Jason M Broderick

Padcev plus Keytruda showed promising clinical activity in UTUC lesions, with a 35% ORR in measurable lesions and an 87.5% disease control rate in primary tumors.

Among patients with upper tract urothelial carcinoma (UTUC) lesions, the combination of Padcev (enfortumab vedotin) and Keytruda (pembrolizumab) resulted in promising clinical activity, study results have shown.

Results from a small retrospective analysis were shared in a poster at the 2025 ASCO Genitourinary Cancers Symposium.

The study, conducted by a team of researchers from the Johns Hopkins Departments of Medical Oncology and Urology, showed that in primary lesions for 16 patients treated with Padcev alone or Padcev plus Keytruda, the overall response rate (ORR) was 25% (four patients), consisting of all partial responses. Primary lesions for an additional 10 patients showed stable disease, for a disease control rate of 87.5% (14 patients). Two patients had progressive disease.

Among all patients with measurable target lesions at baseline (20 patients) the ORR was 35% (seven patients), consisting of all partial responses. An additional seven patients had stable disease for a disease control rate of 70% (14 patients). Six patients had progressive disease.

Overall response rate: Patients in a clinical trial who responded partially or completely to treatment.

In describing the rationale for their retrospective study, the authors explained that patients with UTUC are often ineligible for standard perioperative care with cisplatin due to renal dysfunction related to disease and surgery. They added that, “Given the unprecedented activity of [Padcev] plus [Keytruda] [previously demonstrated] in advanced urothelial carcinoma, and safety in impaired renal function, the assessment of this combination in earlier disease settings for patients with UTUC is an urgent need.”

For their analysis, the researchers included patients with intact primary UTUC tumors who had received single-agent Padcev or Padcev plus Keytruda at Johns Hopkins. They collected baseline patient characteristics through chart review. The study parameters defined primary tumor as any lesion located in the ureter and/or renal pelvis.

The researchers identified 50 patients with UTUC treated with Padcev alone or Padcev plus Keytruda at Johns Hopkins between December 2017 and June 2024. Of these patients, 22 had intact primary tumors and were thus included in the retrospective analysis. Baseline characteristics showed that the median patient age was 72 years, 59% (13 patients) were male, and 77.3% (17 patients) were White. Tumor analysis showed that 86.4% of patients (19 patients) had pure urothelial histology and 81.8% of patients (18 patients) had visceral metastases.

Of the 22 patients with intact primary tumors, 59.1% (13 patients) received Padcev alone and 40.9% (nine patients) received Padcev plus Keytruda. Three patients began their Padcev regimen at a reduced dose. The median number of Padcev cycles received was four. The median treatment duration was 3.3 months.

The combination of Padcev and Keytruda is currently approved by the FDA for the treatment of adult patients with locally advanced or metastatic urothelial cancer.

In their conclusion, the researchers wrote, “Larger prospective studies are needed to assess the efficacy of this promising regimen in the perioperative setting for patients with this rare and aggressive disease.”

Primary tumor response to enfortumab vedotin with/without pembrolizumab in patients with upper tract urothelial cancer, by Dr. Evangelia Vlachou, et al., 

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Articles

A retrospective analysis of patients with upper tract urothelial carcinoma (UTUC) treated with Padcev (enfortumab vedotin) and Keytruda (pembrolizumab) demonstrated promising clinical activity. The study, conducted by Johns Hopkins researchers, revealed a 25% overall response rate (ORR) in primary lesions and a 35% ORR in measurable target lesions. The disease control rate was 87.5% for primary lesions and 70% for target lesions. The study highlights the potential of this combination therapy for patients ineligible for standard cisplatin-based care due to renal dysfunction.

Results from a small retrospective analysis of patients with upper tract urothelial carcinoma lesions were shared at the 2025 ASCO Genitourinary Cancers Symposium.

Padcev Plus Keytruda Shows Promise for Upper Tract Urothelial Carcinoma Lesions

Talzenna plus Xtandi improved overall survival in HRR-deficient mCRPC by 14 months and reduced death risk by 38%, per TALAPRO-2 trial data.

