Tony Berberabe, M.P.H.

The combination of Nubeqa (darolutamide) plus androgen deprivation therapy (ADT; reduces the amount of testosterone in the body) significantly improved radiographical progression-free survival (PFS; the length of time during and after treatment when a patient with cancer lives without the disease worsening) in patients with metastatic hormone-sensitive (still responds to hormone therapy) prostate cancer (mHSPC), according to results presented at the 2024 ESMO Congress.

Compared with ADT alone, the addition of the androgen receptor pathway inhibitor (ARPI; blocks activity of androgen receptor, a protein that aids cancer growth) Nubeqa reduced the risk of radiographical progression or death by 46% and demonstrated low safety risks in the phase 3 ARANOTE trial.

The ARANOTE trial demonstrated that adding Nubeqa to androgen deprivation therapy (ADT) significantly extended the time patients with metastatic hormone-sensitive prostate cancer lived without their disease worsening.

Compared to ADT alone, Nubeqa plus ADT reduced the risk of radiographic progression or death by 46%.

Nubeqa had a low risk of side effects, making it a promising treatment option for patients with prostate cancer.

The ARANOTE trial suggests that Nubeqa plus ADT could be a valuable treatment option for men with metastatic hormone-sensitive prostate cancer, especially for those who may not tolerate or benefit from traditional treatments.

The combination of Nubeqa and ADT outperformed ADT alone in terms of both efficacy and safety.

“[Nubeqa], ADT, plus docetaxel is already a standard of care for men with mHSPC and ARASENS shows that [Nubeqa] plus ADT plus docetaxel had a favorable efficacy and safety profile compared with ADT plus docetaxel in these patients,” explained Dr. Fred Saad, professor and chairman of urology and director of genitourinary oncology at the University of Montreal Hospital Center in Canada, in his presentation. “ARANOTE was designed to evaluate the role of [Nubeqa] [plus] ADT without docetaxel to hopefully provide a new treatment option for men with mHSPC.”

Despite the ARASENS trial establishing the efficacy of ARPI, ADT and chemotherapy, it was only compared with ADT plus docetaxel and Nubeqa plus ADT had not been compared with ADT alone, leading to the ARANOTE trial to determine if this combination can be a treatment option without chemotherapy.

A total of 669 patients were randomly assigned to receive Nubeqa 600 milligrams twice daily plus ADT (446 patients) or placebo plus ADT (223 patients). They must have had metastatic disease confirmed by conventional imaging or soft tissue/visceral metastases on CT or MRI assessed by central review and ECOG performance status of 0 (fully active), 1 (limited activity), or 2 (poor activity). They were stratified by presence or absence of visceral metastases (spreading of cancer to internal organs) and prior local therapy. The primary focus was radiographical PFS (rPFS) by central blinded review, with secondary focuses including overall survival (OS; time from the start of treatment when a patient with cancer is still alive), time to prostate-specific antigen (PSA; time it takes for PSA levels to rise after treatment) progression and safety.

Baseline characteristics and disease characteristics were broadly similar across the groups; Saad highlighted the approximately 30% of the population who were Asian and 10% who were Black, which enabled these groups to be studied more closely. In the Nubeqa group, 71.1% had de novo metastatic disease compared with 75.3% in the ADT alone group. Visceral disease was present in 11.9% and 12.1% of each respective group and 17.9% of each group had prior local therapy.

Primary and Secondary Efficacy End Points

At data cutoff of June 7, 2024, median follow-up was 25.3 months for the Nubeqa group and 25 months for the placebo group. The median rPFS for Nubeqa plus ADT was not reached, meaning less than half of patients did not show disease progression, compared with 25 months for placebo plus ADT. At 24 months, the rate of rPFS was 70.3% for the Nubeqa group versus 52.1% for the placebo group.

