The combination of pembrolizumab (Keytruda) plus axitinib (Inlyta) continued to improve overall survival (OS), progression-free survival (PFS), and overall response rate (ORR) over sunitinib (Sutent) monotherapy in patients with treatment-naïve clear cell renal cell carcinoma (ccRCC), according to data from a 5-year analysis of the phase 3 KEYNOTE-426 trial (NCT02853331) presented at the 2023 ASCO Annual Meeting.

At a median follow-up of 67.2 months (range, 60-75), the median PFS in the intention-to-treat (ITT) population who received the doublet (n = 432) was 15.7 months (95% CI, 13.6-20.2) vs 11.1 months (95% CI, 8.9-12.5) with the monotherapy (n = 429), translating to a 31% reduction in the risk of disease progression or death (HR, 0.69; 95% CI, 0.59-0.81). The 60-month PFS rates were 18.3% vs 7.3%, respectively.

Moreover, the median OS with pembrolizumab plus axitinib was 47.2 months (95% CI, 43.6-54.8) vs 40.8 months (95% CI, 34.3-47.5) with sunitinib alone, translating to a 16% reduction in the risk of death (HR, 0.84; 95% CI, 0.71-0.99). The 60-month OS rates in the investigative and control arms were 41.9% and 37.1%, respectively.

The doublet induced an ORR of 60.6% in the ITT population, which was comprised of a complete response (CR) rate of 11.6%, a partial response (PR) rate of 49.1%, and a stable disease (SD) rate of 22.7%; 11.6% of patients experienced disease progression. In the sunitinib arm, the ORR was 39.6%, with a 4.0% CR rate, a 35.7% PR rate, and a 35.7% SD rate; in this group, 17.0% had progressive disease. The duration of response (DOR) with the doublet was 23.6 months (range, 1.4+ to 68.6+) vs 15.3 months (range, 2.3-68.3) with the monotherapy, with 26.0% and 14.4% of patients, respectively, remaining in response at 60 months.

“[These improvements with the combination] are observed despite the high percentage of subsequent therapy [received] in both arms, but especially in the sunitinib arm,” Brian I. Rini, MD, lead study author and professor of medicine in the Division of Hematology Oncology at Vanderbilt University Medical Center, said in a presentation of the data. “There was a substantial percentage of patients who made it to that 2-year mark, who completed 35 cycles of pembrolizumab, and they have very good long-term outcomes as you might expect. These data continue to support pembrolizumab plus axitinib as a standard of care for [this population].”

Patients with newly diagnosed or recurrent stage IV ccRCC were enrolled to KEYNOTE-426. To be eligible for enrollment, patients could not have received prior systemic treatment for advanced disease, and they needed to have measurable disease by RECIST v1.1 criteria.

A total of 861 patients were randomly assigned 1:1 to receive intravenous pembrolizumab at 200 mg every 3 weeks for up to 35 cycles plus oral axitinib at a twice-daily dose of 5 mg (n = 432) or oral sunitinib at a once-daily dose of 50 mg for the first 4 weeks of every 6-week cycle (n = 429). Key stratification factors included International Metastatic RCC Database Consortium (IMDC) risk group (favorable vs intermediate vs poor) and geographic region (North America vs Western Europe vs rest of world).

The co-primary end points for the pivotal trial were PFS by RECIST v1.1 criteria and OS in the ITT population. Important secondary end points included ORR by RECIST v1.1 criteria and blinded independent central review (BICR) in the ITT population. Other end points of interest comprised DOR by BICR and RECIST v1.1 criteria, as well as safety.

Data from the first interim analysis, which had a median follow-up of 12.8 months, showed significant improvements with the doublet over the monotherapy with regard to PFS, OS, and ORR. The median PFS was 15.1 months vs 11.1 months in the investigative and control arms, respectively (HR, 0.69; 95% CI, 0.57-0.84; 

 < .001). The median OS had not yet been reached in either arm (HR, 0.53; 95% CI, 0.38-0.74; 

 < .0001). The doublet induced an ORR of 59.3% vs 35.7% with the monotherapy (

 < .001). These data supported the April 2019 FDA approval of the doublet for use as frontline treatment in patients with advanced RCC.

With extended follow-up, a median follow-up of 42.8 months, pembrolizumab plus axitinib continued to provide PFS and OS benefits over sunitinib monotherapy, with hazard ratios (HRs) of 0.71 and 0.68, respectively.

 Data from the protocol-specified final analysis, which had a median follow-up of 42.8 months, showed HRs of 0.68 and 0.73 for PFS and OS, respectively.

At the 2023 ASCO Annual Meeting, Rini presented efficacy in all patients randomly assigned to treatment.1Notably, there was no formal hypothesis testing “because statistical significance for all the end points was met at that very first analysis,” he explained.

At the time of the data cutoff date, which was January 23, 2023, 7.0% of those on the investigative arm were still receiving treatment vs 4.5% of those on the control arm. In the pembrolizumab/axitinib arm, 88.8% of patients had discontinued treatment due to radiographic disease progression (n = 227), toxicity (n = 92), clinical disease progression (n = 14), physician decision (n = 14), and CR (n = 9), among other reasons.

Baseline characteristics were as previously published and presented. “They’re very representative of an advanced clear cell population, with a median age in the early sixties and predominantly male,” Rini said. “Accrual was about one-quarter North America, one-quarter Western Europe, and half the rest of the world. About 30% of patients [had] favorable[-risk disease] by IMDC criteria, about 12% had sarcomatoid features, and just over 80% had undergone prior nephrectomy.”

Additional data showed that in those with favorable-risk disease, the median OS in the investigative arm was 60.3 months (95% CI, 49.6-not evaluable [NE]) vs 62.4 months (95% CI, 54.1-NE; HR, 1.10; 95% CI, 0.79-1.54). The 60-month OS rates were 50.0% and 52.2%, respectively. “There’s a PFS advantage to the combination therapy for favorable-risk patients,” Rini noted. The median PFS with the doublet was 20.7 months (95% CI, 15.2-28.9) vs 17.9 months (95% CI, 12.5-20.7) with the monotherapy (HR, 0.76; 95% CI, 0.57-1.02), with 60-month PFS rates of 19.3% and 8.0%, respectively. “Response rates are high in both arms but continue to favor pembrolizumab plus axitinib,” he added. The doublet elicited an ORR of 68.8%, with a CR rate of 13.0%. With sunitinib, the ORR was 50.4%. with a CR rate of 6.1% in this group.

