% (n = 65 of 216) in the placebo plus ruxolitinib arm. At week 24, the SVR35 for the respective arms were 65.9% (n = 141 of 214) and 35.2% (n = 76 of 216).

Patients in the intent-to-treat population receiving pelabresib plus ruxolitinib experienced a greater and more durable improvement in their total symptom score (TSS). The absolute change from baseline in TSS was -15.07 in the pelabresib plus ruxolitinib arm vs -12.48 in the placebo plus ruxolitinib arm (95% CI, -5.23 to 0.05). The difference in the arms was -2.59, which was greater than the -1.96 difference at week 24. A reduction in TSS from baseline of at least 50% (TSS50) was achieved by 36.9% (n = 79 of 214) of patients in the pelabresib plus ruxolitinib arm vs 28.2% (n = 61 of 216) in the placebo plus ruxolitinib arm.

The rate of achieving both a significant SVR and a significant symptom improvement was more than double in the combination therapy arm: 31.8% (68/214) of patients in the pelabresib plus ruxolitinib arm vs 15.7% (34/216) in the placebo plus ruxolitinib arm. This maintained the dual response benefit of 40.2% vs 18.5%, respectively, seen at week 24.

The pelabresib plus ruxolitinib combination demonstrated favorable effects on anemia, a common and challenging complication of myelofibrosis. In the pelabresib plus ruxolitinib arm, the hemoglobin response was 17.8% vs 11.6% in the placebo plus ruxolitinib arm. Red blood cell transfusions were required up to week 96 in 33.1% of patients in the pelabresib plus ruxolitinib arm vs 39.9% in the placebo plus ruxolitinib arm.

While the study was not statistically powered for survival end points, the longer-term follow-up showed numerically fewer deaths and progression-free survival (PFS) events in the pelabresib plus ruxolitinib arm.

In the pelabresib plus ruxolitinib arm, there were 28 deaths vs 32 in the placebo plus ruxolitinib arm (HR, 0.986; 95% CI, 0.590–1.647). In the pelabresib plus ruxolitinib arm the number of PFS events was 22 vs 34 in the placebo plus ruxolitinib arm (HR, 0.746; 95% CI, 0.432–1.291).

Bone marrow fibrosis was improved in 52.5% of evaluable patients with pelabresib plus ruxolitinib vs 27.5% with placebo plus ruxolitinib, and there were also greater reductions in bone marrow morphology seen with the combination. Similar reductions in variable allele frequency of 

“The week 96 results from the phase 3 MANIFEST-2 trial of pelabresib and ruxolitinib vs placebo and ruxolitinib constitute the longest follow-up to date of a randomized combination trial in JAK inhibitor-naive patients with [MF],” Raajit Rampal, MD, PhD, the director of the Center for Hematologic Malignancies and the director of the Myeloproliferative Neoplasms Program at Memorial Sloan Kettering Center in New York, New York, said during the presentation.

In patients who were evaluable at week 96, combination therapy was associated with SVR35 in 91.5% of patients (97/106) vs 57.5% (65/113) with ruxolitinib plus placebo.

At week 24, the SVR35 was 82.9% (141/170) with the combination vs 41.8% (76/182) with placebo plus ruxolitinib.

The median duration of spleen response was not reached in the combination arm vs 138.3 weeks in the placebo arm (HR, 0.692; 95% CI, 0.454-1.056).

The long-term safety profile of pelabresib plus ruxolitinib was comparable to that of placebo plus ruxolitinib. Treatment-emergent adverse events (TEAEs) were mainly low-grade and remained similar between the arms over the follow-up period.

Any-grade TEAEs occurred in 99.5% of patients in the pelabresib plus ruxolitinib arm vs 98.1% in the placebo plus ruxolitinib arm. Grade 3 or higher TEAEs occurred in 67.5% of patients in the pelabresib plus ruxolitinib arm vs 70.1% in the placebo plus ruxolitinib arm.

