Yoga can promote an improved quality of life among patients with prostate cancer, show phase 2 trial findings presented at the 2021 AUA Annual Meeting. In addition, the meditative activity may result in antitumor immune responses and reduced inflammation in patients undergoing prostatectomy.

Yoga has a direct effect on the vagus nerve, which can shape how a person thinks, remembers, and feels. And patients with prostate cancer have a 20% to 30% incidence and prevalence of depression and anxiety.

In previous studies, yoga has demonstrated an improved quality of life for patients with cancer, as well as lower inflammation. Additionally, newer, emerging data has demonstrated that mindfulness exercises, such as yoga, can cause the frontal and limbic parts of the brain to structurally change.

“However, if you look at hierarchy of evidence, most data on immune benefits of yoga is from small series and case reports, no such data exists for prostate cancer. Given these findings of improvement in quality of life with yoga, we started looking at [the] role of yoga in prostate cancer,” said Dharam Kaushik, MD, associate professor in the department of urology at the University of Texas Health, San Antonio, during the presentation of the data.

The primary outcomes of this clinical trial [NCT02620033] was self-reported outcomes of quality of life at baseline, and 6 weeks. Secondary outcomes included immune cell status and cytokine levels, also at baseline and 6 weeks.

“We wanted to evaluate the quality of life from multiple vantage points, therefore we utilized 4 different quality of life questionaries,” Kaushik mentioned. Self-reported outcomes were assessed by the Expanded Prostate Index Composite (EPIC), Functional Assessment of Cancer Therapy-Prostate (FACT-P), Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) and Five Facets of Mindfulness Questionnaire (FFMQ).

The study consisted of 30 men who were newly diagnosed with localized prostate cancer and scheduled for a radical prostatectomy. Patients were randomized to either yoga (n = 15) or standard of care (n = 15). And patients in the yoga group, performed the activity for 60 minutes twice a week for 6 weeks before their prostatectomy and 3 to 6 weeks after.

Yoga “meaningfully” improved EPIC-sexual scores, FACIT-F, FACT general and FACT-P. In substratification, there were improvements in sexual, physical, and social well-being in the yoga group.

Additionally, participants in the yoga group demonstrated increased numbers of CD4+ (

There was also an increase in the natural killer cells IFNNK (

 = .041), “indicating a robust immune response,” Kaushik added.

Yoga also had an enhanced effect on antitumor activity, decreasing the numbers of regulator T-cells and myeloid-derived suppressor cells: CD11b+CD33+ (

There was also a decrease in cytokine cells including, G-CSF (

 = .032), which had shown to activate production endothelial cell and cytokines. Additionally, there was a decrease in MCP-1 (

 = .044), which are associated with proception against dementia, and FLt-3L (

 = .053) which has been linked to reducing chronic inflation, Kaushik mentioned.

The benefits demonstrated in this study require further investigation, the authors concluded in the abstract.

Kaushik D, Shah P, Mukherjee N, et al. A phase 2 randomized clinical trial of yoga in men with prostate cancer. Presented at: 2021 American Urological Association Annual Meeting; September 10-13, 2021; virtual. Abstract LBA02-03.

Articles

Yoga has a positive impact on the vagus nerve, which influences how people think, remember, and feel, and therefore can improve the mental well-being of patients with prostate cancer. 

Yoga Encourages Antitumor Response, Boosts Quality of Life in Patients with Prostate Cancer 

Patients with nonmetastatic castration-resistant prostate cancer (nmCRPC) may have a decreased immediate need for locally invasive procedures, as well as a minimized speed of deterioration in health-related quality of life (HRQOL ) after treatment with the androgen receptor inhibitor darolutamide (Nubeqa), suggest findings reported at the 2021 American Urological Association annual meeting.

For the study, investigators evaluated the effect of darolutamide on local symptom control. Specifically, they examined incidence and time to first prostate cancer-related invasive procedures, time to deterioration in health-related quality of life measures, and incidence of urinary and bowel treatment-related adverse events and their correlation with PSA decline from baseline to week 16 in patients receiving darolutamide.

Time to deterioration in HRQOL measures was assessed using the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Prostate Cancer Module and the Functional Assessment of Cancer Therapy-Prostate (FACT-P) prostate cancer subscale.

In assessing incidence and time to first locally invasive procedures, “The results of these analyses showed that fewer patients receiving darolutamide, 4.7%, underwent locally invasive procedures, compared with patients receiving placebo, 9.6%,” said first author Neal D. Shore, MD, FACS, director of Carolina Urologic Research Center in Myrtle Beach, South Carolina. The most common procedures included catheterization, transurethral resection of the prostate, nephrostomy, and surgical excisions and resections.

Darolutamide also significantly prolonged the time to first prostate cancer-related locally invasive procedure compared with placebo (hazard ratio [HR], 0.42; 95% CI, 0.28-0.62).

“For the EORTC urinary symptom subscale, darolutamide significantly delayed the time to deterioration in quality of life for total urinary symptoms and for each individual question about urinary symptoms versus placebo,” Shore said.

The 4 questions that contributed the most to the delay in time to deterioration of HRQOL with darolutamide were:

• urinate frequently during the day (HR, 0.764; 95% CI, 0.648-0.902)

• urinate frequently at night (HR, 0.664; 95% CI, 0.559-0.790)

• pain when urinating (HR, 0.569; 95% CI, 0.441-0.734)

• urinary problems interfere with daily activities (HR, 0.748; 95% CI, 0.614-0.910).

Darolutamide was also found to significantly delay the time to deterioration of total bowel symptoms vs placebo (HR, 0.781; 95% CI, 0.664-0.918).