Among patients with metastatic castration-resistant prostate cancer (mCRPC), new final overall survival (OS) data from the TALAPRO-2 trial confirm that the combination of Talzenna (talazoparib) plus Xtandi (enzalutamide) provides a significant survival benefit, according to findings presented at the 

The trial demonstrated an 8.8-month improvement in median OS, with the combination therapy extending survival to 45.8 months compared with 37 months with Xtandi alone, representing a 20.4% reduction in the risk of death.

Patients with homologous recombination repair (HRR)-deficient tumors had an even greater 38% reduction in the risk of death, translating to a 14-month OS improvement. In this group, the median OS with Talzenna plus Xtandi was 45.1 months and 31.1 months in the placebo and Xtandi arm. However, the benefit extended beyond patients who were HRR-deficient, as those without DNA repair mutations also saw an OS gain of approximately nine months.

“TALAPRO-2 is the first PARP inhibitor plus [androgen receptor pathway inhibitor (ARPI)] combination study to show not only a statistically significant, but also a clinically meaningful improvement in overall survival in patients with metastatic CRPC in unselected and in HRR-deficient [patients],” Dr. Neeraj Agarwal, FASCO, professor of medicine, Presidential Endowed Chair of Cancer Research, director, the Genitourinary Oncology Program, the Center of Investigational Therapeutics, the Huntsman Cancer Institute (HCI), University of Utah.

ECOG performance status of 1 or lower: patients are fully active (0) or restricted in strenuous activity but ambulatory and able to perform light work (1).

Overall survival (OS): time from treatment initiation to death from any cause.

Metastasis: spread of cancer from the primary site to distant organs.

Castration-resistant: prostate cancer that progresses despite androgen deprivation therapy.

HRR-deficient: tumors with homologous recombination repair gene mutations, affecting DNA repair.

PARP inhibitor plus androgen receptor pathway inhibitor (ARPI): combination therapy targeting DNA repair and androgen signaling in prostate cancer.

Radiographic progression-free survival (rPFS): time until radiographic disease progression or death.

Looking at OS in subgroups of patients with no alterations detected by both circulating tumor DNA and tumor tissue, those with no BRCA alterations detected had a median OS of 48.4 months in the Talzenna and Xtandi arm and 37.1 months in the placebo and Xtandi arm. For those with no HRR alterations detected, the median OS in the Talzenna plus Xtandi arm was 46.6 months and 37.4 months for those given placebo and Xtandi.

In patients with BRCA1/2 alterations, the median OS was not reached in the Talzenna plus Xtandi arm versus 28.5 months in the placebo plus Xtandi arm. For those with non-BRCA1/2 HRR alterations, the median OS was 42.4 versus 32.6 months.

The trial’s primary end point, radiographic progression-free survival (rPFS), also saw a substantial improvement. Patients receiving Talzenna plus Xtandi had a median rPFS of 33.1 months, compared with 19.5 months with Xtandi alone.

In the HRR-deficient cohort, patients given Talzenna plus Xtandi had a median rPFS of 30.7 months, compared with 12.3 months with Xtandi alone.

For safety, there were no new safety signals seen after an additional two years of follow-up in either patient population. While grade 3 (severe) or 4 (life-threatening) anemia was the most common side effect, occurring in 49% of patients in the unselected population and 43.4% in the HRR-deficient population, it was largely manageable with dose adjustments. Patients also reported that their quality of life was maintained, even with the extended treatment duration.

In the unselected patient population, the rate of discontinuation due to side effects was 21.6%, which was similar to that seen in the primary analysis, and 8.5% of patients discontinued Talzenna treatment due to anemia. In the HRR-deficient population, the rate of discontinuation of Talzenna due to side effects was 13.1% and 4.5% of patients discontinued treatment due to anemia.

Overall, these data support the broad use of this combination in both HRR-deficient and non-deficient populations.

“We are very encouraged, very happy with these results and also there were no safety signals seen. So, we really hope this combination makes a difference in our patients lives,” added Agarwal.

The phase 3, double-blind, placebo-controlled TALAPRO-2 trial was designed to test whether combining the PARP inhibitor Talzenna with Xtandi could provide longer-lasting disease control and improve survival outcomes in patients with HRR gene-mutated mCRPC compared with placebo plus Xtandi.