Externally and independently adjudicated cases of leukemic transformation were reported in both arms. The frequency was noted to be in line with what is historically seen in myelofibrosis, and an early imbalance between the arms decreased over time (5.1% vs 3.7%).

What was the design of the MANIFEST-2 trial?

The MANIFEST-2 study is a double-blind, randomized, phase 3 trial designed to assess the efficacy and safety of combining pelabresib with ruxolitinib in patients with myelofibrosis who have not previously been treated with a JAK inhibitor.

Standard-of-care treatment with JAK inhibitor monotherapy improves splenomegaly and symptom burden but provides responses of limited depth and durability. There is a significant need for new combination strategies that can address the underlying biology of the disease and improve long-term clinical outcomes.

Patients were randomized on a 1:1 basis to receive either pelabresib or a placebo once daily, in combination with ruxolitinib administered twice daily.

The data cut off for this analysis was March 2, 2025, with a median follow-up period of 115.9 weeks.

At the cut off, approximately half of the patients in both arms remained on their assigned treatment (48.6% in the pelabresib plus ruxolitinib arm vs 48.1% in the placebo plus ruxolitinib arm). A total of 56.5% of patients in the pelabresib plus ruxolitinib arm and 59.3% in the placebo plus ruxolitinib arm completed 96 weeks of the assigned treatment.

The most common reasons for treatment discontinuation included AEs (21.0% vs 13.4%), physician decision (7.5% vs 14.8%), withdrawal of consent (10.3% vs 6.0%), and protocol-defined disease progression (5.1% vs 6.9%).

The findings strongly suggest that the pelabresib plus ruxolitinib combination provides clinically meaningful benefits over the standard of care for JAK inhibitor–naive patients with myelofibrosis.

Rampal R, Mascarenhas J, Grosicki S, et al. Durable efficacy and long-term safety with pelabresib plus ruxolitinib in JAK inhibitor-naive myelofibrosis: 96-week results from the phase III MANIFEST-2 study. 

. 2025;146(suppl 1):910. doi:10.1182/blood-2025-910

Pelabresib combined with ruxolitinib shows superior efficacy over ruxolitinib alone in JAK inhibitor-naive myelofibrosis patients, as demonstrated in the phase 3 MANIFEST-2 trial. The combination therapy resulted in significant and sustained improvements in spleen volume reduction, symptom score, and anemia management. The safety profile was comparable to ruxolitinib monotherapy, with mainly low-grade adverse events. The trial design involved a double-blind, randomized approach, highlighting the need for new combination strategies to enhance clinical outcomes in myelofibrosis. The findings suggest meaningful benefits of the combination therapy over standard care.

Pelabresib plus ruxolitinib improved primary and secondary efficacy end points vs ruxolitinib alone in JAK inhibitor-naive myelofibrosis.

Pelabresib Plus Ruxolitinib Bests Ruxolitinib Monotherapy in JAK Inhibitor-Naive Myelofibrosis

Teclistamab plus daratumumab in R/R Myeloma | Image Credit: 

Teclistamab-cqyv (Tecvayli) plus daratumumab and hyaluronidase-fihj 

 significantly improved overall survival (OS) and progression-free survival (PFS) vs standard daratumumab-based regimens in patients with 

multiple myeloma who had received 1 to 3 prior lines of therapy, according to findings from the phase 3 MajesTEC-3 trial (NCT05083169) presented at the 

The 36-month OS rate was 83.3% with the bispecific BCMA-directed CD3 T-cell engager teclistamab plus subcutaneous daratumumab (Tec-Dara) vs 65.0% with patients receiving investigator’s choice of subcutaneous daratumumab plus dexamethasone and either pomalidomide (DPd) or bortezomib (DVd).

Tec-Dara reduced the risk of death by 54% vs DPd/DVd (HR, 0.46; 95% CI, 0.32-0.65; 

At a median follow-up of 34.5 months, the median PFS had not been reached with Tec-Dara vs 18.1 months with DPd/DVd, translating to an 83% reduction in the risk of disease progression or death (HR, 0.17; 95% CI, 0.12-0.23; 

 <.0001). The 36-month PFS rates were 83.4% vs 29.7%, respectively.