“For each of the 4 bowel symptom-related questions, darolutamide delayed the time to deterioration versus placebo with hazard ratios ranging from 0.87 to 0.91, but 95% confidence intervals were wide and crossed 1,” Shore said.

Regarding the FACT-P Prostate Cancer Subscale, darolutamide significantly delayed time to deterioration for total urinary symptoms as well as for each of the 3 urinary symptom questions. The time to deterioration in trouble moving bowels was not significantly affected by treatment with darolutamide, however (HR, 1.089; 95% CI, 0.0862-1.376).

In the overall study population, urinary retention occurred in 36 patients (3.8%) in the treatment arm vs 41 patients (7.4%) in the placebo arm. Dysuria occurred in 25 patients (2.6%) in the treatment arm vs 29 patients (5.2%) in the placebo arm.

“The incidences of other urinary and bowel adverse events showed minimal differences of 2% or less between treatments,” Shore said.

In addition, for patients treated with darolutamide, greater prostate-specific antigen response was associated with a lower incidence of urinary retention and dysuria.

Specifically, patients receiving darolutamide who had a PSA decline of 90% or greater from baseline to week 16 had incidences of urinary retention and dysuria of 2.2% and 0.5% respectively compared with 5.1% for urinary retention and dysuria in patients with a PSA response of less than 50%.

“In conclusion, darolutamide was associated with a reduction in locally invasive procedures and delayed time to deterioration in patient health-related quality of life with respect to urinary and bowel symptoms. No increase in urinary and bowel-related adverse events compared with placebo confirms the favorable safety profile of darolutamide. These findings demonstrate that darolutamide had a positive effect on local disease recurrence and symptom control in patients with nonmetastatic CRPC,” Shore said.

1. Shore S, Stenzl A, Pieczonka C, et al. Impact of darolutamide on local symptoms in patients with nonmetastatic castration-resistant prostate cancer. Paper presented at the 2021 American Urological Association Annual Meeting; Sep

Researchers identified a slower rate of health-related quality of life deterioration, as well as an ability to postpone locally invasive procedures, in patients with nonmetastatic castration-resistant prostate cancer who received darolutamide. 

Darolutamide Postpones Need For Procedure, Slows Down Quality of Life Deterioration in Patients with nmCRPC

The FDA has granted full approval to pembrolizumab (Keytruda) for the treatment of patients with locally advanced or metastatic urothelial carcinoma (mUC) and are not deemed eligible for platinum-containing chemotherapy.

Pembrolizumab’s original indication had been granted an accelerated indication based off the tumor response rate and duration of response with continued approval remaining contingent upon certification of clinical benefit in confirmatory trials.

“While the treatment landscape has evolved, an unmet need remains for appropriate patients newly diagnosed with certain types of advanced urothelial carcinoma who are not eligible for platinum-containing chemotherapy,” Scot Ebbinghaus, MD, vice president, clinical research, Merck Research Laboratories, stated in a press release. “We are confident in the role [pembrolizumab] will continue to play for these patients who have few other treatment options and are working with urgency to advance studies to help more patients living with bladder and other types of cancer.”

Earlier this year, the drug was assessed by the FDA’s Oncologic Drugs Advisory Committee (ODAC) during an industry wide evaluation of accelerated approvals that had not yet met their post-marking requirements. ODAC members voted 5-3 to maintain the accelerated approval of pembrolizumab for the first-line bladder indication.

The following phase 3 KEYNOTE-361 trial, which evaluated pembrolizumab both as a monotherapy and in combination with chemotherapy for early treatment of patients with advanced or metastatic urothelial cancer and were fit to receive platinum-containing chemotherapy, did not achieve its pre-specified dual primary end points of overall or progression-free survival, in comparison with the current standard-of-care chemotherapy.

Pembrolizumab is also approved to treat patients with locally advanced or mUC following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy as well as for the treatment of patients with Bacillus Calmette-Guerin-unresponsive, high-risk, non-muscle invasive bladder cancer and are ineligible for or have chosen not to undergo cystectomy.

The humanized monoclonal antibody functions by blocking the interaction between PD-1 and its ligands, PD-L1 and PD-L2. Patients receiving pembrolizumab should be monitored for potential immunotherapy-related adverse events (irAEs). Liver enzymes, creatinine, and thyroid function should be assessed at baseline and revisited throughout treatment.

For serious irAEs, corticosteroid therapy should be administered (1 to 2 mg/kg/day prednisone or equivalent) until the grade is diminished to grade 1 or less. Pembrolizumab should be withheld or discontinued if the steroids do not improve symptoms.

Some AEs occur at a 10% higher rate in pediatric patients compared with adults, including pyrexia (33%), vomiting (30%), leukopenia (30%), upper respiratory tract infection (29%), neutropenia (26%), headache (25%), and Grade 3 anemia (17%).

FDA approves updated indication for Merck's KEYTRUDA (pembrolizumab) for the treatment of certain patients with urothelial carcinoma (bladder cancer). News release. Merck. August 31, 2021. Accessed August 31, 2021. https://bwnews.pr/3zCgh3N


Pembrolizumab has been granted full approval as a first-line treatment for a select population of patients with bladder cancer. 


FDA Approves Pembrolizumab for First-Line Treatment of Advanced Bladder Cancer

The FDA approved adjuvant nivolumab (Opdivo) to treat patients with urothelial carcinoma who are at high risk of recurrence after undergoing radical resection, irrespective of prior neoadjuvant chemotherapy, nodal involvement or PD-L1 status, according to Bristol Myers Squibb.

