Benjamin Saylor

Treatment with darolutamide (Nubeqa), an androgen receptor inhibitor, showed significant delay in time to locally invasive procedures and time to deterioration in health-related quality of life (HRQOL) measures in patients with nonmetastatic castration-resistant prostate cancer (nmCRPC).

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, according to presentation given during the American Urological Association 2021 Annual Meeting .

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.

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; September 10-13; virtual. Abstract PD34-10

Articles

Darolutamide has shown an impact on local symptoms in patients with nonmetastatic castration-resistant prostate cancer. One of the impacts was a delay in time to HRQOL deterioration. 

Darolutamide Significantly Stalls Time to Deterioration of HRQOL in Patients With nmCRPC

 metastatic castration-sensitive prostate cancer (mCSPC) treated in the phase 3 PEACE-1 study (NCT01957436), the addition of abiraterone acetate (Zytiga) and prednisone to androgen-deprivation therapy (ADT) and docetaxel improved radiographic progression-free survival (rPFS), according to initial results presented during the 2021 ASCO Annual Meeting.

The findings showed that adding abiraterone/prednisone to standard docetaxel/ADT was associated with an approximately 2.5-year absolute benefit in median rPFS in this patient population.

 mCSPC in a 1:1:1:1 ratio to standard of care (SOC), SOC plus abiraterone acetate/prednisone, SOC plus radiotherapy (RT), or SOC plus abiraterone plus RT. Initially, SOC was ADT alone, but from October 2015 onward, the use of docetaxel was permitted. This was done at the investigator’s discretion until 2017, at which point, following the publication of the LATITUDE (NCT01715285) and STAMPEDE (NCT00268476) trials, docetaxel was mandatory.

Patient stratification was based on ECOG performance status, metastatic sites, type of castration, and docetaxel status.

The 2 coprimary end points were rPFS and overall survival. Key secondary end points included castration resistance–free survival, prostate cancer–specific survival, time to next skeletal-related event, PSA response rate, quality of life, and safety.

Between November 2013 and December 2018, 1173 men were enrolled. The median patient age was 67 years (interquartile range, 60-72). High-volume disease was present in 57% of patients, with 43% of patients having low-volume disease. Median follow-up was 3.5 years.

The investigators found no interaction between the effect of local RT and that of abiraterone on rPFS, which allowed the pooling of the 2 abiraterone arms for analysis. When divided into abiraterone and SOC arms, patient characteristics were similar between the arms.

The investigators reported a median rPFS of 4.5 years in the abiraterone arm in the overall population versus 2.2 years for SOC (

< .0001). Similarly, better rPFS was observed in the abiraterone arm versus the SOC arm in the ADT plus docetaxel population (4.5 vs 2.0 years; 

<.0001). In addition, PFS including PSA progression as an event was also improved with abiraterone in both the overall population (3.8 vs 1.5 years; 

<.0001) and the ADT plus docetaxel population (3.2 vs 1.4 years; 

“Importantly, all tested subgroups pretty much seemed to benefit from the addition of abiraterone,” said lead study author Karim Fizazi, MD, PhD, head of the Department of Cancer Medicine at the Institut Gustave Roussy, Villejuif, France, and a professor of Oncology at the University of Paris-Sud.

In the docetaxel population, grade 3 to 5 toxicities that were higher in patients receiving abiraterone and docetaxel versus patients receiving docetaxel but not abiraterone included liver toxicities (6% vs 0%) and hypertension (12% vs 8%).

“It was very reassuring to see that abiraterone, even used concomitantly with docetaxel, did not increase the risk of febrile neutropenia…or other hematological toxicities related to docetaxel,” Fizazi said.

Grade 3 to 5 gastrointestinal toxicity and fatigue, which are typically associated with docetaxel, had a lower incidence in the group of patients receiving abiraterone (2% vs 4%), which Fizazi said may be due to the abiraterone cohort also receiving prednisone.

“In conclusion, adding abiraterone and prednisone to ADT plus docetaxel clearly improves radiographic PFS in men with 

 metastatic prostate cancer,” Fizazi said.

Fizazi K, Maldonado X, Foulon S, et al. A phase 3 trial with a 2x2 factorial design of abiraterone acetate plus prednisone and/or local radiotherapy in men with de novo metastatic castration-sensitive prostate cancer (mCSPC): First results of PEACE-1. 