The depth of response was also greater with Tec-Dara. The median duration of response was not yet evaluable for Tec-Dara compared with 23.5 months with DPd/DVd. Further, 81.8% of patients receiving Tec-Dara achieved a complete response or better compared with 31.1% of patients treated with DPd/DVd (

 <.0001). Among evaluable patients, the MRD negativity rate (10-5) was 89.3% vs 63.0%, respectively (

“MajesTEC-3 showed unprecedented efficacy, supporting a new second line and later standard of care with broad potential across academic and community settings,” said lead study author María-Victoria Mateos, MD, PhD, Hospital Universitario de Salamanca, Salamanca, Spain.

What were the safety data from the trial?

Teclistamab plus daratumumab demonstrated statistically siginificant improvements in both PFS and OS.

Teclistamab plus daratumumab achieved lower rates of discontinuation compared with daratumumab-based regimens.

The combination achieved deeper responses in patients compared with daratumumab-based regimens.

The safety profile for Tec-Dara showed that all cases of cytokine release syndrome were grade 1 (44.2%) or grade 2 (15.9%) and all cases were resolved.

The rate of immune effector cell-associated neurotoxicity syndrome was low with Tec-Dara at 1.1%. The most common hematologic adverse event (AE) with Tec-Dara was any grade neutropenia at 78.4% vs 82.8% with DPd/DVd. The most common nonhematologic AEs were infections, which occurred at grade 3/4 rates of 54.1% vs 43.4% in the Tec-Dara vs control arms, respectively.

Mateos noted that the rates of infections were much higher with Tec-Dara vs the control arm during the first 6 months; however, “beyond month 6, the incidence [of infections] was comparable, and what’s especially important is that the overall incidence of infection declined over time.”

Explaining the reason for the decrease in infections over time, Mateos said, “The study was initiated before the approval of teclistamab, when we did not yet have any peer-reviewed guidelines for the management of patients with bispecific monoclonal antibodies. When we observed this rate of infections, especially during the first 6 months, the trial protocol was amended and it was reinforced that investigators should use immunoglobulin replacement therapy and antimicrobial prophylaxis.”

At the time of the study analysis, 71% of patients remained on Tec-Dara. Fewer patients discontinued Tec-Dara at 4.6% vs 5.5% who discontinued DPd/DVd in the control arm. Fewer patients died in the Tec-Dara arm at 15.9% vs 33.1%, respectively.

The phase 3 MajesTEC-3 trial enrolled patients with R/R multiple myeloma who had received 1 to 3 prior lines of therapy including a proteosome inhibitor and lenalidomide (Revlimid). Patients who had received only 1 prior line had to be lenalidomide refractory per IMWG criteria, and all patients had to have an ECOG performance status of 0 to 2. Patients were not eligible to enroll if they had previously received BCMA-directed therapy or if they were refractory to anti-CD38 monoclonal antibodies.

Overall, 587 patients were randomized from October 22, 2021, to September 29, 2023. The median patient age was 65 years (range, 25-88) and the median number of prior lines of therapy was 2 (range, 1-3). There were 291 patients randomized to Tec-Dara and 296 patients randomized to DPd (n = 269) or DVd (n = 27).

Following the approved step-up dose schedule, patients in the experimental arm received teclistamab at 1.5 mg/kg weekly in cycles 1 and 2 followed by 3 mg/kg every 2 weeks in cycles 3 to 6 and 3 mg/kg every 4 weeks in cycle 7 onward. The cycles were 28 days. Subcutaneous daratumumab was administered at 1800 mg every week for cycles 1 and 2, every 2 weeks for cycles 3 to 6, and every 4 weeks for cycles 7 onward. In the control arm, patients received investigator’s choice of DPd or DVd according to the approved schedules of the regimens. 