The regulatory decision is based on data from the phase 3 CheckMate-274 trial (NCT02632409), in which the immunotherapy resulted in a median disease-free survival (DFS) that was nearly double that reported in those who received placebo, at 20.8 months (95% CI, 16.5-27.6) and 10.8 months (95% CI, 8.3-13.9), respectively. Nivolumab resulted in a 30% reduction in the risk of disease recurrence or death vs placebo (HR, 0.70; 95% CI, 0.57-0.86; P = .0008).

In the patients whose tumors had a PD-L1 expression of 1% or higher, the median DFS had not yet been reached (95% CI, 21.2–not evaluable) with nivolumab vs 8.4 months (95% CI, 5.6-21.2) with placebo. In this subset, the immunotherapy resulted in a 45% reduction in the risk of disease recurrence or death (HR, 0.55; 95% CI, 0.39-0.77; P = .0005).

“This approval is a major milestone for patients who have undergone major surgery to remove the bladder or parts of the urinary tract and are in need of additional treatment approaches that can help reduce the risk of their urothelial carcinoma returning,” Matthew D. Galsky, MD, primary trial investigator, professor of medicine, director of Genitourinary Medical Oncology, co-director of the Center of Excellence for Bladder Cancer, and associate director for Translational Research at The Tisch Cancer Institute and the Icahn School of Medicine at Mount Sinai, stated in a press release. “Nivolumab provides a new FDA-approved treatment shown to reduce the risk of disease recurrence or death based on the safety and efficacy findings from CheckMate-274, and has the potential to become a new standard-of-care option in this setting.”

The multicenter, double-blind, placebo-controlled CheckMate-274 trial enrolled patients with ypT2-ypT4a or yPN-positive muscle-invasive urothelial carcinoma (MIUC) who had received neoadjuvant cisplatin chemotherapy. Patients with pT3-pT4a or pN-positive MIUC who did not receive prior neoadjuvant cisplatin chemotherapy and were not candidates for or refused adjuvant cisplatin chemotherapy, were also permitted.

Additionally, patients were required to have undergone radical surgery within the past 120 days and to have disease-free status within 4 weeks of dosing on the trial.

Study participants were randomized 1:1 to receive intravenous (IV) nivolumab at a dose of 240 mg every 2 weeks (n = 351) or IV placebo every 2 weeks (n = 348). They received adjuvant treatment for up to 1 year.

Patients were stratified based on PD-L1 expression (<1% vs ≥1%), prior neoadjuvant cisplatin-based chemotherapy, and nodal status.

The primary end points of the trial were DFS in the intent-to-treat population and DFS in all randomized patients with a PD-L1 expression of 1% or higher. Key secondary end points comprised non–urothelial tract recurrence-free survival, disease-specific survival, and overall survival. Exploratory end points included distant metastasis-free survival, safety, and health-related quality of life (HRQoL).

Bristol Myers Squibb. U.S. Food and Drug Administration Approves Opdivo® (nivolumab) for the Adjuvant Treatment of Patients with High-Risk Urothelial Carcinoma. Published August 20, 2021. 

https://news.bms.com/news/details/2021/U.S.-Food-and-Drug-Administration-Approves-Opdivo-nivolumab-for-the-Adjuvant-Treatment-of-Patients-with-High-Risk-Urothelial-Carcinoma/default.aspx

The Food and Drug Administration approved adjuvant nivolumab to treat urothelial carcinoma in patients who are at high risk of recurrence after undergoing radical resection, irrespective of prior neoadjuvant chemotherapy, nodal involvement or PD-L1 status.

FDA OKs Adjuvant Nivolumab to Treat High-Risk Urothelial Carcinoma

to treat adult patients with von Hippel-Lindau (VHL)- associated renal cell carcinoma (RCC), central nervous system (CNS) hemangioblastomas, or pancreatic neuroendocrine tumors (pNETs), who do not require immediate surgery, according to a release issued by the agency.

The regulatory decision was based off updates from the ongoing, open label Study 004 trial (NCT03401788) that evaluated the hypoxia-inducible factor inhibitor in 61 patients with VHL-RCC. To be eligible, patients had to have a VHL germline alteration and at least 1 solid tumor localized to the kidney. Participants with VHL-related tumors like CNS hemangioblastomas and pNETs were also included. 

Patients were administered 120 mg oral belzufitan once daily until progressive disease or intolerable toxicity.

Primary efficacy end points include overall response rate (ORR), duration of response (DOR), and time-to-response (TTR). ORR will be assessed via radiology assessment and an independent review committee in accordance with RECIST v1.1 criteria. Current data show an ORR of 49% (95% CI, 36-62) for patients with VHL-RCC, 63% for patients with CNS hemangioblastomas, and 83% for patients with measurable pNETs.

Median DOR has not been reached. Patients with VHL-RCC were followed for a minimum of 18 months from treatment initiation, and 56% of responders experienced a DOR greater or equal to 6 months. The median TTR in this group was 8 months. Among the CNS hemangioblastoma cohort, 73% of responders experienced a DOR of ≥12 months, as did 50% of responsive patients in the pNET group.

Adverse events (AEs) reported in the study included laboratory abnormalities, decreased hemoglobin, anemia, fatigue, increased creatinine, headache, dizziness, increase glucose, and nausea. Nurses should be aware that the anemia and hypoxia associated with belzutifan use can be severe. In total, 90% of patients in the study experienced anemia and 7% reported the severity of their anemia to be grade 3. In addition, 1.6 % of patients experienced hypoxia.

Erythropoiesis stimulating agents are not recommended in patients treated with belzutitfan. Investigators reported that belzutifan renders some hormonal contraceptives infective and that the drug can inflict embryo-fetal harm.