The rPFS benefit with Nubeqa was consistent across all analyzed subgroups. For patients with low disease volume, the hazard ratio (HR; a statistical measure comparing the risk of an event between two groups) was 0.3 compared with an HR of 0.6 for those with high-volume disease. Those with prior local therapy had an HR of 0.34 whereas those with no prior local therapy had an HR of 0.59.

Although OS was not mature and was not reached in both groups, the stratified HR was 0.81 favoring Nubeqa. Adding Nubeqa also showed a benefit across other secondary focuses including time to metastatic castration-resistant prostate cancer, time to PSA progression, time to initiation of subsequent systemic therapy and time to pain progression. It also led to 62.6% of patients with PSA less than 0.2 nanograms/milliliter at any time during treatment, compared with only 18.5% in the placebo group.

The median treatment duration was 24.2 months in the Nubeqa group compared with 17.3 months for the placebo group. Incidence of treatment-emergent adverse events (TEAEs; treatment induced side effects) was similar between the groups, with 91% any-grade and 30.8% grade 3 (severe) or 4 (life threatening) TEAEs with Nubeqa plus ADT and 90% any-grade and 30.3% grade 3 or 4 with ADT plus placebo. There was a rate of 4.7% grade 5 (fatal) TEAEs in the Nubeqa group versus 5.4% for the placebo group. Serious TEAEs occurred at a rate of 23.6% in the Nubeqa group versus 23.5% in the placebo group and 6.1% discontinued treatment due to TEAEs in the Nubeqa group, a lower rate than the 9% in the placebo group.

When looking at TEAEs associated with ARPIs in particular, they were similar across the groups. Fatigue, mental impairment disorder, hypertension, cardiac arrythmias, coronary artery disorders, heart failure, falls, bone fracture, vasodilation (the widening of blood vessels) and flushing, diabetes and hyperglycemia, and rash all occurred in fewer than 10% of patients in either group and exposure-adjusted incidence rate per 100 patient years was also similar in the Nubeqa and placebo groups.

“[Nubeqa] and ADT significantly improved rPFS in patients with mHSPC, showed a benefit across all secondary endpoints, [and] had a favorable safety profile, confirming previous studies using [Nubeqa],” said Saad. “We believe that Nubeqa and ADT, without the need of docetaxel, could become an additional standard of care for mHSPC.”

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Articles

Adding Nubeqa to androgen deprivation therapy improved radiographic progression-free survival in patients with metastatic hormone-sensitive prostate cancer.

Nubeqa Plus ADT Outperformed ADT Alone in Treating Prostate Cancer

Patients with high-risk muscle-invasive urothelial carcinoma (MIUC) who underwent radical surgery experienced notable improvements in disease-free survival (DFS, the time a patient lives without signs of cancer) when treated with adjuvant (postsurgical) Keytruda (pembrolizumab) when compared with patients who underwent observation after a 45-month follow-up, study findings have shown.

Findings from the phase 3 AMBASSADOR trial were presented during the 2024 ESMO Annual Congress by Dr. Andrea B, Apolo, a senior investigator in the Genitourinary Malignancies Branch of the National Cancer Institute in Bethesda, Maryland.

Adjuvant Keytruda significantly extended disease-free survival (DFS) in patients with high-risk muscle-invasive urothelial carcinoma (MIUC) compared to observation.

The benefit of Keytruda was observed regardless of PD-L1 expression and lymph node status, suggesting its potential effectiveness for a wide range of patients.

Patients with lower tract MIUC, primarily bladder cancer, demonstrated a more significant improvement in DFS with Keytruda compared to those with upper tract disease.

While the final analysis of overall survival is pending, interim data suggest a potential benefit of Keytruda in extending the lives of patients with high-risk MIUC.

The study reported manageable toxicity associated with Keytruda, making it a promising treatment option for patients with MIUC.

Urothelial carcinoma, as defined by the National Cancer Institute, begins in the urothelial cells lining the urethra, bladder, ureters, renal pelvis and other organs, and almost all bladder cancers are urothelial carcinomas.