 39, 2021 (suppl 15; abstr 5001). doi: 10.1200/JCO.2021.39.15_suppl.5000

In men with de novo metastatic castration-sensitive prostate cancer treated in the phase 3 PEACE-1 study, the addition of abiraterone acetate and prednisone to androgen-deprivation therapy  and docetaxel improved radiographic progression-free surviva.

Abiraterone Added to ADT and Docetaxel Prolongs PFS in De Novo mCSPC

Disparities in prostate cancer care have been highlighted through a study examining gnomic profiling.

Among the notable findings were that patients with African ancestry are less likely to receive comprehensive genomic profiling earlier in their treatment course, and are also less likely to be treated on clinical trials.

For the study, which was presented at the 2021 ASCO Annual meeting by Brandon A. Mahal, MD, 11,741 patients with prostate cancer with comprehensive genomic profiling done as part of routine care were evaluated, of whom 12% had African ancestry. A single-nucleotide polymorphism-based approach was used to infer predominant ancestry. In addition, the investigators queried a de-identified clinico-genomic database (CGDB) of 897 evaluable patients with prostate cancer to examine trends in comprehensive genomic profiling utilization, treatment patterns, and clinical trial enrollment.

In the larger cohort, the median age was 67 years and 98% had adenocarcinoma histology. The median age of patients with African ancestry was 64 years vs 67 years for patients with European ancestry (

<.001). In addition, 4.2% of patients with African ancestry were younger than 50 years of age vs 2.5% of patients with European ancestry.

Several gene alterations were significantly enriched in patients with African ancestry versus patients with European ancestry in 

Gene alterations that occurred less frequently in patients with African ancestry versus European ancestry included 

rearrangements also occurred less frequently in patients with African ancestry (15% vs 33%).

When comparing targetable gene alterations, the investigators found similar rates of actionable genes (22.1% in patients with African ancestry vs 22.4% in patients with European ancestry) as well as DNA damage response-associated genes (17.8% in patients with African ancestry vs 18.7% in patients with European ancestry). Mahal noted, however, that 

alterations were slightly enriched in patients with African ancestry (5.0% vs 3.2%; 

Turning to the CGDB cohort, Mahal reported that 91% of patients with African ancestry were treated in the community versus 63% of patients with European ancestry.

“Notably, less than 10% of individuals with African ancestry were treated in an academic setting, whereas 37% of individuals with European ancestry were treated in an academic setting,” said Mahal, assistant professor of radiation oncology and assistant director of community outreach and engagement, University of Miami Sylvester Comprehensive Cancer Center, Miami, Florida.

Eighty-five percent of patients with African ancestry had castration-resistant prostate cancer versus 72% of patients with European ancestry.

Also in the CGDB cohort, it was noted that patients with African ancestry received a median of 2 lines of therapy prior to undergoing comprehensive genomic profiling, compared with 1 line of therapy in patients with European ancestry.

“While there were no significant differences in the use of targeted therapies, including PARP inhibitors or other therapies, only 11% of African-ancestry patients received a clinical study drug compared with 30% of European-ancestry patients,” Mahal said. This was observed both for patients treated in the academic setting as well as for patients treated in the community.

“Please note that these findings are from a small cohort, and in particular, in the academic setting, there were only 5 individuals with African ancestry that were treated at academic centers and therefore, these findings must be interpreted within these limitations,” Mahal noted as a caveat.

“Ultimately, equitable use of comprehensive genomic profile testing, clinical trial enrollment, and subsequent precision medicine treatment pathways could lead to a major reduction in disparities,” Mahal concluded.

Sivakumar S, Lee JK, Moore JA, et al. Ancestral characterization of the genomic landscape, comprehensive genomic profiling utilization, and treatment patterns may inform disparities in advanced prostate cancer: A large-scale analysis. J Clin Oncol 39, 2021 (suppl 15; abstr 5003). doi: 10.1200/JCO.2021.39.15_suppl.5003

Disparities in prostate cancer care have been highlighted through a study examining genomic profiling.

Early Genomic Profiling Performed Less in African American Men With Prostate Cancer

The protocol of pembrolizumab (Keytruda) in combination with gemcitabine and concurrent hypofractionated radiotherapy (RT) for muscle-invasive bladder cancer (MIBC) demonstrated safety and efficacy, according to an early analysis.