Commenting on the Tec-Dara regimen, Mateo said, “It's important to note that the combination of teclistamab plus daratumumab is a subcutaneous administration with a convenient monthly dosing after cycle 6, and the combination is free of steroids after cycle 1 day 8, and [this is all] extremely important from the patient perspective.”

The primary end point was PFS per IRC. Secondary end points included OS, response, MRD negativity, symptom score/quality of life, safety, and pharmacokinetics/immunogenicity.

Teclistamab is currently approved by the FDA for the treatment of adult patients with R/R multiple myeloma who have received at least 4 prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody.

Mateos M-V, Bahlis N, Perrot A, et al. Phase 3 randomized study of teclistamab plus daratumumab versus investigator’s choice of daratumumab and dexamethasone with either pomalidomide or Bortezomib (DPd/DVd) in patients (Pts) with relapsed refractory multiple myeloma (RRMM): Results of majestec-3. Blood. 2025;146(suppl 2): LBA-6. doi:10.1182/blood-2025-LBA-6

FDA approves teclistimab-cqyv for relapsed or refractory multiple myeloma. FDA. Published online October 25, 2022. Accessed December 8, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-teclistamab-cqyv-relapsed-or-refractory-multiple-myeloma

Teclistamab-cqyv combined with daratumumab and hyaluronidase-fihj significantly improved overall and progression-free survival in relapsed/refractory multiple myeloma patients compared to standard daratumumab-based regimens. The MajesTEC-3 trial demonstrated a 54% reduction in mortality risk and an 83% reduction in disease progression risk with the Tec-Dara regimen. The safety profile was manageable, with most adverse events being mild to moderate. The trial design included patients with 1-3 prior therapy lines, and the regimen offered a convenient dosing schedule, enhancing patient compliance and quality of life.

Teclistamab/daratumumab improved survival outcomes and led to deep MRD-negative responses vs daratumumab-based regimens in relapsed/refractory myeloma.

Teclistamab Plus Daratumumab Yields OS, PFS Benefit in R/R Multiple Myeloma

The novel CD19-targeted CAR T-cell therapy GLPG5101 generated responses and displayed a manageable safety profile in patients with relapsed/refractory (R/R) non-Hodgkin lymphoma (NHL), including mantle cell lymphoma (MCL), according to findings from the phase 1/2 ATALANTA-1 trial (NCT06561425).

Results from the MCL cohort were presented at the 

 by Marie Jose Kersten, MD, PhD, professor of hematology at Amsterdam UMC, on December 7, 2025.

The therapy showed high and durable antitumor activity across the studied NHL subtypes. In the R/R MCL patient cohort (n = 24), at 9.1 months’ median follow-up, all the patients achieved an overall response, and the complete response (CR) rate was 95.8%.

The therapy is distinguished by its use of a fresh, stem-like, early memory T-cell phenotype and a rapid, decentralized manufacturing platform that enables a 7-day vein-to-vein time.

Efficacy was evaluated in 42 patients who had reached the first response assessment. The objective response rate (ORR) was 88% (n = 37/42).

 The CR rate was 83% (n = 35/42). Of 11 responding patients in phase 1 of the study, 10 had an ongoing response at the data cutoff and 1 patient completed the study while in CR. In phase 2 of the study, all 21 patients had an ongoing response at the data cutoff. Of the total patients, 4 (3 with diffuse large B-cell lymphoma [DLBCL] and 1 with MCL) experienced progression after achieving an initial response.

GLPG5101 demonstrated robust expansion in the body across all tested dose levels and disease indications. Persistent CAR T-cells were detected in peripheral blood for up to 21 months post-infusion, indicating long-term durability.

Minimal residual disease (MRD) negativity in plasma was achieved in 12 of 15 (80%) evaluable patients who had achieved a CR. Crucially, all 11 MRD-negative patients with a minimum of 6 months follow-up remained in ongoing CR at the time of data cutoff, linking deep molecular remission to durable clinical benefit.