FDA approves belzutifan for cancers associated with von Hippel-Lindau disease. FDA. News release. Accessed August 13, 2021. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-belzutifan-cancers-associated-von-hippel-lindau-disease?utm_medium=email&utm_source=govdelivery

Belzutifan, a hypoxia-inducible factor inhibitor, has been approved for treatment of adults with cancers related to von Hippel-Lindau disease. 

FDA Approves Belzutifan For Adults With Von Hippel-Lindau Related Cancers

The evolution of checkpoint blockade and VEGF TKIs, as well as the regulatory approval of combination therapies involving these inhibitors, have led to a significant improvement in the 5-year survival rates of patients with renal cell carcinoma (RCC).

“[We see that] there is a definitive role in having dual therapy,” said Laura S. Wood, RN, MSN, OCN, Renal Cancer Research Coordinator at Cleveland Clinic Taussig Cancer Center, in a presentation during the 

 School of Nursing Oncology meeting. “We’re seeing a number of new combinations with PD-1/PD-L1 inhibitors plus 1 of our TKIs, so the story continues as far as the evolution of our therapies. And, this is what will account for improvements in response rate, progression-free survival, and overall survival.”

The shifted balance of treatment toward anticancer immunity with combination strategies involving PD-1/PD-L1 and VEGF inhibitors has been reported through several pivotal clinical trials that have led to improved outcomes in RCC: CheckMate-214 (NCT02231749), KEYNOTE-426 (NCT02853331), CheckMate-9ER (NCT03141177), and CLEAR (NCT02811861).

Such clinical findings led to the approvals of nivolumab (Opdivo) plus ipilimumab (Yervoy), pembrolizumab (Keytruda) plus axitinib (Inlyta), avelumab (Bavencio) plus axitinib, and cabozantinib (Cabometyx) plus nivolumab. While nivolumab/ipilimumab is approved in intermediate- and poor-risk patients only, the other dual strategies are approved for all-comers with RCC.

“It’s very difficult and challenging to do cross-trial comparisons,” said Wood. “It’s definitely not highly recommended, but it is what we use in clinical practice to help us in patients use shared decision-making to make treatment decisions.”

The phase 3 CheckMate-214 trial was the basis for the April 2018 FDA approval of nivolumab/ipilimumab as first-line treatment for intermediate- and poor-risk patients with RCC.

In the trial, patients with metastatic clear cell RCC were randomized to receive 3 mg of nivolumab plus 1 mg of ipilimumab or sunitinib as first-line therapy. Four-year follow-up data showed that, at a median follow-up of 55 months, the combination led to a 31% reduction in the risk of death when compared with sunitinib (Sutent) in the intent-to-treat population.

 Specifically, the median overall survival (OS) was not reached with nivolumab/ipilimumab and 38.4 months with sunitinib (HR, 0.69; 95% CI, 0.59-0.81).

The median progression-free survival (PFS), however, was 12.2 months and 12.3 months, respectively; the ORR rates were 39% and 32%, respectively. The complete response (CR) rates were 11% vs 3%, respectively.

In intermediate- and poor-risk patients, nivolumab/ipilimumab was also favored over sunitinib for OS (HR, 0.65; 95% CI, 0.54-0.78).

Pembrolizumab and axitinib was tested up front in the phase 3, open-label KEYNOTE-426 trial, in which treatment-naïve patients with advanced clear cell RCC were randomized to receive the PD-1/VEGF TKI combination or sunitinib.

Extended follow-up results showed that the median OS was not reached compared with 35.7 months with sunitinib (HR, 0.68; 95% CI, 0.55-0.85; 

 = .0003) at a 30.6-month median follow-up.3 Additionally, the median PFS was 15.4 months and 11.1 months, respectively (HR, 0.71; 95% CI, 0.60-0.84; 

 <.0001). The combination elicited a 60% ORR while sunitinib’s ORR was 40% (

 <.0001); the CR rates were 9% and 3%, respectively.

Based on earlier data from KEYNOTE-426, the FDA approved pembrolizumab and axitinib in the up-front setting for patients with RCC in April 2019.

Avelumab/axitinib is also available as a frontline combination regimen in patients with advanced RCC as of May 2019. The decision was based on the phase 3 JAVELIN Renal 101 trial, which showed that the combination led to a 31% reduction in the risk of disease progression or death vs sunitinib in the overall group of patients with treatment-naïve advanced RCC, regardless of PD-L1 expression.

In the international, phase 3 CheckMate-9ER trial, investigators evaluated nivolumab plus cabozantinib compared with sunitinib in the frontline setting for patients with advanced clear cell RCC.

At a median follow-up of 23.5 months, the median OS with the combination was not reached vs 29.5 months with sunitinib (HR, 0.66; 95% CI, 0.50-0.87; 

 = .0034), and the median PFS was doubled at 17.0 months vs 8.3 months with sunitinib (HR, 0.52; 95% CI, 0.43-0.64; 

 <.0001).5 The ORRs were 55% and 27% with nivolumab/cabozantinib and sunitinib, respectively; the CR rates were 9% vs 4%, respectively.

The FDA approved nivolumab plus cabozantinib in this setting in January 2021, based on the earlier phase 3 CheckMate-9ER data. The recommended dose is 240 mg of nivolumab every 2 weeks via a 30-minute intravenous (IV) infusion, or at 480 mg every 4 weeks via 30-minute IV infusion, in combination with oral, once-daily cabozantinib at 40 mg once daily without food until either progressive disease or intolerable toxicity.