Findings from the phase 2 trial (NCT02621151) were reported at the 2021 ASCO Annual Meeting1 by lead author Arjun V. Balar, MD, an associate professor of medicine at the NYU Grossman School of Medicine and genitourinary medical oncology program director at NYU Langone’s Perlmutter Cancer Center, New York.

The trial included patients with cT2 to T4aN0M0 MIBC who declined or who were ineligible for cystectomy. Patients had an ECOG performance status of 0 or 1, estimated glomerular filtration rate of more than 30 cc/min, and no contraindications to pelvic radiotherapy or pembrolizumab. No perioperative chemotherapy was allowed.

Patients received a single dose of pembrolizumab at 200 mg followed in 2 to 3 weeks by maximal transurethral resection of the bladder tumor and then whole-bladder RT with twice weekly gemcitabine at 27 mg/m2 and pembrolizumab every 3 weeks for 3 doses. Six patients were enrolled in a safety cohort, and 48 patients were enrolled in an efficacy cohort.

The median age of the entire population was 74 years (range, 51-97). Thirty-nine patients (72%) were male, and the majority of patients (n = 38; 70%) had T2N0 disease at baseline, with T3N0 and T4N0 disease present in 14 (26%) and 2 (4%) men, respectively. Regarding histology, 34 patients (63%) had conventional urothelial carcinoma, 20 (37%) had divergent differentiation, and 14 (26%) had carcinoma in situ. Hydronephrosis was present in 6 patients (11%). Fifteen patients (28%) were not candidates for surgery, whereas 39 patients (72%) declined radical cystectomy.

The primary end point of the study was 2-year bladder-intact disease-free survival (BIDFS), which was defined as muscle-invasive recurrence, regional or distant metastases, need for cystectomy, or death. The key secondary end points were safety, 12 weeks’ complete response rate, metastases-free survival, and overall survival.

A total of 42 patients (85%) completed all protocol therapy in the study. Twelve patients (25%) had dose reductions of gemcitabine. One patient (2%) discontinued RT/gemcitabine, 3 (6%) discontinued gemcitabine only, and 4 (8%) discontinued pembrolizumab.

Twelve-week complete response was 100% in the safety cohort and 77% in the efficacy cohort. The investigators reported a 1-year BIDFS rate in the efficacy cohort of 88%, “which is quite encouraging, but obviously this is at a median follow-up of 14.6 months for the population here,” Balar said. The rate increased slightly to 89% when the safety cohort was added. Metastases-free survival was 85% at 1-year follow-up for the entire cohort.

In the efficacy cohort, the majority of treatment-related toxicities were grade 1 and 2, with fatigue, nausea, diarrhea, urinary urgency, maculopapular rash, decreased platelets, and anorexia observed in 20% or more of the efficacy cohort. Grade 3 and 4 treatment-related toxicities included diarrhea, decreased lymphocyte count, colitis, fatigue, anemia, urinary tract pain, hypokalemia, hyponatremia, urinary tract infection, neutropenia, febrile neutropenia, protein-losing enteropathy, immune-related polyneuropathy, and colonic perforation. Balar noted that 1 patient died of fungemia that was not related to study treatment.

Regarding toxicities suspected to be related to pembrolizumab, grade 1 and 2 fatigue, maculopapular rash, alanine aminotransferase, and pruritis were seen in 10% or more of the efficacy cohort. Grade 3 toxicities suspected to be related to pembrolizumab included immune-related protein-losing enteropathy, immune-related polyneuropathy, neutropenia, and urinary tract infection. One grade 4 case of colonic perforation was observed. In addition, 9 patients (19%) were treated with systemic corticosteroids for the management of an immune-related adverse event.

In his concluding remarks, Balar said, “Trimodality bladder preservation therapy is an effective nonsurgical option for patients with muscle-invasive bladder cancer and with curative intent.”

Balar also noted that correlative studies on serially collected tumor tissue and blood are underway; these studies will evaluate the local and systemic impact of pembrolizumab added to chemoradiation on antitumor immunity.

“What we need are randomized studies…and the ongoing studies SWOG 1806 [NCT03775265] and KEYNOTE-992 [NCT04241185] will better define the role of immunotherapy added to bladder preservation therapy,” Balar said.

