Jason M. Broderick

DecipherProstate Biopsy, a 22-gene microarray-based genomic classifier, showed potential as a tool to help guide decisions between active surveillance and radical treatment in men with early-stage prostate cancer, according to a real-world study published in 

"We have long needed better risk stratification tools for early-stage prostate cancer patients to reduce the uncertainty that is often part of initial treatment decisions," Randy Vince Jr., MD, Society of Urologic Oncology Fellow, University of Michigan, and the paper's lead author, stated in a press release. "The findings from our analysis, which show that men with high Decipher scores are more likely to transition off of active surveillance and are over 2-fold times more likely to experience treatment failure after initial therapy, provide evidence that molecular testing could have significant utility in this setting."

The data for the study were obtained from the Michigan Urological Surgery Improvement Collaborative (MUSIC) registry. The study included 855 men with localized prostate cancer who received Decipher testing between February 2015 and October 2019.

The median patient age was 66 (interquartile range [IQR], 60-72), including 500 patients aged 65 to 74. Regarding race, 75% of patients were White, 13.1% were Black, 0.9% were Asian, 0.1% were Native American, and 10.9% of patients were unknown/other. The median body mass index (BMI) was 28.6 kg/m2. Specifically, 19.1% of patients had a BMI ≤25 kg/m2, 46% of patients had a BMI between 25.1 kg/m2 and 30 kg/m2 and 34.9% of patients had a BMI >30 kg/m2. The median PSA at baseline was 6.1 ng/ml. The majority (59.1%) of patients had a PSA between 4.1 ng/ml and 10 ng/ml.

About one-third (32.6%) of patients had 1 to 2 positive cores, 26.4% had 3 to 4 positive cores, and 41% had >4 positive cores. Regarding NCCN risk group status, 19.1% were low, 30.9% were favorable/intermediate, 39.7% were unfavorable/intermediate, and 10.3% were high.

Across the study population, 31% (n = 264) of patients elected active surveillance upfront and 53% (n = 454) chose to receive radical therapy. The investigators adjusted for several factors—risk status, PSA, age, BMI, prostate volume, positive cores—and found that in men who chose active surveillance, there was an independent association between a high-risk Decipher score and a shorter time to conversion from active surveillance to radical therapy (HR, 2.51; 

 <.001). The median time on active surveillance was 13.6 months in men with high-risk Decipher scores versus 33 months in patients with low/intermediate scores (

A similar pattern was observed in patients receiving definitive treatment. Among 479 evaluable patients who underwent radical therapy either upfront or following active surveillance, there was an independent association between a high-risk Decipher score and a significantly shorter time to treatment failure (

“We believe this real-world study and the resulting findings fill a critical gap in prostate cancer treatment, which is the need for an objective tool that can help physicians identify those early-stage patients who are good candidates for active surveillance as well as those who should move directly to definitive treatment with surgery or radiotherapy,” Elai Davicioni, PhD, senior vice president, Scientific and Clinical Operations, Urologic Cancers, at Veracyte, the developer of the Decipher test, stated in the press release.

1. New Study Suggests Decipher Prostate Biopsy Test May Help Guide Use of Active Surveillance in Prostate Cancer. Published online July 27, 2021. Accessed July 30, 2021. https://bwnews.pr/3C8FYeb.

2. Vince RA Jr, Jiang R, Qi J, et al. Impact of Decipher Biopsy testing on clinical outcomes in localized prostate cancer in a prospective statewide collaborative [published online ahead of print June 20, 2021]. 

Articles

Decipher Prostate Biopsy, a 22-gene microarray-based genomic classifier, showed potential as a tool to help guide decisions between active surveillance and radical treatment in men with localized prostate cancer.

Real-world data show clinical utility of novel genomic test in early-stage prostate cancer

The FDA has issued a complete response letter (CRL) to Ardelyx stating that an additional clinical trial is needed to support approval of tenapanor, the company’s novel treatment for the control of serum phosphorus in adult patients with chronic kidney disease (CKD) on dialysis.

Ardelyx previously submitted a new drug application (NDA) to the FDA hoping to obtain approval of tenapanor in this setting; however, the CRL explained that the data in the NDA left the FDA “unclear of the clinical significance”of the treatment. According to Ardelyx, the CRL did not identify any issues in other key areas, such as safety; clinical pharmacology/biopharmaceutics; chemistry, manufacturing and control; or nonclinical items.

"Lowering serum phosphorus is a priority for me in managing my patients on dialysis, and is an established standard of care driven by the peer-reviewed globally accepted KDIGO clinical practice guidelines. Years of research have demonstrated the negative consequences associated with even slight elevations in serum phosphorus. Despite our best efforts with currently available therapies, managing phosphorus remains a significant challenge. We need new tools,” Arnold Silva, MD, PhD, director of Clinical Research at Boise Kidney and Hypertension Institute, stated in the press release.

“I've closely followed the extensive clinical development of tenapanor, not only as an interested nephrologist, but also as a clinical investigator. I've seen the clinical benefits of tenapanor first-hand in my patients and I'm stunned that the FDA is not granting approval of this novel mechanism drug, despite extensive clinical data demonstrating its safety and efficacy," added Silva.

