Jason M. Broderick

Nadofaragene firadenovec induced complete responses (CRs) in over half of patients with high-grade

 BCG-unresponsive non-muscle invasive bladder cancer (NMIBC), according to phase 3 data now published in the 

In patients with carcinoma in situ with or without concomitant high-grade Ta or T1 disease (CIS ± Ta/T1), the CR rate with nadofaragene firadenovecwas 53.4% at 3 months. The 12-month CR rate was 24.3% and the median duration of CR was 9.69 months.

“Once patients with high-grade, non-muscle invasive bladder cancer no longer benefit from their initial BCG treatments, patients often make an informed decision to decline cystectomy—a highly complex and life-altering bladder removal surgery—or are often medically ineligible for this complex operation, leaving them with limited options,” Colin P. N. Dinney, MD, chairman, Department of Urology, Division of Surgery, University of Texas MD Anderson Cancer Center, and senior author of the publication, stated in a press release.

 show that nadofaragene firadenovec, a first-of-its-kind therapy, may be an effective treatment option for BCG-unresponsive non-muscle invasive bladder cancer patients,” added Dinney.

The multicenter, open-label, repeat-dose phase 3 study (NCT02773849) accrued patients with BCG-unresponsive NMIBC at 33 clinical sites in the United States. Among 157 treated patients, there were 107 patients with CIS ± Ta/T1 tumors. The median patient age in this group was 72 years (range, 66-77), 89% were male, 93% were white, and the median time from initial bladder cancer diagnosis was 20 months (range, 13-35).

Overall, 90.7% of patients had an ECOG performance score of 0, and 3.7% had prior radiotherapy. The number of prior BCG courses included 1 (0.9%), 2 (42.1%), 3-8 (53.3%), and ≥9 (3.7%).

The novel intravesical gene-mediated therapy nadofaragene firadenovec was administered by catheter as a single dose into the bladder. Those patients without recurrence received repeat doses at 3, 6, and 9 months. The primary end point was the CR rate in patients with CIS± Ta/T1 tumors.

Of the 107 patients with CIS± Ta/T1 disease, 103 were included in the efficacy analysis (4 patients were excluded because they did not meet the study definition of BCG-unresponsive NMIBC). Among these 103 patients, 55 (53.4%) had a CR at month 3, and 25 (24.3%) were in CR at 12 months.

“As a practicing urologist, I’m encouraged by these efficacy and safety data which demonstrate the potential for a novel treatment option that fits within the urology practice and gives patients the choice of receiving treatment once every 3 months—which may be a particularly important consideration in this evolving healthcare environment,” Gennady Bratslavsky, MD, president of the Society of Urologic Oncology Clinical Trials Consortium (SUO-CTC), and professor and chair of Urology at SUNY Upstate Medical University, stated in the press release. “Our organization is proud to have played a key role in the mid- and late-stage clinical studies for nadofaragene firadenovec.”

The safety analysis included all 157 patients enrolled on the trial who received at least 1 dose of nadofaragene firadenovec. The most common grade 3 treatment-related adverse event (TRAE) was micturition urgency, which occurred in 2 patients. There were four other grade 3 TRAEs occurring in 1 patient each: bladder spasm, syncope, hypertension, and urinary incontinence.No grade 4 TRAEs were reported and there were no treatment-related deaths.

The trial remains ongoing with the study design set up for a 4-year treatment and monitoring phase.

In their study summary, the authors wrote, “Future research [of nadofaragene firadenovec] should include analyses to help to identify early treatment responders and provide insights into the potential mechanisms of treatment non-response.

1. FerGene announces Landmark Phase 3 study published in Lancet Oncology. Published online November 30, 2020. https://bit.ly/3mnNzx1. Accessed November 30, 2020.

2. Boorjian SA, Alemozaffar M, Bad Konety BR, et al. Intravesical nadofaragene firadenovec gene therapy for BCG-unresponsive non-muscle-invasive bladder cancer: a single-arm, open-label, repeat-dose clinical trial [published online November 27, 2020]. 

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“These data published in the Lancet Oncology show that nadofaragene firadenovec, a first-of-its-kind therapy, may be an effective treatment option for BCG-unresponsive non-muscle invasive bladder cancer patients,” Colin P. N. Dinney, MD.