“In this setting, [Keytruda] doubled the median DFS at 29.6 months compared with 14.2 months in the observation arm,” Apolo said during a presentation of the data in the intention-to-treat population that was published in 

A total of 702 enrolled patients were randomly assigned to receive 200 milligrams of Keytruda every three weeks (354 patients) versus observation (348 patients) with dual primary end points of DFS and overall survival (OS, the time a patient lives regardless of disease status). Across both cohorts, the median age was 68 years, and the majority of patients were men (74.6%).

In the Keytruda arm, 57.3% of patients were PD-L1 positive compared with 57.8% of patients in the observation arm. In the Keytruda arm, the primary tumor sites were bladder (75.4%), upper tract (22.9%) and urethra (1.7%) compared with the observation arm: 75.6%, 21% and 3.4%, respectively.

When evaluating subgroups, Apolo noted that DFS in patients who were PD-L1 positive showed a benefit in terms of prognosis. “The marker was prognostic, but not predictive because both arms, PD-L1–positive and –negative, benefited from adjuvant [Keytruda],” Apolo added.

Turning to DFS for primary tumor sites in the upper and lower tract, investigators reported small numbers, “so it is hard to draw conclusions from these cohorts,” Apolo said. Exploratory DFS subgroups were also evaluated and included an evaluation of lymph node status (if the cancer has spread to the lymph nodes), upper tract neoadjuvant therapy, ECOG performance status (evaluating a patient’s ability to perform daily tasks) and histologic variants.

In all patients with N0 stage disease (cancer has not spread to the lymph nodes, with higher numbers indicating increasing spread to the lymph nodes), the hazard ratio (HR) for DFS was 0.53, meaning there was a 47% likelihood the disease would return compared with the observation group. In N1, the HR was 0.81, and for patients with N2/N3 stage disease, the HR was 0.71. “This was prognostic, but adjuvant Keytruda benefited all groups including N0 and N1, and N2 and N3,” she continued.

Evaluation of lymph node stage by lower tract versus upper tract demonstrated that “patients with disease present in the lower tract, which were predominantly bladder patients, showed benefit from adjuvant [Keytruda], regardless of N0 or N-plus status,” Apolo said. “Looking at patients with upper tract disease, we noted that the [DFS] numbers are very small and the data are inconclusive,” Apolo continued.

The investigators reported that the most common sites of metastatic disease occurrence (702 patients) were abdominal lymph nodes (40%), pelvic lymph nodes (30%), bone (22%), chest/neck lymph nodes (20%) and liver (18%). Apolo noted that these recurrence sites were “interesting and hypothesis-generating.”

In the primary analysis of the AMBASSADOR study, Keytruda showed a significant improvement in DFS versus observation after a 22-month follow-up.

DA approval of Opdivo (nivolumab) in high-risk MIUC after surgery

. At that point, 34% of patients in the observation arm and 20% of patients in the Keytruda arm had received a non-protocol checkpoint inhibitor or withdrew consent. “The interim OS had been presented, although the final analysis of OS had not been performed because only 8% of events had been reached,” Apolo said.

Apolo concluded the presentation noting that subgroup analysis showed a DFS benefit with Keytruda versus observation regardless of PD-L1 expression and lymph node status.

“Based on the doubling of the median DFS and the previously presented manageable toxicity, this trial supports adjuvant [Keytruda] as a therapeutic option in patients with high-risk MIUC,” Apolo said.

Among patients with high-risk muscle-invasive urothelial carcinoma, postsurgical Keytruda extended the time some lived without signs of cancer.

Keytruda Improves Disease-Free Survival in Some With Urothelial Carcinoma

Minimal residual disease may offer treatment insights for patients with AML.