Male patients aged 18 and older were eligible to enroll in the study if they had progressive disease at study entry, an ECOG performance status of 1 or lower, and a life expectancy of at least 12 months. Those who had been previously treated with a second-generation ARPI, PARP inhibitor, cyclophosphamide or mitoxantrone for prostate cancer; clinically significant cardiovascular disease; or significant renal or hepatic dysfunction were ineligible for participation.

A total of 805 patients were randomly assigned in cohort 1 to receive Talzenna 0.5 milligrams (mg) with Xtandi 160 mg per day (402 patients) or placebo and Xtandi 160 mg per day (403 patients). Randomization was stratified by HRR gene alteration status. The study’s primary end point was rPFS.

One hundred percent of patients underwent prospective tumor tissue testing before enrollment. In this cohort, 20% of patients were found to have HRR alterations. For specific gene alterations, BRCA1, BRCA2, ATM and CDK12 mutations were evenly distributed between the treatment arms. Notably, BRCA1 and BRCA2 alterations were present in approximately 7% of patients.

In June 2023, the Xtandi combination for the treatment of HRR gene-mutant mCRPC, supported by data from TALAPRO-2. The data the FDA considered at the time showed that the combination led to a 55% reduction in the risk of disease progression or death. The median rPFS at the time was not reached with Talzenna and Xtandi versus 21.9 months with placebo plus Xtandi.

“Final overall survival (OS) with talazoparib (TALA) + enzalutamide (ENZA) as first-line (1L) treatment in patients (pts) with homologous recombination repair (HRR)-deficient metastatic castration-resistant prostate cancer (mCRPC) in the phase 3 TALAPRO-2 trial.” By Dr. Karim Fizazi, et al. 

“Final overall survival (OS) with talazoparib (TALA) + enzalutamide (ENZA) as first-line treatment in unselected patients with metastatic castration-resistant prostate cancer (mCRPC) in the phase 3 TALAPRO-2 trial,” by Dr. Neeraj Agarwal et al. 

“Talazoparib plus enzalutamide in men with first-line metastatic castration-resistant prostate cancer (TALAPRO-2): a randomised, placebo-controlled, phase 3 trial,” by Dr. Neeraj Agarwal, et al. 

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The TALAPRO-2 trial demonstrated that combining Talzenna (talazoparib) with Xtandi (enzalutamide) significantly improves overall survival (OS) in patients with metastatic castration-resistant prostate cancer (mCRPC). The combination therapy extended median OS by 8.8 months compared to Xtandi alone, with a notable 20.4% reduction in the risk of death. Patients with homologous recombination repair (HRR)-deficient tumors experienced even greater benefits. The trial also showed improved radiographic progression-free survival (rPFS) and manageable safety profiles, supporting the combination's use in both HRR-deficient and non-deficient populations.

Patients with HRR-deficient metastatic castration-resistant prostate cancer experienced a 14-month gain in OS and a 38% lower death risk with Talzenna plus Xtandi.

Talzenna Plus Xtandi May Improve Survival in mCRPC

Opdivo plus Yervoy significantly improved overall survival and response rates compared to Lenvima or Nexavar as first-line treatment for unresectable hepatocellular carcinoma.

Among patients with unresectable hepatocellular carcinoma (uHCC), the combination of Opdivo (nivolumab) and Yervoy (ipilimumab) significantly improves overall survival (OS) and offers manageable safety, according to findings from the CheckMate 9DW study, presented at the 

For overall survival (OS), the combination of Opdivo plus Yervoy showed a significant improvement in median OS compared with Lenvima (lenvatinib) or Nexavar (sorafenib) at 23.7 versus 20.6 months, respectively. Opdivo with Yervoy also demonstrated a significantly higher overall response rate (ORR) at 36% compared with the Lenvima plus Nexavar combination at 13%.

At the 24-week landmark, the median OS for patients with complete or partial responses (101 patients) was not reached, indicating superior survival outcomes versus those with stable disease (105 patients) or progressive disease (47 patients).