The efficacy behind the combination of lenvatinib (Lenvima) and pembrolizumab, also compared with sunitinib, in the frontline setting of RCC was recently presented at the 2021 Genitourinary Cancers Symposium.

Additionally, investigators tested the efficacy and safety of lenvatinib plus everolimus (Afinitor) vs sunitinib in this setting as a separate cohort.

At a median follow-up of 27 months in the phase 3 CLEAR trial, pembrolizumab/lenvatinib had a 34% reduction in the risk of death when compared with sunitinib; the median OS was not reached in either arm at a median 27-month follow-up (HR, 0.66; 95% CI, 0.49-0.88; 

 = .005). The median PFS was 23.9 months and 9.2 months, respectively (HR, 0.39; 95% CI, 0.32-0.49; 

 <.001); the ORRs were 71% vs 36% and the CR rates were 16% vs 4%, respectively.

Regarding the arm of lenvatinib plus everolimus vs sunitinib, the data showed statistically significant improvements in PFS and ORR, but not in OS (HR, 1.15; 95% CI, 0.88-1.5; 

Based on the CLEAR findings, the FDA granted a priority review designation in May 2021 to a supplemental biologics license application to the combination of lenvatinib and pembrolizumab as a frontline treatment for patients with advanced RCC. The agency is expected to make a decision on the approval by August 25, 2021.

“What’s important to note is that even though [lenvatinib and pembrolizumab] has one of the shorter overall duration of evaluation for the date, [it has a] 71% overall response rate and 16% complete response rate in just 27 months of follow-up for patients on active treatment,” Wood explained. “So, we are continuing to see improvements in our combinations and improvements in outcomes for these regimens.”

Utilizing Guidelines, Prognostic Factors and More for the Best RCC Treatment

The regulatory decisions and encouraging clinical data have also made an impact on the National Comprehensive Cancer Network (NCCN) guidelines for frontline therapy in advanced kidney cancer, and combination therapies are now defined by favorable, intermediate-, and poor-risk status.

Preferred regimens (category 1) for favorable-risk patients include axitinib/pembrolizumab, nivolumab/cabozantinib, and lenvatinib/pembrolizumab; poor-/intermediate-risk patients are recommended to receive axitinib/pembrolizumab, nivolumab/cabozantinib, nivolumab/ipilimumab, lenvatinib/pembrolizumab (all category 1), or cabozantinib.

Preferred agents, listed as category 1 recommendations, for subsequent lines of treatment in clear cell RCC include cabozantinib, lenvatinib/everolimus (Afinitor), and nivolumab.

Updates to NCCN guidelines have also occurred in the advanced non–clear cell RCC setting, Wood noted; preferred regimens include cabozantinib, sunitinib, and a clinical trial.

Overall, evidence-based decision-making, International Metastatic RCC Database Consortium (IMDC) risk stratification, histology, biomarkers, and comorbidities are all factors to consider when choosing treatment for a patient with RCC, Wood emphasized.

Regarding biomarkers, she added that based on data with pembrolizumab/axitinib, avelumab/axitinib, and nivolumab/ipilimumab, PD-L1 expression does not predict benefit or response in RCC compared with other malignancies.

“Patients irrespective of biomarker status will benefit from these combination therapies, so we’re continuing to try to identify biomarkers which will contribute to the knowledge of treatment decision-making,” Wood said.

Other disease characteristics are being identified as poor prognostic features, including sarcomatoid histology. However, in the KEYNOTE-426 study, patients with advanced RCC who had sarcomatoid features had an improved response to pembrolizumab/axitinib (58.8%) vs sunitinib (31.5%), providing clinicians with an option to recommend to their patients with this poor prognostic indicator, Wood added.

Cytoreductive nephrectomy has been evaluated as an immediate or deferred approach in patients with metastatic RCC. However, Wood explained that it’s been demonstrated that deferred surgery may have improved outcomes compared with immediate cytoreductive nephrectomy.

“A delayed cytoreductive nephrectomy allows for the identification of patients with aggressive or inherently resistant disease to our VEGF-targeted therapies, and those are individuals who may not benefit from a nephrectomy up front” she said, adding that initial systemic therapy is preferred in those with Memorial Sloan Kettering Cancer Center/IMDC poor-risk disease, poor [Karnofsky performance score] and/or large-volume metastatic burden.

However, select patients are likely to benefit from an up-front surgery, including those with single-site metastatic disease and those with good performance status, Wood mentioned.

Sixty-five percent of patients with RCC present with localized disease, suggesting a need for adjuvant treatment in this malignancy. At the 2021 ASCO Annual Meeting, data from the phase 3 KEYNOTE-564 trial (NCT03142334) were presented and demonstrated the benefit of adjuvant pembrolizumab vs placebo in the post-nephrectomy setting for patients with RCC.

In the double-blind, multicenter study, investigators explored pembrolizumab vs placebo following nephrectomy in patients with clear cell RCC. Eligibility criteria included categorizing patients as high risk for recurrence, which included: pT2, grade 4 or sarcomatoid, N0, M0; pT3, any grade, N0, M0; pT4, any grade, N0, M0; any pT, any grade, N-positive, M0; or M1 with no evidence of disease after surgery.

Patients had to have undergone nephrectomy within 12 weeks prior to randomization, could not have previously received systemic treatment, had to have an ECOG performance status of 0 or 1, and obtainable tissue sample for PD-L1 assessment.

All patients were randomized 1:1 to receive pembrolizumab at 200 mg every 3 weeks or placebo every 3 weeks, both for approximately 1 year.