In those with intermediate- or poor-risk disease, “there was a strong OS signal,” Rini said. The median OS with pembrolizumab plus axitinib was 42.2 months (95% CI, 36.5-47.9) vs 29.3 months (95% CI, 23.7-34.3) with sunitinib (HR, 0.76; 95% CI, 0.62-0.93). The 60-month OS rates were 38.0% and 30.4%, respectively. The median PFS “favored pembrolizumab plus axitinib,” he added, at 13.8 months (95% CI, 12.3-18.0) and 8.3 months (95% CI, 6.6-10.0), respectively (HR, 0.68; 95% CI, 0.56-0.82). The 60-month PFS rates were 17.9% and 7.1%, respectively. The ORRs in the investigative and control arms were 56.8% and 34.9%, respectively, with CR rates of 10.9% and 3.0%, respectively.

Rini also shared findings from an ad-hoc, hypothesis-generating analysis that was conducted for OS utilizing the 2-stage estimation method to assess the potential impact of subsequent anticancer therapy on survival.

“The vast majority of patients have discontinued treatment, at nearly 90% and 95% in the arms, respectively,” Rini said. “As you would expect in kidney cancer with multiple available regimens, most of these patients will receive subsequent anticancer therapy.”

In the doublet arm, 62.2% of patients went on to receive subsequent treatment, which included a PD-1/PD-L1 inhibitor (26.6%) or a VEGF/VEGFR inhibitor (86.9%). In this group, 99.6% received at least 1 subsequent line of therapy, 50.2% received at least 2 lines, and 25.3% received 3 or more subsequent lines. In the monotherapy arm, 73.9% of patients received subsequent treatment, with 80% receiving a PD-1/PD-L1 agent and 72.0% receiving a VEGF/VEFGR inhibitor. In this arm, all patients received at least 1 line of subsequent treatment, 57.3% received at least 2 lines, and 31.3% received 3 or more lines. “[This] reflects the field of kidney cancer with active drugs, and I think, in part, [accounts] for the prolonged survivals that are seeing in this and other trials,” Rini noted.

In the analysis of OS adjusted by subsequent therapy using the 2-stage estimation method, the median OS with pembrolizumab plus axitinib was 38.8 months (95% CI, 34.6-43.6) vs 25.3 months (95% CI, 22.5-28.6) with axitinib (adjusted HR, 0.67; 95% CI, 0.52-0.84).

Additionally, PFS, OS, and ORR was evaluated for all patients who completed 35 cycles, or 2 years, of pembrolizumab. Rini referred to this effort as the completer analysis, which looked at 120 patients (27.8% of the total population) who completed treatment.

The median age in this group was 61.5 years (range, 30-89), and 72.5% were male. Regarding IMDC risk category, 37.5% had favorable risk and the remainder had intermediate or poor risk. Moreover, 14.2% of patients had sarcomatoid features, and 61.7% had at least 2 metastatic sites. The majority (87.5%) underwent prior nephrectomy.

“Not surprisingly, these patients had somewhat more favorable features [than the ITT population],” Rini noted. “Largely, a higher percentage of patients had IMDC favorable-risk [disease]; a higher percentage of patients had sarcomatoid features, which would be favorable in the context of getting immunotherapy; a lower percentage had 2 metastatic sites…and a slightly higher percentage had prior nephrectomy.”

In the completer group, the ORR with treatment with the doublet was 85.0%, with a CR rate of 18.3% and a PR rate of 66.7%. The median OS was not yet reached (95% CI, 70.6-not reached), and the 36- and 60-month OS rates were 94.2% and 70.7%, respectively. Lastly, the median PFS was 37.4 months (95% CI, 32.3-43.7); the 36- and 60-month PFS rates were 55.2% and 32.8%, respectively.

Editor’s Note: Dr Rini disclosed that he has leadership relationships with MashupMD and MJH Life Sciences and stock ownership in PTC Therapeutics. He also has consulting or advisory roles for Alkermes, Aravive, Arrowhead Pharmaceuticals, Athenex, AVEO, Bristol-Myers Squibb, Corvus Pharmaceuticals, Debiopharm Group, Eisai, EUSA Pharma, Genentech, HiberCell, Merck, NiKang Therapeutics, Pfizer, and Surface Oncology. Research funding was received from ADC Therapeutics, Adela, Aravive, Arcus Biosciences, Arrowhead Pharmaceuticals, AstraZeneca/MedImmune, AVEO, Bristol-Myers Squibb, Daiichi Sankyo/UCB Japan, Dracen, Dragonfly Therapeutics, Exelixis, Gilead Sciences, HiberCell, Incyte, Janssen, Merck, Pionyr, Point Therapeutics, Roche/Genentech, Seagen, Stata, Surface Oncology, and Vasgene Therapeutics. Travel expenses were paid by Bristol-Myers Squibb, Merck, and Pfizer.

Rini BI, Plimack ER, Stus V, et al. Pembrolizumab plus axitinib versus sunitinib as first-line therapy for advanced clear cell renal cell carcinoma. 

. 2023;41(suppl 17):LBA4501. doi:10.1200/JCO.2023.41.17_suppl.LBA4501

FDA approves pembrolizumab plus axitinib for advanced renal cell carcinoma. FDA. April 19, 2019. Accessed June 5, 2023. 

https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-pembrolizumab-plus-axitinib-advanced-renal-cell-carcinoma

Powles T, Plimack ER, Soulières D, et al. Pembrolizumab plus axitinib versus sunitinib monotherapy as first-line treatment of advanced renal cell carcinoma (KEYNOTE-426): extended follow-up from a randomised, open-label, phase 3 trial. 

. 2020;31(12):1563-1573. doi:10.1016/S1470-2045(20)30436-8

Rini BI, Plimack ER, Stus V, et al. Pembrolizumab (pembro) plus axitinib (axi) versus sunitinib as first-line therapy for advanced renal cell carcinoma (ccRCC): results from 42-month follow-up of KEYNOTE-426. 

. 2021;39(suppl 15):4500. doi:10.1200/JCO.2021.39.15_suppl.4500

Articles

The combination of pembrolizumab plus axitinib continued to improve overall survival, progression-free survival, and overall response rate over sunitinib monotherapy in patients with treatment-naïve clear cell renal cell carcinoma.

Long-Term KEYNOTE-426 Data Continue to Support Frontline Pembrolizumab Plus Axitinib as SOC for Advanced ccRCC

The addition of atezolizumab (Tecentriq) to cabozantinib (Cabometyx) did not improve progression-free survival (PFS) or overall survival (OS) compared with cabozantinib alone in patients with advanced renal cell carcinoma (RCC) who previously received treatment with an immune checkpoint inhibitor (ICI), missing the primary end points of the phase 3 CONTACT-03 trial (NCT04338269) that was presented during the 2023 ASCO Annual Meeting.

