Benjamin Saylor

 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

Articles

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.

Benjamin Saylor | Authors

Articles

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

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

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

Investigational PSMA-Targeted Treatment Demonstrates Antitumor Activity in mCRPC