After patients with acute monocytic leukemia (AML) undergo induction chemotherapy (treatment with the goal of killing all or most cancer cells to induce remission), molecular minimal residual disease (MRD) assessments (tests for malignant cells remaining in the patient’s body following treatment) may be helpful in determining which patients have NPM1-mutated disease. This distinction can guide treatment decisions — especially in those with FLT3 internal tandem duplication (ITD), according to data presented at the 2023 

American Society of Hematology Annual Meeting

Of note, at first remission, the role of allogeneic stem cell transplant (ASCT) in NPM1-mutated AML remains controversial as there is significant variation in practice.

Historically, the benefit of ASCT was observed in patients with NPM1-mutated AML in the presence of FLT3 ITD; however, with the increased understanding of MRD and its improvement on survival, the need to identify the primary determinant of benefit has grown. Although ASCT can benefit patients with AML, research suggests that patients with favorable risk generally do better with chemotherapy and that the risks and adverse events from ASCT outweigh the benefits in these patients. Alternatively, in patients who are at adverse risk with AML generally do poorly with chemotherapy and are likely to benefit from transplant.

“In general, an allogeneic transplant is offered in first remission to patients with AML who have an adverse risk. It is not offered in favorable risk,” lead author Dr. Jad Othman, of Guy’s and St Thomas’ NHS Foundation Trust in London, said in a presentation of the data. “The question of (offering transplant) in intermediate risk has always been one that has been controversial.”

To determine if patients who were MRD-positive had improved survival when they received an ASCT compared with patients who were MRD-negative, data were compared from two large United Kingdom studies, AML17 and AML19. A total of 737 patients who achieved complete remission, meaning that there was no remaining detectable disease, and had a valid MRD result were evaluated. In AML17, 17% of patients were MRD-positive and 21% in AML19 were MRD-positive. Overall, ASCT was performed in 20% of patients in AML17 and 25% of patients in AML19.

“Importantly, the selection of patients for transplant in the two studies were very different,” Othman said. “In AML17, patients were selected based on a validated risk score, as determined by age, sex, secondary disease, cytogenetics, white cell count and response after one course of chemotherapy.” In AML19, patients underwent ASCT only if they were MRD-positive in the peripheral blood after chemotherapy cycle 2.

Time-to-event variables were analyzed using the Kaplan-Meier method, and the impact of ASCT was assessed using Cox regression and visualized with Simon-Makuch plots, said Othman.

It had been previously reported in AML17 that patients who were MRD-positive had poor outcomes with a three-year cumulative incidence of relapse (CIR) rate of 84% and a three-year overall survival (OS; percentage of patients who are still alive) rate of 25%.In AML19, the three-year CIR was 50% and 3-year OS rate of 51%.

A significant survival advantage was observed in patients who had detectable MRD after the first two courses of chemotherapy if they received a transplant in their first remission compared with patients who were MRD-negative after chemotherapy.

“Those patients who were MRD-negative after chemotherapy did not derive any survival advantage from having a transplant in their first remission,” Othman said.

MRD also predicts ASCT benefit in patients with NPM1-mutated AML and FLT3 ITD, which has traditionally been considered to be a strong indication for transplant, Othman said. In this patient population, patients who were MRD-positive benefited from ASCT versus no ASCT compared with patients who were MRD-negative.

“This held true even if it was limited to those patients with a high allelic ratio for FLT3 ITD,” Othman said. In other subgroups, the investigators “weren’t able to identify any MRD-negative population in whom a transplant and chemotherapy provided a survival advantage,” Othman added.

Based on this analysis, the investigators concluded that MRD after induction chemotherapy identifies patients with NPM1-mutated AML who benefit from ASCT in first remission. Further, after second induction, patients who were MRD-negative show no benefit from transplant, even with FLT3 ITD co-mutation.

Molecular minimal residual disease status may offer clues as to which patients with acute monocytic leukemia will benefit from certain therapies. 