Results showed that through central review, the median PFS with the combination was 10.6 months (95% CI, 9.8-12.3) compared with 10.8 months (95% CI, 10.0-12.5) with cabozantinib alone (HR, 1.03; 95% CI, 0.83-1.28; 

 = .784). The 12-month PFS rates were 44% (95% CI, 38%-50%) and 48% (95% CI, 42%-54%, respectively).

An interim analysis of OS showed a similar trend; the median OS was 25.7 months (95% CI, 25.1-not evaluable [NE]) with the doublet vs NE (95% CI, 21.1-NE) with the monotherapy (HR, 0.94%; 95% CI, 0.70-1.27; 

“The addition of atezolizumab to cabozantinib did not result in improved clinical outcomes in patients with mRCC who progressed on or after prior ICI treatment,” said Toni K. Choueiri, MD, who is the lead study author, director of the Lank Center for Genitourinary Oncology, and medical director of International Strategic Initiatives, at Dana-Farber Cancer Institute, as well as the Jerome and Nancy Kohlberg Professor of Medicine at Harvard Medical School, in an oral presentation of the findings. “These data in my opinion, and the opinion of the investigators, highlight the importance of randomized, prospective assessment of re-challenge with checkpoint inhibitors in RCC and potentially in other tumor types.”

The use of ICIs in the frontline setting has led to questions surrounding sequencing for the second-line setting, Choueiri explained. Cabozantinib, among other VEGFR TKIs, have demonstrated activity in previously treated patients with ICI-based regimens.

 Rechallenge of PD-1/PD-L1 inhibitors following initial disease progression is becoming an emerging practice in mRCC therapy but this has not been studied in a phase 3 setting.

To assess this practice, investigators launched the phase 3 CONTACT-03 trial, which compared atezolizumab plus cabozantinib with cabozantinib alone in patients with metastatic or advanced clear cell or non–clear cell RCC with or without a sarcomatoid component who had radiographic progression on or after a prior ICI. The immunotherapy must have been given in the immediately preceding line of therapy and could have been given in the adjuvant, first-, or second-line setting as a single agent or for use in combination with another permitted agent.

A total of 522 patients were randomly assigned 1:1 to receive atezolizumab at 1200 mg intravenously (IV) every 3 weeks with cabozantinib at 60 mg daily orally or cabozantinib alone.

Stratification factors included International Metastatic RCC Database Consortium (IMDC) risk group (0 vs 1 to 2 vs 3 or higher), histology (dominant clear cell without sarcomatoid vs dominant non–clear cell without sarcomatoid vs any sarcomatoid), and the most recent line of ICI (adjuvant vs frontline vs second line).

The coprimary end points were independent centrally assessed PFS, and OS. Key secondary end points were investigator-assessed PFS, objective response rate (ORR) both per central review and via investigator, duration of response (DOR) via central review and investigator, and safety.

Regarding baseline characteristics, the median age was 62.5 years (18-89), and 76.9% of patients were male. Most patients were White (82.8%), while 10.7% and 6.6% were Asian and other, respectively. The most recent line of ICI therapy was given in the frontline locally advanced or metastatic setting (52.9%), followed by the second-line setting (46.4%), and in the adjuvant setting (0.4%).

Most patients had dominant clear cell RCC without sarcomatoid histology (78.0%) vs non–clear cell without sarcomatoid (11.7%) and any sarcomatoid (10.2%). A total 62.3% of patients had an IMDC score of 1 to 2 vs 22.6% with a score of 0 and 14.8% with a score of 3 or greater. Patients previously received 0 (36.1%), 1 (62.3%), or 2 prior VEGR TKIs (1.7%).

The most common frontline treatment was nivolumab (Opdivo) plus ipilimumab (Yervoy; 28.8%), followed by sunitinib (Sutent; 28.7%), pazopanib (Votrient; 15.2%), axitinib (Inlyta) plus pembrolizumab (Keytruda; 12.3%), nivolumab (3.1%), avelumab (Bavencio) plus axitinib (2.5%), bempegaldesleukin (Bempeg) plus nivolumab (2.3%), lenvatinib (Lenvima) plus pembrolizumab (1.8%), and sorafenib (Nexavar; 0.8%).

The most common second-line treatment was nivolumab (90.1%), nivolumab plus ipilimumab (2.9%), and axitinib plus pembrolizumab (2.1%). Sunitinib was the sole adjuvant treatment (37.5%).

The lack of PFS difference between the 2 arms was seen across most prespecified subgroups. Although there was a benefit with the combination seen in patients who had a complete or partial response to their prior ICI (HR, 0.76; 95% CI, 0.40-1.43), this was not significant as the confidence interval crossed 1.

The confirmed ORRs via RECIST 1.1 criteria and per central review were 40.5% (95% CI, 34.5%-46.8%) with the combination and 40.9% (95% CI, 34.8%-47.3%) with cabozantinib alone; the complete response (CR) rates were 0% and 2%, respectively. The partial response (PR), stable disease (SD), progressive disease (PD), and not evaluable/missing rates were 40.5% vs 40.2%, 50.6% vs 47.6%, 4.2% vs 5.1%, and 4.6% vs 6.3%, respectively.

At the data cutoff, 50.5% in the combination arm were still responding to treatment vs 52.9% of those in the monotherapy arm. The median DOR was 12.7 months (range, 2.1+ to 22.9+) and 14.8 months (range, 2.3+ to 25.6+), respectively.

When evaluated via investigator review, the ORRs were 38.0% (95% CI, 32.1%-44.2%) with the combination and 41.7% (95% CI, 35.6%-48.0%) with cabozantinib alone; the complete response (CR) rates were 1.5% and 0.8%, respectively. The PR, SD, PD, and not evaluable/missing rates were 36.5% vs 40.9%, 48.3% vs 46.3%, 9.1% vs 6.6%, and 4.6% vs 5.4%, respectively. At the data cutoff, 58.0% of patients who received the combination were still responding to treatment vs 44.4% of those who received cabozantinib alone. The median DOR was NE (range, 2.1+ to 23.2+) and 12.2 months (range, 2.1+ to 25.6+), respectively.

The most common subsequent systemic anticancer treatment was a TKI/VEGF inhibitor in the combination (23.2%) and cabozantinib-alone (24.7%) arms, followed by an mTOR inhibitor (12.9% vs 10.0%, respectively) with everolimus (Afinitor; 12.5% and 10.0%), another ICI (4.6% and 9.3%), chemotherapy (0.8%, each), and an investigational/other agent (0.4% and 1.2%).