In the R/R MCL cohort, 90% (n = 9/10) of MRD-evaluable patients were MRD-negative at CR. Additionally, 7 of the 9 MRD-negative patients remained in CR at the time of the data cutoff.

GLPG5101 produced responses and had a manageable safety profile in R/R NHL, including MCL.

At a median follow-up of 9.1 months, the ORR in the MCL cohort was 100%, including a CR rate of 95.8%.

GLPG5101 previously received FDA regenerative medicine advanced therapy designation for MCL.

GLPG5101 demonstrated a manageable safety profile with low incidence of high-grade toxicities in the MCL cohort. The reported data reflects treatment-emergent adverse effects (TEAEs) reported up to 14 weeks post-infusion.

In phases 1 and 2, any grade cytokine release syndrome (CRS) occurred in 9 vs 10 patients. Grade 3 or higher CRS occurred in 1 vs 0 patients. Any grade immune effector cell–associated neurotoxicity syndrome (ICANS) occurred in 6 vs 4 patients, and grade 3 or higher ICANS occurred in 0 vs 1 patients.

The most frequently reported TEAEs of grade 3 or higher were hematologic. Out of 49 infused patients, 2 died during the treatment period, and 1 died during follow-up.

This is an ongoing phase 1/2 study designed to evaluate the safety and efficacy of GLPG5101.

The primary objectives of phases 1 and 2 are to establish the safety, determine the recommended phase 2 dose, and to evaluate the efficacy of GLPG5101. The secondary objectives are to assess manufacturing feasibility, further safety parameters, and additional efficacy metrics such as duration of response and MRD.

The ATALANTA-1 trial enrolled heavily pretreated adult patients with various subtypes of R/R NHL. Patients had a median of 2 prior systemic therapies. Eligible indications included DLBCL, MCL, follicular lymphoma, marginal zone lymphoma, Burkitt lymphoma, and primary central nervous system lymphoma.

In the MCL cohort, the median age of patients in phase 1 was 66.5 years (range, 25–78), and 67 years (range, 40–81) in phase 2. The median range of prior therapies between both phases was 2.5 (range, 1–7) vs 3 (range, 2–11). The majority of patients had received prior Bruton tyrosine kinase inhibitor.

As of the data cutoff, 53 patients had undergone leukapheresis, 49 received an infusion, and 47 of the 49 patients received fresh product. In the R/R MCL cohort, 25 patients received CAR T-cell infusion, with 24 patients receiving fresh product.

A 7-day vein-to-vein time was successfully achieved in 43 of the 47 patients (91%) who received the fresh product. In the R/R MCL cohort specifically, 23 of 24 patients achieved a 7-day vein-to-vein time. Short vein-to-vein time eliminated the need for cytotoxic bridging therapy for all patients who received a fresh product.

The final product demonstrated significant enrichment of desired T-cell phenotypes compared to the starting material. The proportion of early T-cell phenotypes (naive/stem cell memory and central memory) was significantly increased in both CD4+ and CD8+ CAR T cells. A median increase in the CD4:CD8 ratio of CAR+ T cells was observed in the final product.

In August 2025, GLPG5101 received a regenerative medicine advanced therapy designation in MCL from the FDA based on preliminary clinical data.

The interim results from the ATALANTA-1 study provide strong evidence for the potential of GLPG5101 as a novel CAR T-cell therapy for R/R NHL. The rapid, 7-day vein-to-vein manufacturing time is a significant logistical advantage that can accelerate access to treatment for patients with urgent clinical needs.

“In conclusion, in the ATALANTA-1 study, we saw deep and durable responses in patients with MCL, including patients with high-risk features, of course with relatively short follow-up,” concluded Kersten during the presentation.

 “And we saw…a 96% CR in patients with high-risk disease and a duration of response at 9 months of 83%. We have a very favorable safety profile, no grade 3 or higher CRS and only 1 patient with grade 3 ICANS. We would feel very comfortable even in [patients with MCL] to deliver this therapy on an outpatient basis…All in all, we think this product should be further developed.”