Data showed that, at a median follow-up of approximately 2 years, the median investigator-assessed disease-free survival (DFS) was not reached with either pembrolizumab or placebo (HR, 0.68, 95% CI, 0.53-0.87; 

 = .0010).8 The estimated 1-year DFS rates were 85.7% and 76.2% with pembrolizumab and placebo, respectively. The 2-year rates were 77.3% and 68.1%, respectively.

The Emphasis on Multidisciplinary Care in RCC

In conclusion, the spectrum of GU malignancies embodies the multidisciplinary care approach, with Wood expressing the importance of urologic surgeons, medical oncologists, radiation oncologists, and palliative care in a patient’s course of treatment.

“Palliative care is huge for us. At least for renal cell carcinoma, there are many patients who see palliative care for assistance with symptom management before we even get started on systemic therapy,” she concluded. “If we don’t get palliative care’s input to help us manage the underlying disease and the symptoms associated with it, patients are never going to tolerate an aggressive regimen, which is necessary to control the disease and improve their overall survival.”

Wood LS. Renal cell carcinoma and supportive care in GU cancers. Presented at: 

School of Nursing Oncology; August 6-7, 2021; virtual.

Albiges L, Tanniir NM, Burotto M, et al. Nivolumab plus ipilimumab versus sunitinib for first-line treatment of advanced renal cell carcinoma: extended 4-year follow-up of the phase III CheckMate 214 trial. 

. 2020;5(6):e001079. doi:10.1136/esmoopen-2020-001079

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;21(12):1563-1573. doi:10.1016/S1470-2045(20)30436-8

FDA approves Bavencio (avelumab) plus Inlyta (axitinib) combination for patients with advanced renal cell carcinoma. Pfizer Oncology. May 14, 2019. Accessed August 9, 2021. https://on.pfizer.com/2HtdCzF.

Motzer RJ, Choueiri TK, Powles T, et al. Nivolumab + cabozantinib (NIVO+CABO) versus sunitinib (SUN) for advanced renal cell carcinoma (aRCC): Outcomes by sarcomatoid histology and updated trial results with extended follow-up of CheckMate 9ER. 

. 2021;39(suppl 6):308. doi:10.1200/JCO.2021.39.6_suppl.308

Motzer RJ, Porta C, Eto M, et al. Phase 3 trial of lenvatinib (LEN) plus pembrolizumab (PEMBRO) or everolimus (EVE) versus sunitinib (SUN) monotherapy as a first-line treatment for patients (pts) with advanced renal cell carcinoma (RCC) (CLEAR study). 

. 2021; 39(suppl_6):269. doi:10.1200/JCO.2021.39.6_suppl.269

Motzer RJ, Alekseev B, Rha S.-Y., et al. Lenvatinib plus pembrolizumab or everolimus for advanced renal cell carcinoma. 

. 2021;384(14):1289-1300. doi:10.1056/NEJMoa2035716

Choueiri TK, Tomczak P, Park SH, et al. Pembrolizumab vs placebo as post-nephrectomy adjuvant therapy for patients with renal cell carcinoma: randomized, double-blind, phase 3 KEYNOTE-564 study. 

. 2021;39(suppl 15):LBA5. doi:10.1200/JCO.2021.39.15_suppl.LBA5

This article was originally published on OncLive as

 “Checkpoint Inhibitor/TKI Combos Jump RCC Treatment to Next Level”

Recently approved combination therapies have contributed to significantly improved survival rates in renal cell carcinoma. 

Checkpoint Inhibitor/TKI Combos Increase Survival in Renal Cell Carcinoma

The combination of pembrolizumab (Keytruda) and lenvatinib (Lenvima) has been FDA approved as a frontline therapy for the treatment of adult patients with advanced renal cell carcinoma.

The regulatory decision is supported by data from the phase 3 CLEAR/KEYNOTE-581 trial (Study 307; NCT02811861), in which the doublet demonstrated statistically significant improvements in terms of progression-free survival (PFS), overall survival (OS), and confirmed objective response rate (ORR) compared with sunitinib (Sutent).

Specifically, pembrolizumab plus lenvatinib resulted in a 61% reduction in the risk of disease progression or death vs sunitinib (HR, 0.39; 95% CI, 0.32-0.49; 

< .0001). The median PFS in the investigative arm was 23.9 months (95% CI, 20.8-27.7) vs 9.2 months (95% CI, 6.0-11.0) in the control arm. The doublet also resulted in a 34% reduction in the risk of death over sunitinib (HR, 0.66; 95% CI, 0.49-0.88; 

Moreover, the combination regimen also a elicited confirmed ORR of 71% (95% CI, 66%-76%) vs 36% (95% CI, 31%-41%) with single-agent sunitinib. The ORR achieved with the doublet was comprised of a 16% complete response rate and a 55% partial response rate; with sunitinib, these rates were 4% and 32%, respectively.

"This approval is based in part on data demonstrating that pembrolizumab plus lenvatinib significantly reduced the risk of disease progression or death vs sunitinib," Robert J. Motzer, MD, Jack and Dorothy Byrne Chair in Clinical Oncology, Kidney Cancer section head of the Genitourinary Oncology Service at Memorial Sloan Kettering Cancer Center, stated in a press release. "This is a significant milestone for newly diagnosed patients with advanced RCC and introduces a promising combination option in the first-line setting."

The multicenter, open-label, phase 3 trial enrolled a total of 1069 patients with advanced RCC. Notably, patients could enroll irrespective of PD-L1 tumor expression status, and those with autoimmune disease or a condition that required immunosuppression were excluded.

Study participants were stratified based on geographic region (North American and Western Europe vs rest of the world) and Memorial Sloan Kettering Cancer Center prognostic risk groups (favorable vs intermediate vs poor risk).