Regarding safety, the incidence of any-grade treatment-related adverse effects (TRAEs) was similar in both arms, at 96.2% and 97.3%, respectively. However, grade 3/4 TRAEs occurred in 55.3% of those in the cabozantinib/atezolizumab arm vs 47.3% of those in the cabozantinib-alone arm; deaths due to adverse effects (AEs) occurred in 6.5% and 3.5% of patients, respectively. Three of the deaths in the combination arm were related to treatment; these TRAEs included immune-mediated enterocolitis and renal failure, which were tied to atezolizumab, and intestinal perforation, which was related to cabozantinib. Serious TRAEs occurred in 24.0% of combination-treated patients and 11.7% of those who received the monotherapy.

The most common all-grade AEs were diarrhea (65.3% with the combination vs 70.7% with cabozantinib alone), palmar-plantar erythrodysesthesia syndrome (38.5% vs 41.0%), decreased appetite (38.2% vs 37.9%), hypothyroidism (36.3% vs 37.9%), nausea (29.4% vs 35.9%), asthenia (29.4% vs 29.3%), hypertension (27.5% vs 34.0%), fatigue (27.5% vs 23.8%), increased alanine aminotransferase (23.7% vs 22.3%), increased aspartate aminotransferase (22.9% vs 23.8%), anemia (20.2% vs 18.8%), and decreased weight (17.6% vs 25.0%).

AEs resulted in treatment withdrawal for 15.6% of those on the doublet arm vs 3.9% of those on the monotherapy arm. Toxicities resulted in dose interruption of atezolizumab in 60.7% of patients. AEs resulted in interruption or reduction of cabozantinib in 89.3% of those on the combination arm vs 87.1% of those on the monotherapy arm.

 Choueiri listed the following disclosures: stock ownership and honoraria with Curesponse, Osel, Pionyr, Precede Bio, and Tempest Therapeutics; consulting or advisory roles with Alkermes, Analysis Group, Aravive, Arcus Biosciences, ASCO, AstraZeneca, Bayer, Bristol-Myers Squibb, Clinical Care Options, Eisai, EMD Serono, ESMO, Exelixis, Foundation Medicine, Gilead Sciences, GlaxoSmithKline, Harborside Press, Infinity Pharmaceuticals, Ipsen, Janssen Oncology, Kanaph Therapeutics, 

, Lilly, Merck, MJH Life Sciences, Navinata Health, NCCN, NiKang Therapeutics, Novartis, Peloton Therapeutics, Pfizer, PlatformQ Health, Precede Bio, Prometheus, Roche/Genentech, Sanofi/Aventis, Scholar Rock, Tempest Therapeutics, 

, and UpToDate; research funding from Agensys, Arcus Biosciences, AstraZeneca, AVEO, Bayer, Bristol-Myers Squibb, Calithera Biosciences, Eisai, Exelixis, GlaxoSmithKline, Ipsen, Merck, NiKang Therapeutics, Novartis, Peloton Therapeutics, Pfizer, Roche, Roche/Genentech, Seattle Genetics/Astellas, Takeda, and TRACON Pharma; patents and royalites from Biomarkers of Clinical Response and Benefit to Immune Checkpoint Inhibitor Therapy, ctDNA technologies, and PBRM1 Biomarkers Predictive of Anti-Immune Checkpoint Response; travel expenses from Alexion Pharmaceuticals, Allegiant, Analysis Group, AstraZeneca, Bayer, Bristol-Myers Squibb, Cerulean Pharma, Clinical Care Options, Corvus Pharmaceuticals, Eisai, EMD Serono, ESMO, Exelixis, Foundation Medicine, GlaxoSmithKline, Harborside Press, HERON, Ipsen, Kidney Cancer Association, 

, Lilly, Lpath, Merck, MJH Life Sciences, Navinata Health, NCCN, Novartis, Peloton Therapeutics, Pfizer, PlatformQ Health, Prometheus, Roche/Genentech, Sanofi/Aventis, 

 and UpToDate; and that medical writing and editorial assistance support may have been funded by communications companiesfunded by pharmaceutical companies such as ClinicalThinking, Health Interactions, Envision Pharma Group, Fishawack Group of Companies, and Parexel.

Choueiri TK, Albiges L, Tomczak P, et al. Efficacy and safety of atezolizumab plus cabozantinib vs cabozantinib alone after progression with prior immune checkpoint inhibitor (ICI) treatment in metastatic renal cell carcinoma (RCC): primary PFS analysis from the phase 3, randomized, open-label CONTACT-03 study. 

. 2023;41(suppl 17):LBA4500. doi:10.1200/JCO.2023.41.17_suppl.LBA4500

Atezolizumab plus cabozantinib versus cabozantinib monotherapy for patients with renal cell carcinoma after progression with previous immune checkpoint inhibitor treatment (CONTACT-03): a multicentre, randomised, open-label, phase 3 trial. 

. Published June 5, 2023. doi:10.1016/S0140-6736(23)00922-4

Choueiri TK, Escudier B, Powles T, et al. Cabozantinib versus everolimus in advanced renal cell carcinoma (METEOR): final results from a randomised, open-label, phase 3 trial. 

. 2016;17(7):917-927. doi:10.1016/S1470-2045(16)30107-3

Tannir NM, Agarwal N, Porta C, et al. Efficacy and safety of telaglenastat plus cabozantinib vs placebo plus cabozantinib in patients with advanced renal cell carcinoma: the CANTATA randomized clinical trial. 

. 2022;8(10): 1411-1418. doi:10.1001/jamaoncol.2022.3511

The addition of atezolizumab to cabozantinib did not improve progression-free survival or overall survival vs cabozantinib alone in patients with advanced renal cell carcinoma who previously received treatment with an immune checkpoint inhibitor, missing the primary end points of the phase 3 CONTACT-03 trial.

Cabozantinib/Atezolizumab Combo Misses PFS, OS End Points in ICI-Treated, Advanced RCC

The combination of enfortumab vedotin-ejfv (Padcev; EV) and pembrolizumab (Keytruda) generated responses and demonstrated a manageable safety profile in patients with locally advanced or metastatic urothelial carcinoma who were ineligible for cisplatin, according to long-term data from cohort A of the phase 1/2 EV-103 trial (NCT03288545) presented at the 2023 ASCO Annual Meeting.

“As a background, despite [gemcitabine/carboplatin] as the frontline treatment for cisplatin-ineligible patients with locally advanced and metastatic urothelial cancer, there is a significant need to further improve outcomes. Avelumab [Bavencio] maintenance is only indicated in patients who do not progress after gem/carbo, and PD-1 or PD-L1 monotherapy is only indicated in a very select group of patients,” explained first author Shilpa Gupta, MD, director of Genitourinary Medical Oncology at Taussig Cancer Institute and co-leader of the Genitourinary Oncology Program at Cleveland Clinic, Cleveland, Ohio.