Kersten M, Vermaat J, Mutsaers P, et al. High complete response rates and minimal residual disease (MRD) negativity, with durable responses, in high-risk mantle cell lymphoma (MCL) with GLPG5101, a fresh, early memory-enriched CAR T-cell therapy with a 7-day vein-to-vein time: Results from the ATALANTA-1 MCL cohort. Presented at: 2025 ASH Annual Meeting; December 7, 2025; Orlando, Florida. Abstract 662.

Kersten M, Saevels K, Willems E, et al. ATALANTA-1: A phase 1/2 trial of GLPG5101, a fresh, stem-like, early memory CD19 CAR T-cell therapy with a 7-day vein-to-vein time, for the treatment of relapsed/refractory non-Hodgkin lymphoma. 

. 2024;144(suppl 1):93. doi:10.1182/blood-2024-205360.

GLPG5101, a novel CD19-targeted CAR T-cell therapy, has shown promising results in patients with relapsed/refractory non-Hodgkin lymphoma, including mantle cell lymphoma, as demonstrated in the ATALANTA-1 trial. The therapy achieved high overall and complete response rates, with durable antitumor activity and manageable safety profile. The rapid 7-day vein-to-vein manufacturing process is a significant advantage, eliminating the need for bridging therapy. The study highlights the potential of GLPG5101 as an effective treatment option, particularly for high-risk patients, with favorable safety outcomes.

GLPG5101 produced responses and had a manageable safety profile in relapsed/refractory non-Hodgkin lymphoma, including mantle cell lymphoma.

GLPG5101 Produces Responses With Manageable Safety in R/R NHL, MCL

Saruparib plus an ARPI in metastatic prostate cancer:

Saruparib in combination with an androgen receptor pathway inhibitor (ARPI) was safe and effective for the treatment of patients with metastatic prostate cancer, according to data from the phase 1/2 PETRANHA trial (NCT05367440).

Data from the efficacy-evaluable population presented during the 

 showed that objective response rates were 88.5% (23/26) in patients with metastatic castration-sensitive prostate cancer (mCSPC), 25% (2/8) in patients with metastatic castration-resistant prostate cancer (mCRPC) who had prior ARPI, and 73.3% (11/15) in patients with ARPI-naive mCRPC. Rates of prostate specific antigen (PSA) reduction >90% were 100%, 5.6%, and 53.3% in the 3 groups, respectively, and rates of undetectable PSA (<0.2 ng/mL), were 83.3%, 5.3%, and 29.0%, respectively.

“Saruparib plus ARPI has promising safety and preliminary efficacy in patients with mCSPC and ARPI-naïve mCRPC,” first study author Arun A. Azad, MBBS, FRACP, PhD, Department of Oncology, Peter MacCallum Cancer Centre, Melbourne, Australia, said when presenting the data at ESMO. “Exploratory analyses demonstrated PSA responses in pts irrespective of whether their tumor harbored an HRRm or not,” added Azad.

What was the safety profile of saruparib?

Across the overall population, the median duration of exposure to saruparib was 12.8 months (range, 0.2-28.2). The median duration of saruparib exposure among patients with mCSPC, mCRPC and prior ARPI, and ARPI-naive mCRPC was 17.8 months (range, 0.2-28.2), 5.5 months (range, 1.2-17.7), and 14.7 months (range, 0.3-24.8), respectively. The median exposure to ARPI in these 3 groups was 19.7 months (range, 0.2-28.2), 5.5 months (range, 1.1-17.7), and 15.7 months (range, 0.4-24.8), respectively.

Among the mCSPC, prior ARPI mCRPC, and ARPI-naive mCRPC groups, any grade adverse events (AEs) occurred at rates of 96.3%, 94.7%, and 100%, respectively. AEs specifically related to saruparib occurred at rates of 85.2%, 84.2%, and 90.3%, respectively. Grade ≥3 AEs were experienced by 51.9%, 31.6%, and 51.6% of the 3 groups, respectively, and serious AEs were reported in 14.8%, 21.1%, 32.3% of patients, respectively.