The risk of disease progression was 14% lower for patients with complete or partial response compared to those with progressive disease in the Opdivo plus Yervoy group. For patients with stable disease compared to those with progressive disease, the risk of disease progression was 40% lower.

Overall Survival (OS): the length of time from diagnosis or treatment initiation that a patient with cancer is still alive

Overall Response Rate (ORR): the percentage of patients whose cancer shrunk or disappeared after treatment.

Complete Response: there are no longer any detectable signs of cancer in the patient’s body.

Partial Response: treatment caused a significant decrease in tumor size, but the cancer has not completely disappeared.

Progressive Disease: the tumor is growing or spreading.

Stable Disease: the tumor is neither shrinking nor growing.

Immune-mediated hepatitis: liver inflammation caused by a dysregulation of the body’s immune system.

In both treatment groups, the ORR was associated with improved OS outcomes. The risk of disease progression was 55% lower for patients with complete or partial response compared to those with progressive disease in the Lenvima plus Nexavar group. For patients with stable disease compared to those with progressive disease, the risk of disease progression was 31% lower.

The median duration of response (DOR) for Opdivo plus Yervoy was significantly longer at 30.4 months compared with 12.9 months for Lenvima or Nexavar. The survival benefit of the Opdivo plus Yervoy combination was consistent across various subgroups, including different HCC etiologies and disease stages.

“In CheckMate 9DW, [Opdivo plus Yervoy] demonstrated clinical benefit in terms of improving OS, higher objective response rate, and higher CR rate, and also acceptable safety profile,” Dr. Masatoshi Kudo, professor and chairman, Department of Gastroenterology and Hepatology, Kindai University, Osaka, Japan, stated in the presentation.

The safety profile of Opdivo and Yervoy was consistent with prior studies, with side effects generally manageable and no new safety signals identified.

The majority of treatment-related side effects were grade 1 (mild) or 2 (moderate) and did not lead to treatment discontinuation. Though 12 patients had treatment-related deaths, most in the Opdivo and Yervoy group (9 patients) occurred in patients with severe and underlying liver disease. Disease progression was confirmed in one patient and was suspected in three additional patients.

Among side effects, immune-mediated hepatitis occurred in 2% of patients receiving Opdivo and Yervoy, while high levels of bilirubin in the blood were observed in 2% of those receiving Lenvima and Nexavar. Hypertension occurred in 2% of patients in the Opdivo plus Yervoy group and 41% of patients receiving Lenvima plus Nexavar. Bleeding events were rare (less than 1%) in the Opdivo plus Yervoy group, while nosebleeds occurred in 4% of the Lenvima plus Nexavar group.

In August 2024, the FDA accepted the supplemental biologics license application of Opdivo and Yervoy for the first-line treatment of uHCC, and a Prescription Drug User Fee Act target action date of April 21, 2025, was set.

CheckMate 9DW is a phase 3, randomized-controlled trial evaluating the combination of Opdivo, a PD-1 inhibitor, and Yervoy, a CTLA-4 inhibitor, in patients with uHCC. The trial aimed to assess the clinical benefit of Opdivo and Yervoy compared with the standard-of-care tyrosine kinase inhibitors Lenvima and Nexavar in this challenging population.

Patients were randomized to receive Opdivo plus Yervoy every three weeks for up to four cycles, followed by Opdivo every four weeks, or Lenvima daily, or Nexavar twice daily. Opdivo was administered for a maximum of two years. Treatment continued until disease progression or unacceptable toxicity.

The primary end point was OS and secondary end points were ORR, DOR, safety and time to symptom deterioration with response.

“These results support Opdivo and Yervoy as a new first-line standard of care for patients with unresectable HCC,” said Kudo.

“Nivolumab (NIVO) plus ipilimumab (IPI) versus Lenvima (LEN) or Nexavar (SOR) as first-line (1L) therapy for unresectable hepatocellular carcinoma (uHCC): CheckMate 9DW expanded analyses.” Kudo M, et al. J Clin Oncol. suppl.520

“Bristol Myers Squibb receives U.S. Food and Drug Administration sBLA acceptance for first-line treatment of unresectable hepatocellular carcinoma.” News release. Bristol Myers Squibb.