1. Balar AV, Milowsky MI, O’Donnell PH, et al. Pembrolizumab (pembro) in combination with gemcitabine (Gem) and concurrent hypofractionated radiation therapy (RT) as bladder sparing treatment for muscle-invasive urothelial cancer of the bladder (MIBC): A multicenter phase 2 trial. 

The protocol of pembrolizumab in combination with gemcitabine and concurrent hypofractionated radiotherapy for muscle-invasive bladder cancer demonstrated safety and efficacy. 

Trimodal Pembrolizumab-Based Regimen, which is Bladder-Sparing Shows Promise in MIBC

In patients with metastatic castration-resistant prostate cancer (mCRPC) treated in a phase 1/2a study, the HPN424, a tri-specific half-life extended prostate-specific membrane antigen (PSMA)-targeting T cell engager was well tolerated and demonstrated antitumor activity.

The findings from an ongoing dose escalation study (NCT03577028) were presented at the 2021 American Society of Clinical Oncology annual meeting by Johann De Bono, MB CHB, PhD, MSC, head of drug development at The Institute of Cancer Research, London, and The Royal Marsden NHS Foundation Trust.

According to the study’s abstract, HPN424 is “engineered with three binding domains: anti-PSMA for tumor cell engagement, anti-albumin for half-life extension, and anti-CD3 for T cell engagement.”

The phase 1/2a study evaluated the agent in patients with mCRPC who have received more than 2 prior systemic therapies. The median age was 70 years (range, 43-91) and the median number of prior therapies was 5 (range, 1-12), with 73% of the men having received prior chemotherapy. A majority (78%) of the patients were White, whereas 9% were Black, 2% were Asian, and 11% were classified as other/not reported.

The mean and median PSA were 464 and 129 ng/mL, respectively (range, 0.1-5000). As a reason for entering the study, 27 (42%) men had PSA progression, 3 (5%) had PSA and clinical progression, 10 (16%) had PSA and radiographic progression, and 24 (38%) had radiographic progression.

The primary end points include safety, tolerability, and determination of maximum-tolerated dose (MTD)/recommended phase 2 dose. Secondary objectives included pharmacokinetics, pharmacodynamics, immunogenicity, and preliminary antitumor activity.

The study included a fixed dose arm comprised of 70 patients and a step dose arm comprised of 19 patients. As of the April 23 cutoff date, 89 patients had received the treatment. The highest target doses assessed to date are 160 mg/kg in the step dose arm and 300 mg/kg in the fixed dose arm.

Confirmed RECIST partial response, PSA decline, and circulating tumor cell (CTC) reduction were observed across both arms. Reduction in CTC was observed in 32 (57%) of 56 evaluable patients, including 14 CTC0 responses.

“Overall, across the entire study, 15 of 74 patients…with at least 6 months of follow-up have remained on treatment beyond 24 weeks. PSA declines from baseline have been observed in 20% of evaluable patients, including 4 PSA50 and 2 PSA30 responses,” de Bono said.

Cytokine release syndrome (CRS) and transaminitis were the most common treatment-related adverse events (AEs), and they occurred most often in cycle 1, according to de Bono. Other cytokine-related AEs included chills, pyrexia, hypotension, infusion-related reaction, flushing, and hypoxia. Liver function tests revealed all-grade and grade 3+ aspartate aminotransferase increases in 28 (31%) and 19 (21%) men, respectively, and all-grade and grade 3+ alanine aminotransferase increases in 26 (29%) and 14 (16%) men, respectively. Other reported AEs included fatigue, nausea, vomiting, anemia, headache, back pain, tachycardia, constipation, and decreased appetite.



“HPN424 has been generally well tolerated. Two patients discontinued due to treatment-related adverse events. The MTD has not yet been reached for either the step dose or fixed dose arms,” de Bono commented.

The most common dose-related toxicities were grade 4 transaminitis and grade 3 CRS. No grade 4/5 CRS or grade 5 treatment-related AEs were observed.

De Bono JS, Fong L, Beer TM, et al. Results of an ongoing phase 1/2a dose escalation study of HPN424, a tri-specific half-life extended PSMA-targeting T-cell engager, in patients with metastatic castration-resistant prostate cancer (mCRPC). 

In patients with metastatic castration-resistant prostate cancer treated in a phase 1/2a study, the HPN424, a tri-specific half-life extended prostate-specific membrane antigen-targeting T cell engager was well tolerated and demonstrated antitumor activity.