The FDA approved the combination of EV and pembrolizumab in the treatment of cisplatin-ineligible locally advanced or metastatic urothelial carcinoma based on findings from EV-103 dose-escalation cohort, cohort A, and cohort K, which showed that the combination has rapid and durable responses as well as a manageable safety profile in patients with previously untreated urothelial cancer. For the present study, Gupta presented an update on the results of dose escalation/cohort A after a median follow-up of 47 months.

“Enfortumab vedotin has a multifaceted mechanism of action due to the intracellular release of MMAE, which leads to direct cytotoxicity of the nectin-4-containing cancer cells, as well as induces the hallmark of immunogenic cell death…When combined with a checkpoint inhibitor there’s believed to be a complementary activity for further immune engagement and hence pembrolizumab is a rational partner for this combination,” Gupta said.

The analysis included a total of 45 patients, who received EV, 1.25 mg/kg intravenously (IV) on days 1 and 8, and pembrolizumab, 200 mg IV on day 1 of every 3-week cycle. Primary end points included adverse events (AEs) and lab abnormalities, and key secondary end points included confirmed objective response rate (ORR), duration of response (DOR), profession-free survival, and overall survival (OS).

Most of the patients were male (36, 80.0%), and median age was 69.0 years. Nearly all the patients were Caucasian (42, 93.3%), with ECOG performance status of 0, 1, or 2 in 15 (33.3%), 22 (48.9%), and 8 (17.8%) patients, respectively. Fourteen patients (31.1%) had liver metastases, and 38 patients (84.4%) had visceral disease.

After nearly 4 years of follow-up 40% of patients remained on study. All had discontinued treatment. Median treatment duration was 7 months, and median number of treatment cycles was 9. Reason for treatment discontinuation included progressive disease in 19 patients (42.2%), AEs in 15 patients (33.3%), patient decision in 9 patients (20.0%), and physician decision or other in 1 patient each (2.2%). Death was most common reason for study discontinuation, occurring in 22 patients (48.9%).

ORR was 73.3% (95% CI, 59.1-85.4), and disease control rate was 84.4% (95% CI, 70.5-93.5). Median DOR was 22.1 months, and median OS was 26.1 months.

Any-grade AEs occurred in 43 patients (95.6%) and included peripheral sensory neuropathy (25 patients, 55.6%), fatigue (23 patients, 51.1%), alopecia (22 patients, 48.9%), diarrhea (21 patients, 46.7%), decreased appetite (18 patients, 40.0%), maculo-papular rash (16 patients, 35.6%), pruritus (15 patients, 33.3%), and dysgeusia (15 patients, 33.3%). AEs of grade 3 or higher occurred in 29 patients (64.4%) and included increased lipase (8 patients, 17.8%); maculo-papular rash in 5 patients (11.1%); fatigue in 5 patients (11.1%); neutropenia, anemia, hyperglycemia, and increased amylase in 4 patients each (8.9%); and increased transaminases in 3 patients (6.7%).

Treatment-related AEs of special interested for EV included skin reactions of any grade in 30 patients (66.7%) and grade 3 or higher in 9 patients (20.0%), as well as peripheral neuropathy in 28 patients (62.2%). The investigators noted that treatment-related AEs for EV were consistent with previously reported results.

The most common treatment-emergent AEs of special interest for pembrolizumab included severe skin reaction of any grade in 11 patients (24.4%) and grade 3 or higher in 10 patients (22.2%).

Of patients receiving subsequent cancer-related therapy(ies), the most common was systemic therapy in 22 patients (48.9%).

“In EV-103 dose escalation/cohort A, the safety profile of the combination was manageable, with no new safety concerns observed at nearly 4 years of follow-up. EV and pembrolizumab demonstrated clinically meaningful efficacy, with a high confirmed high confirmed overall response rates, durable responses and a median survival exceeding two years in this patient population,” Gupta said in her concluding remarks.

Gupta S, Rosenberg JE, McKay RR, et al. Study EV-103 dose escalation/cohort A: Long-term outcome of enfortumab vedotin + pembrolizumab in first-line (1L) cisplatin-ineligible locally advanced or metastatic urothelial carcinoma (la/mUC) with nearly 4 years of follow-up. 

. 2023;41(suppl):4505. doi:10.1200/JCO.2023.41.16_suppl.4505

The combination of enfortumab vedotin-ejfv and pembrolizumab generated rapid and durable responses and demonstrated a manageable safety profile in patients with locally advanced or metastatic urothelial carcinoma who were ineligible for cisplatin.

Enfortumab Vedotin Plus Pembrolizumab Produces Durable Responses, Safety in Metastatic Urothelial Carcinoma

Erdafitinib (Balversa) reduced the risk of death by 36% vs investigator’s choice of chemotherapy in patients with 

-altered metastatic urothelial cancer who were previously treated with anti–PD-1 therapy, according to findings from the phase 3 THOR trial (NCT03390504). The results were presented in a late-breaking abstract session during the 2023 ASCO Annual Meeting by Yohann Loriot, MD, PhD, who states that the targeted therapy should be considered the new standard of care for this patient population.

At a median follow-up of 15.9 months, the median overall survival (OS) was 12.1 months with erdafitinib (n = 136) vs 7.8 months with investigator’s choice chemotherapy (n = 130; HR, 0.64; 95% CI, 0.47-0.88; 

 = .005). Loriot explained that based on the interim analysis, the independent monitoring committee recommended to stop the study, unblind the data, and cross over patients from chemotherapy to erdafitinib.

The median progression-free survival (PFS) was 5.6 months with erdafitinib vs 2.7 months with chemotherapy, translating to a reduction in the risk of disease progression of death of 42% (HR, 0.58; 95% CI, 0.44-0.78; 

 = .0002). The overall response rate (ORR) was 45.6% with a complete response (CR) rate of 6.6% and a partial response (PR) rate of 39.0% in the erdafitinib arm. The ORR in the chemotherapy arm was 11.5% with 1 CR (0.8%) and a PR rate of 10.8%.

“The phase 3 THOR study supports the clinical efficacy of erdafitinib as the standard of care option for patients with metastatic urothelial cancer with 

 alteration after immune checkpoint inhibitor treatment,” Loriot, deputy head of Therapeutic Innovation and Early Trials Department at Gustave Roussy Institute, INSERM 981, University Paris-Saclay in France said in a presentation of the data.