Also commenting in the press release, Glenn Chertow, MD, division chief of nephrology and professor of medicine at Stanford University, stated, "Neither peritoneal nor hemodialysis provides adequate control of serum phosphorus, obligating the use of medications. Unfortunately, phosphate binders—individually or in combination—rarely yield consistent control of serum phosphorus concentrations, and persistent hyperphosphatemia leads to dystrophic calcification, accelerated arteriosclerotic vascular disease, fractures, and other complications that profoundly affect patients' lives. The effect of tenapanor on serum phosphorus observed in the phase 3 trials is clinically meaningful. Tenapanor would enable a substantially larger fraction of patients to reach target serum phosphorus concentrations and would yield significant clinical benefit to this vulnerable population."

Regarding next steps with tenapanor Mike Raab, president and chief executive officer of Ardelyx, stated, "We continue to believe tenapanor represents an important, first-in-class treatment option for patients with elevated phosphorus. We do not agree with the FDA's subjective assessment on the clinical relevance of the treatment effect of tenapanor in our studies which met all clinical endpoints agreed upon by the FDA. In our view, the serum phosphorus lowering data generated with tenapanor in all of our clinical studies is meaningful and clinically significant. We will work with the agency to address the issues raised and, to the extent possible, find an expeditious path forward."

1. Ardelyx Receives Complete Response Letter from U.S. FDA for New Drug Application for Tenapanor for the Control of Serum Phosphorus in Adult Patients with CKD on Dialysis. Published online July 29, 2021. Accessed July 30, 2021. https://prn.to/3zNth6c.

The FDA has issued a complete response letter regarding a new drug application for tenapanor for the control of serum phosphorus in adult patients with chronic kidney disease on dialysis.

FDA requests additional study to support approval of tenapanor for patients with CKD

The pivotal phase 3 ILLUMINATE-C trial of lumasiran (Oxlumo) in patients of all ages with advanced primary hyperoxaluria type 1 (PH1) or PH1 associated with progressive decline in renal function has met its primary endpoint, according to Alnylam Pharmaceuticals, the developer of the RNA interference agent.

Results of the 6-month primary analysis from the open-label, single arm ILLUMINATE-C trial (NCT04152200) showed that in both dialysis-independent and -dependent patients, lumasiran induced a substantial reduction in plasma oxalate. The treatment also met several key secondary end points, including additional measures of plasma oxalate and measures of urinary oxalate.

Alnylam reported in a release that the actual data from the ILLUMINATE-C trial would be shared at a medical conference by the end of the year. The company also plans to submit the data to regulatory authorities in the United States and the European Union.

"Through the ILLUMINATE clinical program, we are hoping to establish that lumasiran may be a therapeutic option for PH1 patients regardless of age or disease severity, including patients on hemodialysis," Jeroen Valkenburg, general manager, Lumasiran program at Alnylam, stated in the release.

Patients with the rare metabolic disorder PH1 produce excess oxalate, which, when combined with calcium, can cause kidney stones and loss of kidney function. Lumasiran works by inhibiting the production of oxalate.

In November 2020, the FDA approved lumasiran as the first drug for the treatment of patients with PH1.

 The drug was approved for both adult and pediatric patients. The approval of lumasiran was supported by data from the phase 3 ILLUMINATE-A and ILLUMINATE-B studies.

The phase 3 open-label ILLUMINATE-A trial (NCT03681184) included 39 patients aged ≥6 years with PH1. Overall, 26 patients were randomized to lumasiran and 13 were randomized to placebo.

In the treatment arm, patients received subcutaneous lumasiran monthly for 3 months followed by quarterly maintenance doses at 3 mg/kg. The primary outcome measure was percent change in 24-hour urinary oxalate excretion from baseline to month 6.

Among patients in the lumasiran arm, there was a 65% average reduction of oxalate in the urine compared with an average reduction of 12% in the placebo arm. Over half (52%) of patients receiving lumasiran achieved a normal 24-hour urinary oxalate level at 6 months, compared with no patients in the placebo group.

Regarding safety, investigators determined the drug to be safe and tolerable. No severe or serious adverse events (AEs) were reported and there were no patient deaths.

 All AEs were mild to moderate. The most common AE was injection site reactions, which occurred in 35% of patients.

The open-label, single-arm phase 3 ILLUMINATE-B trial (NCT03905694) evaluated lumasiran in patients aged under 6 years with PH1. Among 16 evaluable pediatric patients, lumasiran treatment led to an average decrease of 71% in urinary oxalate at the 6-month point of the study.

The investigators reported that lumasiran had an acceptable safety profile in the pediatric population.

 No patients discontinued treatment or withdrew from the study, and no severe AEs or patient deaths occurred. The most common AE was mild injection-site reactions, which occurred in 3 patients. Also, there were no clinically relevant changes in laboratory measures, vital signs, or electrocardiograms.