MRD Status Can Help Guide Treatments in NPM1-Mutated AML

Findings from the phase 3 EMRALD trial showed that all relevant subgroups of patients with ER-positive/HER2-negative, 

-mutated advanced or metastatic breast cancer tended to experience improved progression-free survival (PFS; time from treatment until disease progression or death) with orserdu (elacestrant) compared to standard of care.

The study analysis — which was presented at the 2023 

 — revealed that exposure to CDK4/6 inhibitors plus estrogen therapy for at least 12 months improved PFS, suggesting that the estrogen receptor (ER) pathway could be the main driver of disease, regardless of the metastatic site or coexistence of 

“We evaluated eigh subsets, including patients with bone, liver and lung metastases, HER2-low expression and HER2-zero expression, 

 mutation,” coauthor Dr. Janice Lu, professor, Northwestern University Lurie Comprehensive Cancer Center, Chicago, Illinois, said during the presentation of data.

Patients (478) were randomly assigned to receive Orserdu (239 patients) or standard of care (239 patients) and 228 patients were identified with an 

 mutation group, 159 patients were treated with prior CDK4/6 inhibitors for 12 months, 71% had liver and or lung metastases, 39% had a 

 mutation and 48% had HER2-low expression.

 mutation, median PFS in the treatment arm was 8.61 months, compared to 1.91 months in the control arm.

In the current analysis, in patients with accompanying liver and/or lung metastases, the median PFS among patients in the Orserdu arm was 7.26 months compared with 1.87 months among patients treated with standard of care. In patients with 

 mutation, median PFS was 5.45 months compared to 1.94 months, respectively. In patients with 

 mutation, median PFS was 8.61 months vs 1.87 months, respectively. In patients with HER2-low expression, median PFS was 9.03 months vs 1.87 months, respectively.

The EMERALD trial enrolled patients with ER-positive/HER2-negative metastatic breast cancer who were previously treated with one to two lines of endocrine therapy and an CDK4/6 inhibitor. Investigators allowed for previous treatment with Faslodex (fulvestrant). In the trial, patients either received 345 mg Orserdu or investigator’s choice of Faslodex or an aromatase inhibitor.

 mutation status (detected vs not detected), prior treatment with Faslodex (yes vs no), and visceral metastasis (yes vs no). The major efficacy outcome measure was PFS, assessed by a blinded imaging review committee. A statistically significant difference in PFS was observed in the intention to treat (ITT) population and in the subgroup of patients with 

 mutations. Efficacy results from the EMERALD study led to the 

Regarding safety, most side effects, including nausea, were grade 1 and 2, and no grade 4 (severe) treatment-related side effects were reported. Investigators reported that quality of life was maintained between treatment groups and no differences were observed between all patients and patients with 

No hematologic safety signal was observed, and no patients in either treatment arm exhibited sinus bradycardia. Further, no deaths were reported as treatment-related in either arm of the trial.

The most common all-grade side effects (10% or greater) reported in patients with 

 mutation in the treatment arm were musculoskeletal pain (50%), nausea (38.5%) and fatigue (25.6%). In the control arm, the most common all grade side effects (10% or greater) were musculoskeletal pain (37.3%), nausea (14.7%) and fatigue (22.7%).

“A clinically meaningful improvement in PFS favoring (Orserdu) compared with standard of care was consistent across all relevant subgroups with 

-mutation tumors and assumed endocrine-sensitivity,” concluded Lu.


Patients with ER-positive, HER2-negative, ESR1-mutant advanced breast cancer experienced improvements in progression-free survival when being treated with Orserdu, study results showed. 

Tony Berberabe, M.P.H.

Nubeqa Plus ADT Outperformed ADT Alone in Treating Prostate Cancer

Keytruda Improves Disease-Free Survival in Some With Urothelial Carcinoma

MRD Status Can Help Guide Treatments in NPM1-Mutated AML

Orserdu Boosts PFS in ESR1-Mutated Metastatic Breast Cancer Subgroups

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