“The OS benefit of erdafitinib supports molecular testing of FGFR in all patients with metastatic urothelial carcinoma,” he added.

Daniel P. Petrylak, MD, echoed that sentiment in a discussion of the abstract, citing recent findings that showed only 41% of patients between 2019 and 2021 underwent testing for 

 alterations, with only 30% of patients proceeding to erdafitinib, which he described as a disappointing number.2 “The most important take home message of the day is that all patients with metastatic urothelial carcinoma need to be tested for 

 alterations,” said Petrylak, a professor of medicine (medical oncology) and of urology and coleader of Cancer Signaling Networks at Yale Cancer Center in New Haven, Connecticut.

Erdafitinib received accelerated approval from the FDA on April 12, 2019, for the treatment of patients with metastatic or locally advanced urothelial carcinoma with susceptible 

 genetic alterations with disease progression on or following at least 1 platinum-based chemotherapy.

 The approval was based on results of phase 2 Study BLC2001 (NCT02365597); THOR was the planned study to confer benefit for regular approval.

THOR is a randomized, open-label, multicenter study, open to patients with stage IV metastatic or unresectable urothelial cancer. Patients were screened for selected 

 alterations and were assigned to 2 cohorts based on prior anti–PD-1 treatment. Those with prior anti–PD-1 therapy (cohort 1 for this analysis) were randomly assigned to erdafitinib or investigator’s choice of chemotherapy. Erdafitinib was given at a dose of 8 mg once daily, with uptitration to 9 mg once daily if serum phosphate level is 9.0 mg/dL or less and there are no associated adverse events are observed at day 14. Chemotherapy was docetaxel 75 mg/m

Treatment was continued until disease progression, intolerable toxicity, or withdrawal of consent. Assessments via CT or MRI were performed every 6 weeks for 6 months, every 12 weeks for the following 6 months, then as clinically indicated. The primary end point was OS, with secondary end points of PFS, ORR, and safety.

In the prior anti–PD-1 cohort, 33.1% of patients in the erdafitinib arm had received 1 line of prior systemic therapy, with 24.3% having received chemotherapy plus anti–PD-1 treatment, and 8.1% receiving anti–PD-1 treatment alone. In the chemotherapy arm, 25.4% of patients received 1 line of prior systemic therapy with 11.5% receiving combination treatment and 12.3% receiving an anti–PD-1 inhibitor alone.

Among patients who received 2 prior lines of systemic therapy in the erdafinib arm (66.2%), the first line of therapy was chemotherapy alone in 56.6%, chemotherapy plus anti–PD-1 in 4.4%, and other in 5.1%. These rates in patients who received chemotherapy (74.6%) were 58.5%, 7.7%. and 8.5%, respectively. Second line of therapy for patients in the erdafitinib and chemotherapy arm were anti–PD-1 alone (55.9% vs 58.5%), chemotherapy alone (7.4% vs 10.8%), and other (2.9% vs 5.4%).

Other baseline characteristics between the arms were well balanced. The median age in the erdafitinib arm was 66 years (range, 32-85), most were men (70.6%), White (59.6%), and had the presence of visceral metastases (74.3%) with 22.8% being in the liver. Nearly all patients had an ECOG performance status of 0 or 1 (91.2%).

Primary tumors were present in the upper tract for 30.1% of patients in the erdafitinib arm and 36.9% of patients in the chemotherapy arm. PD-L1 low expression (combined positive score < 10) was detected in 92.7% of patients in the erdafitinib arm (among 96 evaluable patients) and 86.1% of patients in the chemotherapy arm (among 79 evaluable patients).

 alterations, at baseline these were reported as mutations in 79.4% and 82.3%, fusions in 18.4% and 14.6%, and mutations and fusions in 1.5% and 2.3% of patients in the erdafitinib and chemotherapy arms, respectively.

Results were consistent across all subgroups and those with translocations and upper tract primary tumor location showing deriving the most benefit. Patients with 

 translocations had a median OS of 16.4 months with erdafitinib vs 8.0 months with chemotherapy (HR, 0.49; 95% CI, 0.23-1.03). Those with upper tract tumors had a median OS of 23.3 months vs 7.2 months with erdafitinib and chemotherapy, respectively (HR, 0.34; 95% CI, 0.18-0.64).1 In a question-and-answer session, Loriot noted that thedifference noticed in patients with upper tract location vs the bladder may be attributed to mutations and biologic components, but no conclusive data were available at this time.

In terms of safety, in the erdafitinib safety cohort (n = 135), 45.9% of patients had at least 1 treatment-related adverse effect (TRAE) of grade 3 or 4. The most common TRAEs of any-grade or grade 3/4 in this arm were hyperphosphatemia (78.5% and 5.2%), diarrhea (54.8% and 3.0%), stomatitis (45.9% and 8.1%), dry mouth (38.5% and 0%), palmar-plantar erythrodysesthesia (30.4% and 9.6%), and onycholysis (23.0% and 5.9%).

In the chemotherapy arm (n = 112), 46.4% of patients experienced a TRAE of grade 3 or 4. The most common any-grade and grade 3/4 events were anemia (27.7% and 6.3%), alopecia (21.4% and 0%), nausea (19.6% and 1.8%), neutropenia (18.8% and 13.4%), leukopenia (11.6% and 8.0%), and febrile neutropenia (8.0% and 8.9%).

Treatment discontinuation rates were 8.1% and 13.4% in the erdafitinib and chemotherapy arms, respectively. Serious AEs were reported in 13.3% of patients in the erdafitinib arm and 1 treatment-related death occurred and was cited by investigators as being sudden death. AEs in the erdafitinib arm were mostly manageable with dose modifications and supportive care. In the chemotherapy arm, 24.1% of patients had serious AEs and 6 treatment-related deaths occurred and were because of febrile bone marrow aplasia (n = 2), febrile neutropenia (n = 1), septic shock (n = 2), and atypical pneumonia (n = 1).

AEs of interest included nail disorders, skin disorders, eye disorders (excluding central serous retinopathy), and central serous retinopathy alone. These occurred as any-grade events in the erdafitinib arm at rates of 66.7%, 54.8%, 42.2%, and 17.0%, respectively. Grade 3/4 events were reported in 11.1%, 11.9%, 2.2%, and 2.2%, respectively. None of these events were reported at grade 3/4 in the chemotherapy arm but occurred at grade 1/2 as follows: nail disorders (5.4%), skin disorders (12.5%), eye disorders (5.4%).

Petrylak noted that future studies are needed to develop rational sequencing of eradfitnib, enfortumab vedotin-ejfv (Padcev), and sacituzumab govitecan-hziy (Trodelvy) in the third-line setting, but for now decisions should be made based on toxicity.