According to the FDA, approximately 80% of all PH cases are PH1, and the rare disease affects an estimated 1 to 3 people per million in North America and Europe.

Lumasiran is also approved in the European Union for the treatment of PH1 in both pediatric and adult patients.

1. Alnylam Reports Positive Results From Phase 3 Study Of Lumasiran In Primary Hyperoxaluria Type 1. Published online July 29, 2021. Accessed July 29, 2021. https://bit.ly/3fabWNf.

2. FDA Approves First Drug to Treat Rare Metabolic Disorder. Published online November 23, 2020. https://www.fda.gov/news-events/press-announcements/fda-approves-first-drug-treat-rare-metabolic-disorder. Accessed July 29, 2021

3. ILLUMINATE-A Phase 3 Results for Lumasiran Presented at ERA-EDTA. Published online June 7, 2020. https://www.alnylam.com/2020/06/07/era-edta-2020. Accessed July 29, 2021

4. ILLUMINATE-B Phase 3 Results for Lumasiran Presented at ASN. Published online October 22, 2020. https://www.alnylam.com/2020/10/22/asn-2020. Accessed July 29, 2021.

The FDA approved lumasiran in November 2020 as the first drug for the treatment of patients with primary hyperoxaluria type 1.

Pivotal phase 3 trial of lumasiran in PH1 meets primary end point

The addition of the PI3K-gamma inhibitor eganelisib to the PD-1 inhibitor nivolumab (Opdivo) was associated with a 38% reduction in the risk of death compared with nivolumab alone in patients with advanced urothelial carcinoma enrolled in the phase 2 MARIO-275 trial.

In the overall study population of 49 patients, the median overall survival (OS) was 15.4 months with the combination compared with 7.9 months with nivolumab alone (HR, 0.62). The 1-year OS rates were 59% versus 32%, respectively.

The OS benefit in patients with PD-L1–negative tumors mirrored the benefit in the overall study population. In the PD-L1–negative subset, the median OS was 15.4 months with the combination versus 7.9 months in the control arm (HR, 0.60). The 1-year OS rates in these patients were 54% versus 17%, respectively.

Overall, the global phase 2 MARIO-275 trial (NCT03980041) randomized patients with advanced urothelial carcinoma in a 2:1 ratio to eganelisib /nivolumab (n = 33) or placebo/nivolumab (n = 16). Prior immune checkpoint-inhibitor therapy was not allowed and patients had to have progressed or recurred following treatment with platinum-based chemotherapy. The primary end point of the study was objective response rate (ORR).

Response data from the trial were presented in February at the 2021 Genitourinary Cancers Symposium.

 In the overall population, the ORR was 30% with the combination versus 25% with placebo. The complete response rates and disease control rates were 12% versus 6% and 55% versus 31%, respectively.

Specifically among patients with PD-L1–negative disease, the ORRs were 26% with eganelisib plus nivolumab versus 14% with nivolumab alone. The complete response rates and disease control rates were 9% versus 0% and 57% versus 14%, respectively.

The most frequently reported adverse events (AEs) across all grades in the eganelisib and placebo arms were pyrexia (33% vs 0%, respectively), decreased appetite (30% vs 19%), pruritis (24% vs 6%), asthenia (21% vs 31%), and transaminase elevation (21% vs 6%).

 The most common grade 3 or higher AEs were hepatotoxicity (15% vs 0%, respectively), transaminase elevation (12% vs 6%), and rash (9% vs 0%).

“The promising survival benefit was noted after over a year of following MARIO-275 patients versus the control arm as well as compared to historical trials including CheckMate-275, particularly given the magnitude of the unmet need in second-line urothelial carcinoma, including in the PD-L1–negative patient population,” Brian Schwartz, MD, consulting Chief Physician, Infinity Pharmaceuticals, the developer of eganelisib, stated in a press release.

“We believe OS represents a key registrational endpoint, and given these exciting new OS data, we are exploring the optimal study design for a potential registration study and expect to provide a program update by the end of 2021,” added Schwartz.

1. Infinity Pharmaceuticals Presents Updated Data from Phase 2 MARIO-275 Trial in Urothelial Cancer (UC) and Phase 2 MARIO-3 Trial in Triple Negative Breast Cancer (TNBC). Published online July 27, 2021. Accessed July 28, 2021. https://bwnews.pr/3y6gEmt.

2. Infinity Pharmaceuticals Presents Data from Randomized, Placebo-Controlled, Phase 2 MARIO-275 Trial of Eganelisib and Nivolumab in Advanced Urothelial Cancer at ASCO Genitourinary Cancers Symposium. Published online February 11, 2021. Accessed July 28, 2021. https://bit.ly/3xbIZXk.

The survival benefit in patients with PD-L1–negative tumors mirrored the benefit in the overall study population. 

Jason M. Broderick

Articles

Real-world data show clinical utility of novel genomic test in early-stage prostate cancer

FDA requests additional study to support approval of tenapanor for patients with CKD

Pivotal phase 3 trial of lumasiran in PH1 meets primary end point

Adding eganelisib to nivolumab shows survival benefit in bladder cancer