Across the entire population, AEs led to saruparib discontinuation in 10.4% of patients. AE-related discontinuation of saruparib and ARPI occurred in 11.1% and 3.7% of mCSPC patients, respectively, 5.3% and 5.3% of prior-ARPI mCRPC patients, and 12.9% and 3.2% of ARPI-naive mCRPC patients. AE-related dose reductions of saruparib and ARPI occurred in 29.6% and 0% of mCSPC patients, respectively, 26.3% and 21.1% of prior-ARPI mCRPC patients, and 35.5% and 12.9% of ARPI-naïve mCRPC patients.

Lastly, AE-related treatment interruption of saruparib and ARPI occurred in 51.9% and 44.4% of mCSPC patients, respectively, 36.8% and 31.6% of prior-ARPI mCRPC patients, and 67.7% and 51.6% of ARPI-naïve mCRPC patients.

What was the study design and rationale for the PETRANHA trial?

The rationale for the phase 1/2 PETRANHA trial was to explore the potential of improving upon the established metastatic prostate cancer treatment of combination therapy with a PARP inhibitor and ARPI for selected patients with mCRPC. The researchers were specifically evaluating whether combining a PARP1-selective inhibitor, such as saruparib, could enhance efficacy and safety outcomes compared with the standard approach of combining a non-selective PARP inhibitor with ARPI.

The study design had patients assigned by investigator choice to 1 of 4 treatment arms defined by the ARPI used. Patients in the analysis presented at ESMO received 60 mg of saruparib once daily combined with enzalutamide (Xtandi) at 160 mg once daily (Arm 1; n = 18), abiraterone acetate (Zytiga) at 1000 mg once daily plus 5 mg of prednisone once daily (Arm 2; n = 23), or darolutamide (Nubeqa; n = 36) at 600 mg twice daily (Arm 3). Data from arm 4 of the study, in which patients are receiving saruparib at the same dose plus apalutamide (Erleada) at 240 mg once daily, were not available for this analysis.

All treatment is being administered until disease progression or intolerable toxicity. The primary end points are safety and tolerability, with efficacy outcomes being the secondary end points.

What were the patient characteristics of the PETRANHA trial?

At the data cutoff of October 28, 2024, the phase 1/2 PETRANHA trial included 77 patients with metastatic prostate cancer. Of these patients, 65% (n = 50) had mCRPC and 35% (n = 27) had mCSPC. A little over one-third (n = 19) of the mCRPC population had previously received ARPI and about two-thirds (n = 31) were ARPI-naive. Across the whole population, 20.8% (n = 16) had tumors harboring a homologous recombination repair mutation.

What are the next steps with saruparib in metastatic prostate cancer?

The ongoing, double-blinded, randomized phase 3 EvoPAR-PR01 trial (NCT06120491) is comparing saruparib vs placebo, both given in combination with physician’s choice of ARPI in patients with mCSPC.

 The study will explore this comparison in both populations of patients with HRR mutations (550 patient target) and those without mutations (1250 patient target). The primary outcome measure is radiographic progression-free survival (PFS) and key secondary outcomes measures are overall survival, PFS2, and symptomatic skeletal event–free survival.

Saruparib combined with an androgen receptor pathway inhibitor (ARPI) demonstrated safety and efficacy in treating metastatic prostate cancer, as shown in the phase 1/2 PETRANHA trial. The trial reported high objective response rates in patients with metastatic castration-sensitive prostate cancer (mCSPC) and ARPI-naive metastatic castration-resistant prostate cancer (mCRPC). Adverse events were common but manageable, with some leading to treatment discontinuation. The trial's design aimed to improve outcomes by using a PARP1-selective inhibitor. Future research will further explore saruparib's efficacy in a phase 3 trial.

Saruparib plus an androgen receptor pathway inhibitor was safe and active in metastatic prostate cancer.

Paige Britt