The combination of Opdivo (nivolumab) and Yervoy (ipilimumab) significantly enhances overall survival (OS) and response rates in patients with unresectable hepatocellular carcinoma (uHCC) compared to Lenvima (lenvatinib) or Nexavar (sorafenib), as demonstrated in the CheckMate 9DW study. The median duration of response was notably longer for Opdivo plus Yervoy. The safety profile was consistent with previous studies, with manageable side effects. The FDA has accepted a supplemental biologics license application for this combination as a first-line treatment for uHCC, with a decision expected in April 2025.

Opdivo plus Yervoy shows efficacy and manageable safety as first-line treatment for unresectable hepatocellular carcinoma in the CheckMate 9DW study.

Opdivo Plus Yervoy May Improve Survival and Responses in Frontline uHCC

Opdivo plus chemo in patients with advanced gastric or esophageal cancers showed improved 5-year overall survival compared to chemotherapy alone.

Among patients with advanced gastric and gastroesophageal junction (GEJ) cancer, or esophageal adenocarcinoma (EAC), treatment with first-line Opdivo (nivolumab) plus chemotherapy demonstrated deep responses and an overall survival (OS) benefit versus chemotherapy alone, according to 5-year follow-up data from the phase 3 CheckMate 649 trial.

2025 ASCO Gastrointestinal (GI) Cancers Symposium

 showed that at a minimum follow-up of 60.1 months, the median OS was 14.4 months with Opdivo plus chemotherapy versus 11.1 months with chemotherapy alone in patients with a PD-L1 combined positive score (CPS) of 5 or higher. The 5-year OS rates were 16% and 6%, respectively. OS and progression-free survival (PFS) in this subgroup were the primary end points of the trial.

Across all patients randomized to Opdivo plus chemotherapy or the control arm of chemotherapy alone, the median OS at 5 years was 13.7 months versus 11.6 months, respectively. The 5-year OS rates across all patients were 12% versus 6%, respectively.

The PFS benefit previously reported with the addition of Opdivo to chemotherapy was also maintained with longer follow-up. Among patients with a PD-L1 CPS of 5 or greater, the median PFS at 5 years was 8.3 months in the investigative arm versus 6.1 months in the control arm. Across all randomized patients, the 5-year median PFS was 7.8 months versus 6.9 months, respectively.

Median duration of response (mDOR): the length of time that a patient with a disease experiences a positive response to a treatment before their disease progresses again.

Objective response rate (ORR): patients who have a partial response or complete response to the treatment within a certain period of time.

Overall survival (OS): the average length of time patients are alive after the start of treatment.

Open label: a type of research where both the participants and researchers are aware of which treatment is being administered.

PD-L1 combined positive score (CPS): a method used in cancer pathology to assess the level of PD-L1 expression on tumor cells.

Progression-free survival (PFS): the length of time during and after treatment that a patient lives with the disease but it does not get worse.

Five-year response data highlighted the durability of the clinically meaningful activity of the Opdivo combination in this frontline setting. The objective response rate (ORR) in the CPS greater than or equal to 5 subgroup was 60% in the Opdivo plus chemo arm compared with 45% in the control arm. The median duration of response (mDOR) was 9.6 versus months 7.0 months, respectively. Among all patients, the ORR was 58% versus 46% and the mDOR was 8.5 versus 6.9 months, respectively.

There were no new safety signals observed with the extended follow-up, according to Janjigian. The most common grade 3 (severe) or 4 (life-threatening) treatment-related side effects in the Opdivo plus chemotherapy arm were neutropenia (16%), decreased neutrophil count (11%), anemia (6%) and increased lipase (6%). In the chemotherapy-alone arm, the most common grade 3 or 4 treatment-related side effects were neutropenia (13%), decreased neutrophil count (9%), diarrhea (3%), peripheral neuropathy (3%), anemia (3%) and vomiting (3%).

“To our knowledge, these results represent the longest follow-up in a phase 3 trial of a programmed death-1 inhibitor plus chemo in advanced GC, GEJC and EAC and continue to support [Opdivo] plus chemotherapy as standard first-line treatment,” said presenting author Dr. Yelena Y. Janjigian, chief of the Gastrointestinal Oncology Service at Memorial Sloan Kettering Cancer Center, in New York, New York.