Nadofaragene firadenovec published data show strong efficacy in BCG-unresponsive NMIBC

Long-term oncologic outcomes were superior with adjuvant androgen-deprivation therapy (ADT) over neoadjuvant ADT when combining hormone therapy with radiation therapy (RT) in localized prostate cancer, according to findings from a pooled analysis of 2 randomized phase 3 trials.

At a median follow-up of 15 years, the pooled analysis showed statistically significant improvements with adjuvant ADT over neoadjuvant ADT in biochemical failure, distant metastasis, and progression-free survival rates.

“We demonstrate for the first time that sequencing of ADT with RT significantly impacts long-term oncologic outcomes in localized prostate cancer, favoring an adjuvant- rather than neoadjuvant-based approach, without increasing late toxicity. This data has important implications to ongoing and future clinical trial design,” first study author Daniel E. Spratt, MD, professor of radiation oncology at the University of Michigan, Ann Arbor, and coinvestigators wrote in their study conclusion.

The first trial used for the pooled analysis was a phase 3 trial by Malone et al

 which randomized patients with localized prostate cancer to neoadjuvant/concurrent or concurrent/adjuvant ADT for 6 months with prostate only radiotherapy. These data were combined with the prostate only radiotherapy arms of the phase 3 RTOG 9413 trial,

 in which patients were randomized to 4 months of either adjuvant ADT or neoadjuvant/concurrent ADT.

In the pooled analysis, the “neoadjuvant” group included patients in the neoadjuvant/concurrent arms of both prior studies, and the “adjuvant” group included patients from the adjuvant arm of RTOG 9413 and the concurrent/adjuvant arm of Malone et al’s study.

Overall, there were 1065 patients included in the pooled analysis, comprising 531 patients who received neoadjuvant ADT and 534 patients who received adjuvant ADT. Baseline patient and tumor characteristics were well balanced between the 2 arms.

The biochemical failure rate at 15 years was 33% with adjuvant ADT versus 43% with neoadjuvant ADT (HR, 1.37; 

 = .002). At 15 years, 12% of patients receiving adjuvant ADT had distant metastasis compared with 18% of patients who received neoadjuvant ADT (HR, 1.40; 

 = .04). The 15-year PFS rates were 36% versus 29%, respectively (HR, 1.25; 

Prostate cancer–specific mortality (PCSM) rates were also lower with adjuvant ADT at 15% versus 20% with neoadjuvant ADT; however, the difference was not statistically significant (HR, 1.29; 

 = 0.10). Of note, the difference in PCSM rate favoring adjuvant ADT did approach statistical significance in patients with high-risk disease (HR, 1.39; 

Although the 15-year overall survival rate was higher with adjuvant ADT, the difference was not statistically significant: 39% versus 34% (HR, 1.11; 

Regarding toxicity, late grade ≥3 gastrointestinal (

 = .98) adverse events were not significantly higher with adjuvant ADT.

1. Spratt DE, Malone S, Roy S, et al. Short-Term adjuvant versus neoadjuvant hormone therapy in localized prostate cancer: a pooled individual patient analysis of two randomized phase 3 trials. 

. 2020;108(3):S17. doi.org/10.1016/j.ijrobp.2020.07.2099

2. Malone S, Roy S, Eapen L, et al. Sequencing of androgen-deprivation therapy with external-beam radiotherapy in localized prostate cancer: A phase III randomized controlled trial. 

. 2020;38(6):593-601. doi: 10.1200/JCO.19.01904

3. Roach M, Moughan J, Lawton CAF, et al. Sequence of hormonal therapy and radiotherapy field size in unfavourable, localised prostate cancer (NRG/RTOG 9413): long-term results of a randomised, phase 3 trial. 

. 2018;19(11):1504-1515. doi: 10.1016/S1470-2045(18)30528-X

Analysis supports using adjuvant over neoadjuvant ADT with RT for localized prostate cancer

The FDA has granted Fast Track Designation to RV001, an investigational synthetic long peptide vaccine that targets RhoC, for the treatment to patients with prostate cancer.