Loriot Y, Matsubara N, Park SH, et al. Phase 3 THOR study: results of erdafitinib (erda) versus chemotherapy (chemo) in patients (pts) with advanced or metastatic urothelial cancer (mUC) with select fibroblast growth factor receptor alterations (

Mingaonkar V, Hubbard RA, Carpenter EL, Mamtani R. Biomarker testing, treatment uptake, and survival among patients with urothelial cancer receiving gene-targeted therapy. 

. 2022;8(7):1070-1072. doi:10.1001/jamaoncol.2022.1167

FDA grants accelerated approval to erdafitinib for metastatic urothelial carcinoma. FDA. April 12, 2019. Accessed June 5, 2023. 

https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-erdafitinib-metastatic-urothelial-carcinoma

Ongoing | cancer accelerated approvals. FDA. Updated May 22, 2023. Accessed June 5, 2023. 

https://www.fda.gov/drugs/resources-information-approved-drugs/ongoing-cancer-accelerated-approvals

Erdafitinib reduced the risk of death by 36% vs investigator’s choice of chemotherapy in patients with FGFR2/3-altered metastatic urothelial cancer who were previously treated with anti–PD-1 therapy, according to findings from the phase 3 THOR trial.

Erdafitinib Confers OS Benefit in FGFR-Altered Urothelial Cancer

The combination of talazoparib (Talzenna) and enzalutamide (Xtandi) resulted in a statistically significant and clinically meaningful improvement in radiographic progression-free survival (rPFS) when used as a first-line therapy for patients with metastatic castration-resistant prostate cancer (mCRPC) harboring homologous recombination repair (HRR) gene alterations, according to data from the phase 3 TALAPRO-2 study (NCT03395197) presented at the 2023 ASCO Annual Meeting.

Data from the randomized, double blind, phase 3 trial were simultaneously published in 

 This was the first phase 3 study to compare the combination of the poly(ADP-ribose) polymerase inhibitor talazoparib and androgen receptor enzalutamide compared with placebo and enzalutamide.

The TALAPRO-2 study reached its primary end point of radiographic PFS (rPFS) with a 55% reduced risk of progression of death in patients on the combination arm (n = 200), even though median rPFS was not reached (NR) in the talazoparib arm (95% CI, 21.9-NR) compared with 13.8 months (95% CI, 11.0-16.7) in the placebo arm (HR, 0.45; 95% CI, 0.33-0.61, 

 < 0.0001). Moreover, the combination resulted in a 37% lower risk of rPFS in the combination arm compared with the placebo and enzalutamide arm (HR, 0.63; 95% CI 0.51–0.78; 

According to Karim Fizazi, MD, who presented these data at the ASCO meeting, rPFS benefit extended to all subgroups of HRR deficient patients on the trial (HR, 0.44; 95% CI, 0.32-0.60, 

 < 0.0001), but importantly also for patients who had a 

 alteration in their disease. Overall, patients with 

 alterations in general had a greater benefit in the talazoparib and enzalutamide arm (HR, 0.20; 95% CI, 0.11-0.36, P < 0.0001) compared with patients with non-

 alterations on the combination as well (HR, 0.68; 95% CI, 0.46-1.02; P = 0.060). Patients with a 

 alteration had an approximately 80% reduction in risk of death and disease progression compared to patients with non-

In the baseline of patients on the trial, those with a 

 alteration in their disease made up 31% of patients in the combination arm compared with 36.7% in the placebo arm, whereas patients with a 

 1 alteration made up 5.5% and 6%, respectively. HRR deficient patients with only a 

 alteration (n = 55) in the combination arm still had a significant rPFS compared to the 

 patients (n = 60) on the placebo arm (HR, 0.19; 95% CI, 0.10-0.38, 

 < 0.0001). Similar results were seen with patients who had only a 

 alteration (HR, 0.17; 95% CI, 0.02-1.51, 

 = 0.074) and significant rPFS benefit was seen in patients with a 

cluster in their disease (HR, 0.20; 95% CI, 0.11-0.36, 

“I think it’s [also] important to mention that men who had prior abiraterone, or docetaxel for castration sensitive disease, tend to benefit quite the same as compared to those who did not receive these agents, with a hazard ratio of approximately .45,” Fizazi added, a medical oncologist at Gustave Roussy and professor of oncology at the University of Paris-Saclay.

Patients given prior abiraterone or docetaxel made up 37.5% of patients in the combination arm compared with a similar rate in the placebo arm at 37.2%. More patients in the combination arm and placebo arm had just docetaxel vs abiraterone at 8% vs 30.2% and 8% vs 28.5%, respectively. Overall, most patients disease was in the bone in both arms at 87.5% in the talazoparib arm and 79.4% in the placebo arm, with a similar median range of prostate specific antigen (PSA) at 19.6 ng/mL (range, 0.2-3412.0) in the talzoparib arm compared with 18.0 ng/mL (range, 0.0-1055.0) in the placebo and enzalutamide arm.

The combination of talzoparib with first-line enzalutamide also prolonged the time to PSA progression for these mCRPC patients, which according to Fizazi, was a dramatic improvement of approximately 40% reduction of risk between both arms. A median of 28.6 months (95% CI, 26.7-NR) time to PSA progression in the treatment arm was seen compared with 11.1 months (95% CI, 9.3-13.9) in the placebo and enzalutamide arm (HR, 0.41; 95% CI, 0.30-0.57, 

 < 0.0001). These results extended to improving the time to cytotoxic chemotherapy at 38 events in the combination arm vs 65 in the placebo arm (HR, 0.46; 95% CI, 0.31-0.79, 

 = 0.0001) and a median PFS2 of 36.4 months (95 CI, 364.4-NR) and 28.1 months (95% CI, 24.5-NR), respectively (HR, 0.57; 95% CI, 0.39-0.85, 

An objective response rate (ORR) of”67.1’ was seen in the combination arm with 38.4% of those responses being complete responses and a stable disease rate of 26% was observed, while 5.6% of remaining patients on the combination arm had progressive disease. In comparison, the ORR was 40% in the placebo arm with 18.5% of those responses being complete, 32.3% had stable disease and 20% had progressive disease.

Ultimately, no new safety signals were identified with the combination regimen, but grade 3-4 treatment emergent adverse effects (TEAEs) made were seen in 66.2% of patients on the combination therapy vs 37.2% of those on the placebo and enzalutamide treatment. Dose interruption of talazoparib due to an AE was seen in 67.2% of patients compared with 19.6% of those on the placebo arm and just over half of patients (55.6%) in the combination arm had to dose reduce their talazoparib.