Patients were randomized 1:1:1 to receive oral lenvatinib at a once-daily dose of 20 mg plus intravenous pembrolizumab at a dose of 200 mg given every 3 weeks for up to 24 months; lenvatinib at a once-daily dose of 18 mg plus oral everolimus (Afinitor) at a once-daily dose of 5 mg; or oral sunitinib at a once-daily dose of 50 mg for 4 weeks on treatment, followed by 2 weeks off treatment.

Patients continued to receive treatment until either intolerable toxicity or progressive disease. Pembrolizumab was given for a maximum of 24 months, but lenvatinib could be continued for beyond that time point. Investigators assessed tumor status at baseline and then every 8 weeks.

The median age of study participants was 62 years (range, 29-88), with 42% of patients aged 65 years or older. Moreover, 75% of patients were male, 74% were White, and 82% of patients had a Karnofsky performance status of 90 to 100 at baseline. With regard to risk, 27% were determined to have favorable risk, 64% were intermediate, and 9% were poor. The most common site of metastasis was in the lung (68%), and this was followed by the lymph node (45%) and the bone (25%).

Major efficacy measures included PFS per independent radiologic review (IRC) and RECIST v1.1 criteria, as well as OS. Another notable outcome measure was confirmed ORR per IRC assessment.

The median duration of exposure to the doublet was 17.0 months (range, 0.1-39.0).

Regarding safety, 4.3% of patients who received the doublet experienced fatal adverse reactions; these effects included cardiorespiratory arrest (0.9%), sepsis (0.9%), and one case (0.3%) each of arrhythmia, autoimmune hepatitis, dyspnea, hypertensive crisis, increased blood creatinine, multiple organ dysfunction syndrome, myasthenic syndrome, myocarditis, nephritis, pneumonitis, ruptured aneurysm, and subarachnoid hemorrhage.

Moreover, serious adverse reactions were experienced by 51% of patients on the investigative arm. Serious adverse reactions that were reported in 2% or more of patients comprised hemorrhagic events (5%), diarrhea (4%), hypertension (3%), myocardial infarction (3%), pneumonitis (3%), vomiting (3%), acute kidney injury (2%), adrenal insufficiency (2%), dyspnea (2%), and pneumonia (2%).

Thirty-seven percent of patients who received pembrolizumab plus lenvatinib permanently discontinued treatment of either agent or both because of toxicity; 29% discontinued pembrolizumab only, 26% discontinued lenvatinib only and 13% stopped both treatments. The most frequent toxicities that resulted in permanent discontinuation of the doublet or either agent included pneumonitis (3%), myocardial infarction (3%), hepatotoxicity (3%), acute kidney injury (3%), rash (3%), and diarrhea (2%).

Additionally, 78% of patients receiving the doublet required dose interruptions due to toxicity. Pembrolizumab was interrupted in 55% of patients, lenvatinib was interrupted in 73% of patients, and both treatments were interrupted in 39% of patients.

The most common toxicities that led to a dose interruption of the immunotherapy included diarrhea (10%), hepatotoxicity (8%), fatigue (7%), lipase increased (5%), amylase increased (4%), musculoskeletal pain (3%), hypertension (3%), rash (3%), acute kidney injury (3%), and decreased appetite (3%). Lenvatinib was dose reduced in 69% of patients. The most common toxicities that resulted in dose reduction or interruption of lenvatinib were diarrhea (26%), fatigue (18%), hypertension (17%), proteinuria (13%), decreased appetite (12%), palmar-plantar erythrodysesthesia syndrome (11%), nausea (9%), stomatitis (9%), musculoskeletal pain (8%), rash (8%), increased lipase (7%), abdominal pain (6%), and vomiting (6%), increased alanine aminotransferase (ALT; 5%), and increased amylase (5%).

The most common toxicites observed with the doublet included fatigue (63%), diarrhea (62%), musculoskeletal disorders (58%), hypothyroidism (57%), hypertension (56%), stomatitis (43%), decreased appetite (41%), rash (37%), nausea (36%), weight loss, dysphonia and proteinuria (30% each), PPE syndrome (29%), hemorrhagic events and abdominal pain (27% each), vomiting (26%), constipation and hepatotoxicity (25% each), headache (23%), and acute kidney injury (21%).

The most frequently reported grade 3 or 4 adverse effects with the combination comprised hypertension (29%), diarrhea (10%), fatigue and hepatotoxicity (9% each), weight loss and proteinuria (8% each), acute kidney injury, hemorrhagic events and rash (5% each), musculoskeletal disorders, decreased appetite and PPE (4% each), nausea and vomiting (3% each), stomatitis and abdominal pain (2% each), and constipation, hypothyroidism and headache (1% each).

FDA approves KEYTRUDA (pembrolizumab) plus LENVIMA (lenvatinib) combination for first-line treatment of adult patients with advanced renal cell carcinoma (RCC). News release. Merck. August 11, 2021. Accessed August 11, 2021. https://bwnews.pr/3fXk8Rj

This article was originally published on OncLive as 

“FDA Approves Pembrolizumab Plus Lenvatinib for Frontline Advanced RCC”

The combination of pembrolizumab and lenvatinib has been FDA approved as a frontline therapy for the treatment of adult patients with advanced renal cell carcinoma. 

FDA Approves Pembrolizumab/Lenvatinib Combo for Frontline Advanced RCC Treatment

A meta-analysis of prostate cancer genome-wide association studies has indicated that germline variation contributes to racial disparities in prostate cancer risk. Individuals of African descent, according to the data, demonstrated a higher mean genetic risk score (GRS) compared to those of European ancestry.