Investigational PSMA-Targeted Treatment Demonstrates Antitumor Activity in mCRPC

In patients with advanced clear cell renal cell carcinoma (ccRCC), a phase 1b/2 umbrella platform study is evaluating the safety and efficacy of experimental combinations of investigational agents, according to a poster shared during the 2021 American Association for Cancer Research Virtual Annual Meeting.

Substudy 03B (NCT04626518) will evaluate patients whose disease progresses after treatment with PD-1/PD-L1 inhibitors and VEGF-tyrosine kinase inhibitors (TKIs).

“PD-1/L1-based combination regimens are the standard of care for first-line treatment of advanced clear cell RCC (ccRCC); however, there is no standard of care in the post–immuno-oncology/post-VEGF patient population, resulting in a high-unmet need,” explained the investigators, led by Hans Hammers, MD, PhD, of the University of Texas Southwestern Medical Center, Dallas.

The treatments to be evaluated in the study include the cytotoxic T-lymphocyte-associated protein 4 quavonlimab (MK-1308), belzutifan (MK-6482), lymphocyte activation gene 3 (MK-4280), immunoglobulin-like transcript 4 (MK-4830), pembrolizumab (Keytruda), and lenvatinib (Lenvima).

“Given the promising results in the RCC cohort of the phase 1b/2 trial (KEYNOTE-146; NCT02501096)

 and the recent phase 3 CLEAR study (NCT02811861),

 pembrolizumab in combination with lenvatinib will be used as the reference arm in substudy 03B,” wrote the investigators.

Adults aged 18 years or older with locally advanced or metastatic ccRCC, measurable disease per RECIST v1.1 criteria, disease progression on or after anti-PD-1/PD-L1 treatment, disease progression after VEGF-TKI therapy, and Karnofsky performance status of 70% or higher are eligible for the study.

The study will include a safety lead-in phase followed by an efficacy phase. Treatment arms in the safety lead-in phase will include pembrolizumab plus belzutifan and lenvatinib plus belzutifan cohorts. Patients will be assigned 1:1 to treatment in an experimental arm or the reference arm. Patients will continue treatment until radiographic disease progression, unacceptable toxicity, intercurrent illness that prevents further administration of study treatment, or withdrawal of consent, according to the investigators.

Experimental arms in the efficacy phase will include quavonlimab 25 mg and pembrolizumab 400 mg IV Q6W; MK-4280 800 mg and pembrolizumab 200 mg IV Q3W; pembrolizumab 200 mg IV Q3W plus MK-4830 800 mg IV Q3W; pembrolizumab 400 mg IV Q6W plus belzutifan 120 mg orally QD; and lenvatinib 20 mg orally QD plus belzutifan 120 mg orally QD. The reference arm will evaluate pembrolizumab 400 mg IV Q6W plus lenvatinib 20 mg orally QD.

“Primary end points for safety lead-in phase (if applicable) are safety and tolerability to establish [a recommended phase 2 dose]; co-primary end points for efficacy phase are safety and objective response rate per RECIST v1.1 by blinded independent central review (BICR). Secondary end points during the efficacy phase are duration of response, progression-free survival, and clinical benefit rate per RECIST v1.1 (BICR), and overall survival,” according to the investigators.

Enrollment for the research is taking place at 27 sites in Australia, New Zealand, South Korea, Spain, and the United States.

1. Hammers H, Choueiri T, Plimack E, et al. A phase 1b/2 umbrella study of investigational immune and targeted combination therapies for patients with advanced renal cell carcinoma (RCC) who progressed on PD-1/L1 and VEGF inhibitors. Presented at: 2021 AACR Virtual Annual Meeting; April 10-15, 2021; Virtual. Poster CT243

2. Lee C-H, Shah AY, Hsieh JJ, et al. Phase II trial of lenvatinib (LEN) plus pembrolizumab (PEMBRO) for disease progression after PD-1/PD-L1 immune checkpoint inhibitor (ICI) in metastatic clear cell renal cell carcinoma (mccRCC). 

2020;38, no. 15_suppl:5008. doi:10.1200/JCO.2020.38.15_suppl.5008

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

2021;384(14):1289-1300. doi:0.1056/NEJMoa2035716

In patients with advanced clear cell renal cell carcinoma, a phase 1b/2 umbrella platform study is evaluating the safety and efficacy of experimental combinations of investigational agents.