Still, discontinuation rates were low in the combination arm at 10.1% compared with 7% in the placebo arm, and Aes of interest with talazoparib remained low with no reported cases of myelodysplastic syndrome or acute myeloid leukemia. Fizazi also highlighted that the use of talazoparib and enzalutamide prolonged the time to a clinically meaningful deterioration of quality of life at a median of 27.1 months (95% CI, 21.2-NR) compared with 19.3 months (95% CI, 16.6-23) in the placebo arm (HR, 0.69; 95% CI, 0.49-0.97, 

“Based on these data, I believe that talazoparib plus enzalutamide, if approved, should become a standard of care for patients with mCRPC HRR alterations, [and] mostly those with 

Fizazi K, Azad A, Matsubara N, et al. TALAPRO-2: Phase 3 study of talazoparib (TALA) + enzalutamide (ENZA) versus placebo (PBO) + ENZA as first-line (1L) treatment for patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) harboring homologous recombination repair (HRR) gene alterations. 

. 2023;5004(suppl 16). doi: 10.1200/JCO.2023.41.16_suppl.5004

Agarwal N, Azad A, Carles J, et al. Talazoparib plus enzalutamide in men with first-line metastatic castration-resistant prostate cancer (TALAPRO-2): a randomised, placebo-controlled, phase 3 trial. 

. 2023. doi: 10.1016/S0140-6736(23)01055-3

The combination of talazoparib and enzalutamide resulted in a statistically significant and clinically meaningful improvement in radiographic progression-free survival when used as a first-line therapy for patients with metastatic castration-resistant prostate cancer harboring homologous recombination repair gene alterations.

Talazoparib/Enzalutamide Combo Significantly Improves rPFS in HRR Gene–Altered mCRPC 

Radium-223 (Xofigo) was safe and did not preclude patients with metastatic castration-resistant prostate cancer (mCRPC) from receiving subsequent life-prolonging therapies, including chemotherapy, according to data from an interim analysis of the observational REASSURE trial (NCT02141438).

Findings from the study, which were presented at the 2023 ASCO Annual Meeting, demonstrated that most patients completed 5 to 6 injections of radium-223 and no new safety signals were observed. In addition, treatment with radium-223 resulted in an overall survival of approximately 18 months in patients with mCRPC.

“Our observations in this study show that radium-223 can be integrated into the treatment sequence for patients with mCRPC” Daniel Y. Song, MD, co-director of the prostate cancer multidisciplinary clinic and professor of radiation oncology and molecular radiation sciences at Johns Hopkins Sidney Kimmel Comprehensive Cancer Center in Baltimore, said during the poster presentation.

In this analysis, researchers focused on patients with confirmed metastatic castration-resistant prostate cancer from the U.S. who were scheduled to receive treatment with radium-223. All patients included in this analysis received at least 1 dose of radium-223.

Primary endpoints for this study were short- and long-term safety including second primary malignancies and the incidence of bone marrow suppression. In addition, secondary endpoints included patient-reported pain. Of note, pain response was considered clinically meaningful if it decreased from baseline by at least 2 points in the Brief Pain Inventory-Short Form worst pain item.

Researchers included 498 patients (median age, 74 years) in this analysis who were enrolled in the REASSURE study from 2014 to 2017. The median duration of observation for this analysis was 11.9 months (0.4-41.3) at the data cutoff of March 20, 2019.

In the analysis, 81% of patients had bone metastases only. Between 5 and 6 radium-223 injections were received by 69% of patients.

Most patients — 77% — received at least one prior life-prolonging therapy such as enzalutamide (Xtandi; 48%), abiraterone (Zytiga; 45%), cabazitaxel (Jevtana; 6%), docetaxel (25%) or sipuleucel-T (Provenge; 24%).

Researchers noted that some patients in this analysis received concomitant enzalutamide (Xtandi; 31%) and concomitant bone health agents (47%). Thirty-one percent of patients received at least one life-prolonging therapy after treatment with radium-223.

Song noted that 37% of patients had received prior chemotherapy and 16% of patients who did not receive prior chemotherapy required either therapeutic or preventive treatments for bone marrow suppression. “So, the rate was higher definitely within patients who received prior chemotherapy,” he said.

More than half of the patients (58%) in this analysis who reported a Brief Pain Inventory-Short Form score of 2 or higher at baseline had a clinically meaningful pain response during treatment.

Any-grade drug-related treatment-emergent adverse effects occurred in 32% of patients, whereas adverse events considered grade 3 or worse were observed in 10% of patients. Four percent of patients discontinued treatment with radium-223 as a result of drug-related treatment-emergent adverse effects.

Treatment-emergent serious adverse effects occurred in 21% of patients, and drug-related serious adverse events were observed in 6% of patients. The most common any-grade drug-related treatment-emergent adverse effects, which occurred in 5% or more patients, were fatigue (9%), diarrhea (10%), nausea (7%) and anemia (8%). Song noted in the presentation that these adverse events “were side effects which were known and previously established to be an inherent risk for radium-223.”

Four percent of patients had fractures and 2% developed bone disorders. Eleven second primary malignancies were observed in 10 patients (2%).

During follow-up, 60% of patients died, and the median overall survival was 17.8 months (95% CI 15.6–19.4). Song said that the overall survival in the REASSURE study compares favorably with the ALSYMPCA trial results, which were 14.9 months.

Song DY, George S, Zimberg, et al. Real-world safety and effectiveness of radium-223 (223Ra) in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) treated in the US: The non-interventional REASSURE study. J Clin Oncol. 2023;41(suppl 16):5050. doi: 10.1200/JCO.2023.41.16_suppl.5050

Radium-223 was safe and did not preclude patients with metastatic castration-resistant prostate cancer from receiving subsequent life-prolonging therapies, including chemotherapy.

ASCO 2023 Meeting Reporter: Updates in GU Cancers | Supplements and Featured Publications

Long-Term KEYNOTE-426 Data Continue to Support Frontline Pembrolizumab Plus Axitinib as SOC for Advanced ccRCC

Cabozantinib/Atezolizumab Combo Misses PFS, OS End Points in ICI-Treated, Advanced RCC

Enfortumab Vedotin Plus Pembrolizumab Produces Durable Responses, Safety in Metastatic Urothelial Carcinoma

Erdafitinib Confers OS Benefit in FGFR-Altered Urothelial Cancer

Talazoparib/Enzalutamide Combo Significantly Improves rPFS in HRR Gene–Altered mCRPC

Subsequent Treatments Feasible After Radium-223 in mCRPC