Results showed that the top GRS decile associated with odds ratio was 5.06 for men of European descent (95% CI, 4.84-5.29) and 3.74 for men of African descent (95% CI, 3.36-4.17). When compared with men of European ancestry, men of African ancestry were estimated to have a mean GRS that was 2.18 times higher (95% CI, 2.14-2.22), while men of East Asian ancestry had a mean GRS that was 0.73 times lower (95% CI, 0.71-0.76).

“We not only found new markers of risk, but also demonstrated that, by combining genetic information across populations, we were able to identify a risk profile that can be applied across populations,” said Christopher Haiman, ScD, professor of preventative medicine and AFLAC Chair in Cancer Research at the Keck School of Medicine of USC, and director the USC Center for Genetic Epidemiology.

 “This emphasizes the value of adding multiple racial and ethnic populations into genetic studies.”

Additionally, investigators identified 86 new genetic risk variants, all of which were found to be independently associated with prostate cancer risk, which brings the total known risk variants to 269.

“To understand the aggregate effect of the 269 variants on prostate cancer risk, we constructed a GRS using the multiethnic weights of the risk variants associated with disease,” wrote the study authors. “Compared with men at average genetic risk in the 40% to 60% GRS category, the estimated odds ratio for men in the top 10% of the GRS [90%-100% GRS category] was 5.06 [95% CI, 4.84-5.29] for men of European ancestry, 3.74 [95% CI, 3.36-4.17] for men of African ancestry, 4.47 [95% CI, 3.52-5.68] for men of East Asian ancestry, and 4.15 [95% CI, 3.33-5.17] for Hispanic men. Men in the top 1% of the GRS distribution had higher odds of disease, ranging from 11.65 [95% CI, 10.56-12.85] for men of European ancestry to 5.68 [95% CI, 4.44-7.28] for men of African ancestry.”

Prior research has shown that certain races not only trend towards higher incidences of prostate cancer, but higher rates of disease-related mortality overall. Incidence rates of prostate cancer from 2012 to 2016 indicated that 172.9 non-Hispanic Black men per 100,000 develop prostate cancer compared with 97.2 non-Hispanic White men, 86.8 Hispanic men, 68 American Indian and Alaska Native men, and 52.9 Asian and Pacific Islander men.

Similarly, mortality rates from 2013 to 2017 indicate that 38.7 non-Hispanic Black men per 100,000 died from prostate cancer vs 18.7 American Indian and Alaska Native men, 18 non-Hispanic White men, 15.7 Hispanic men, and 8.6 Asian and Pacific Islander men.

Despite the increased risk of incidence and death seen in Black patients

White patients are often overrepresented in clinical cancer trials

hindering investigators' progress in identifying reasons for these disparities.

This developed the rationale for the meta-analysis, with researchers from the USC Center for Genetic Epidemiology, as well as the Institute for Cancer Research in London, United Kingdom, striving to identify the reasons for these disparities. Investigators compiled data from the majority of global genomic prostate cancer studies, including 234,253 men of different races and ethnicities from the United States, United Kingdom, Sweden, Japan, and Ghana, consisting of 107,247 cases and 127,006 controls.

In what is considered the largest and most diverse genetic prostate cancer analysis, findings point toward genetics playing a role in the disparities seen across different racial groups, which could possibly help physicians apply precision medicine to early prostate cancer detection in the future.

“Our long-term objective is to develop a genetic risk score that can be used to determine a man’s risk of developing prostate cancer,” said Haiman. “Men at higher risk may benefit from earlier and more frequent screening, so the disease can be identified when it’s more treatable.”

Current prostate cancer screening guidelines recommend that men aged 55 years or older with average risk undergo prostate-specific antigen (PSA) testing. Though high PSA levels are indicative of prostate cancer, this method typically detects more indolent tumors, leading to unnecessary treatment, according to investigators.

Additionally, investigators believe that GRS could help to guide more selective PSA testing by helping to identify patients who are at a higher risk for prostate cancer, potentially including high-risk patients younger than 55 years old. A larger clinical trial is needed in order to better translate these findings into improved early prostate cancer detection, investigators noted.

“Most [importantly], unlike previous screening trials, this [study] would need to be more representative of the diversity we see in the world,” Haiman concluded. “No population should get left behind.”

Conti DV, Darst BF, Moss LC, et al. Trans-ancestry genome-wide association meta-analysis of prostate cancer identifies new susceptibility loci and informs genetic risk prediction. 

. 2021;53(65-75). doi:10.1038/s41588-020-00748-0

Largest, most diverse prostate cancer study shows genetic role in health disparities. News release. Keck School of Medicine of the University of Southern California. January 2, 2021. Accessed January 5, 2020. 

Prostate at a glance. American Cancer Society Cancer Statistics Center. Accessed January 5, 2021. 

This article was originally published on OncLive as “

African Ancestry Is Linked With Higher Prostate Cancer Risk Vs European Ancestry

Germline variation may cause men of African descent to have a higher risk of prostate than men of European descent. 

African Ancestry Associated With Increased Prostate Cancer Risk

Ipatasertib plus abiraterone (Zytiga) was associated with improved radiographical progression-free survival (PFS) in patients with metastatic castrate-resistance prostate cancer (mCRPC) and PTEN-loss tumors, according to data from the ongoing IPATential150 trial (NCT03072238), published in 

Of note, the same improvement was not statistically significant in the intention-to-treat population. Adverse events (AEs) reflected previously reported safety profiles.

Patients with metastatic castrate-resistant prostate cancer and PTEN-loss tumors experienced improved radiographical progression-free survival with ipatasertib plus abiraterone. 

Genitourinary Cancer