RhoC is a small GTPase that is overexpressed in advanced solid tumors. Results from a phase 1/2 first-in-human study published in the 

showed that 18 of 21 evaluable patients had an immunological response to RV001.

 Safety data showed that the vaccine was tolerable with no grade ≥3 treatment-related adverse events reported. 

"We are extremely pleased and proud that our drug candidate, RV001, has earned Fast Track Designation by the FDA. We obviously appreciate the benefits that this might entail in terms of access to FDA advice and an accelerated approval process. But also the fact that the FDA has reviewed our data, and found our drug candidate worthy of this level of priority, obviously sends a clear signal of recognition of the drug's potential to all our would-be partners, which is something of great importance to us," Anders Månsson, CEO of RhoVac, the manufacturer of RV001, stated in a press release.

The phase 1/2 study (NCT03199872) included 22 patients aged ≥18 years who had previously received radical prostatectomy. Patients had histologically confirmed adenocarcinoma of the prostate gland and were not receiving anticancer therapy at the time of enrollment. Prior androgen-deprivation therapy was not allowed. Patients had an ECOG performance status of 0 or 1.

RV001 was administered subcutaneously every 2 weeks for 6 injections, then 5 times every 4 weeks for a total treatment regimen duration of 30 weeks. Safety was the primary outcome measure with immunological response as a secondary outcome measure.

Overall, 18 of 21 evaluable patients developed a strong CD4 T cell response against the vaccine. The response durations all lasted at least 10 months after the patient received the last injection of RV001. The investigators identified 3 promiscuously presented HLA-class II epitopes. “Vaccine-specific CD4 T cells were polyfunctional and effector memory T cells that stably expressed PD-1 (CD279) and OX-40 (CD134), but not LAG-3 (CD223),” the study authors explained.

 Additionally, there was 1 detected CD8 T cell response.

“Targeting of RhoC induced a potent and long-lasting T cell immunity in the majority of the patients. The study demonstrates an excellent safety and tolerability profile,” the authors wrote in their study conclusion.

RV001 is currently being evaluated in the double-blind phase 2 BRaVac trial in men with biochemical failure following curatively intended therapy for localized prostate cancer. Patients enrolled on the trial will be randomized to RV001 or placebo. The primary outcome measure is time to PSA progression and the estimated primary completion date is September 2021.

1. RhoVac's Prostate Cancer Drug Candidate, RV001, is granted Fast Track Designation by the FDA. Posted online November 25, 2020. https://prn.to/3m86J9X. Accessed November 25, 2020.

2. Schuhmacher J, Heidu S, Balchen T, et al. Vaccination against RhoC induces long-lasting immune responses in patients with prostate cancer: results from a phase I/II clinical trial. 

. 2020;8(2):e001157. doi: 10.1136/jitc-2020-001157

The vaccine RV001 targets RhoC, a small GTPase that is overexpressed in advanced solid tumors.

FDA grants Fast Track Designation to novel peptide-based vaccine in prostate cancer

The FDA has approved lumasiran (Oxlumo) as the first drug for the treatment of patients with primary hyperoxaluria type 1 (PH1). The drug is approved for both adult and pediatric patients.

Patients with this rare metabolic disorder 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.

“The approval of Oxlumo represents a great triumph of community involvement to address a rare disease. It is a result of input from patients, treating physicians, experts and sponsors at a patient-focused drug development meeting and through other collaborative efforts,” Norman Stockbridge, MD, PhD, director of the Division of Cardiology and Nephrology in the FDA’s Center for Drug Evaluation and Research, stated in a press release.

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 tomonth 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 was also recently approved in the European Union for the treatment of PH1 in both pediatric and adult patients.

1. 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 November 23, 2020.

2. 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 November 23, 2020.

3. 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 November 23, 2020.

The treatment is approved for both adult and pediatric patients.

Jason M. Broderick

Articles

Nadofaragene firadenovec published data show strong efficacy in BCG-unresponsive NMIBC

Analysis supports using adjuvant over neoadjuvant ADT with RT for localized prostate cancer

FDA grants Fast Track Designation to novel peptide-based vaccine in prostate cancer

FDA approves lumasiran as first drug for primary hyperoxaluria type 1