In April 2021, the FDA approved Opdivo for use in combination with select types of chemotherapy in the frontline treatment of this patient population based on earlier findings from CheckMate 649.

The open-label, randomized, global phase 3 CheckMate 649 trial enrolled patients with previously untreated, unresectable, advanced or metastatic gastric cancer, GEJ or EAC. Patients had no known HER2 positivity and an ECOG performance status of 0 or 1.

Study enrollment occurred at 175 hospitals and cancer centers across 29 countries. Patients were randomized in a to one of the following treatment cohorts:

Opdivo (360 milligrams, mg) plus oxaliplatin at 130 mg per square meter (mg/m

 twice daily from days 1 to 14 (XELOX regimen) every three weeks or Opdivo at 240 mg plus oxaliplatin at 85 mg/m

 daily on days 1 and 2 (FOLFOX regimen) every two weeks (789 patients).

XELOX every three weeks or FOLFOX every two weeks (833 patients).

Opdivo at 1 mg per kilogram (kg) plus Yervoy (ipilimumab) at 3 mg/kg every three weeks for 4 cycles followed by Opdivo at 240 mg every two weeks (409 patients).

At the 2025 Symposium, Janjigian shared 5-year data for the Opdivo plus chemotherapy arm and the control arm of chemotherapy alone. Baseline characteristics between these two arms were well balanced. Across both arms, the median age was approximately 62 years, 70% of patients were male, three-quarters of patients were non-Asian and approximately 58% of patients had an ECOG performance status of 1. The primary tumor location at initial diagnosis across all patients was 70% gastric cancer, 16% GEJ and 14% EAC.

Approximately 18% of patients in each arm had signet ring cell carcinoma, 96% had metastatic disease, 40% had liver metastases and 24% had peritoneal metastases. Sixteen percent of patients in each arm had tumor cell PD-L1 expression 1% or greater and 3% had microsatellite instability high status. About 54% of patients in each arm received FOLFOX and 46% received XELOX.

The dual primary end points were OS and PFS in the subset of patients with a PD-L1 CPS of 5 or higher. Secondary end points comprised OS in those with a PD-L1 CPS of 1 or higher and the all-randomized population; OS in those with a PD-L1 CPS of 10 or higher; blinded independent central review–assessed PFS in those with a PD-L1 CPS of 10 or higher, 1 or higher and the all-randomized population; and ORR. Safety and quality of life served as the exploratory end points of the trial. The data cutoff data for the results presented was May 28, 2024.

“Nivolumab (NIVO) + chemotherapy (chemo) vs chemo as first-line (1L) treatment for advanced gastric cancer/gastroesophageal junction cancer/esophageal adenocarcinoma (GC/GEJC/EAC): 5-year (y) follow-up results from CheckMate 649.” By Dr. Janjigian Y, et al. 

The CheckMate 649 trial demonstrated that combining Opdivo (nivolumab) with chemotherapy significantly improves overall survival (OS) and progression-free survival (PFS) in patients with advanced gastric, gastroesophageal junction (GEJ) cancer, or esophageal adenocarcinoma (EAC). At a 5-year follow-up, patients with a PD-L1 combined positive score (CPS) of 5 or higher showed a median OS of 14.4 months with Opdivo plus chemotherapy, compared to 11.1 months with chemotherapy alone. The trial confirmed the combination's safety and efficacy, supporting its use as a first-line treatment.

Among patients with advanced gastric and GEJ cancer, or esophageal adenocarcinoma, treatment with first-line Opdivo and chemo demonstrated deep responses.

Jason M Broderick

Padcev Plus Keytruda Shows Promise for Upper Tract Urothelial Carcinoma Lesions

Talzenna Plus Xtandi May Improve Survival in mCRPC

Opdivo Plus Yervoy May Improve Survival and Responses in Frontline uHCC

Opdivo Plus Chemo Shows 5-Year Efficacy in Gastric, GEJ and Esophageal Cancer

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