SUMMARY

• Liow et al (2022)¹ reported results from a phase 2, open-label study that evaluated the efficacy and safety of BALVERSA plus androgen deprivation therapy (ADT) in men with localized high-risk prostate cancer before prostatectomy (N=9). No patient experienced a pathological complete response (pCR) or had minimal residual disease (MRD). Grade 3 toxicities were observed in 6 patients; no grade 4-5 events were reported. The most common adverse event (AE) was hyperphosphatemia (n=8).¹
• RAGNAR (NCT04083976) is an ongoing, phase 2, open-label, single-arm, global, multicenter study evaluating the efficacy and safety of BALVERSA in adult and pediatric patients with unresectable, locally advanced, or metastatic solid tumor malignancies, fibroblast growth factor receptor (FGFR) mutations or gene fusions, and documented disease progression. The primary endpoint was objective response rate (ORR).^2,3 For complete study details, refer to https://clinicaltrials.gov/study/NCT04083976.
  • Preliminary results of molecular eligibility screening for the RAGNAR study included 2% (2/110) of patients with prostate cancer (FGFR3 fusion and mutation).⁴
  • Pant et al (2023)⁵ reported primary analysis results after a median follow-up of 17.9 months from a primary cohort of patients (N=217) with 16 different solid tumor types in the RAGNAR study. No response was observed in patients with prostate cancer (n=2). In the overall population, BALVERSA-related grade ≥3 treatment-emergent adverse events (TEAEs) were reported in 46% (100/217) of patients. The most common grade ≥3 TEAEs were stomatitis (12%), palmar-plantar erythrodysesthesia (6%), and hyperphosphatemia (5%). Safety was not evaluated separately for patients with prostate cancer.

CLinical DATA

Phase 2 Studies

Liow et al (2022)¹ reported results from a phase 2, open-label study that evaluated the efficacy and safety of BALVERSA in combination with ADT in men with localized high-risk prostate cancer before prostatectomy (N=9).

Study Design/Methods

• Phase 2, nonrandomized, open-label study in the neoadjuvant setting.
• Patients received degarelix 240/80 mg subcutaneously every 4 weeks for up to 16 weeks and BALVERSA 8 mg orally (PO) once daily escalated to 9 mg once daily at day 14 if phosphate levels were <5.5 mg/dL for the first 12 weeks. Surgery was scheduled within 2 weeks of completion of the last cycle.
• Inclusion criteria: histologically confirmed prostate cancer; prostate-specific antigen (PSA) >20 ng/mL, Gleason pattern ≥4 (Gleason sum 4+3=7, 8-10), and/or clinical stage ≥T2c (≥cT2c); no evidence of metastatic disease on a bone scan; amenable to radical prostatectomy.
• Exclusion criteria: evidence of endocrine alteration of calcium-phosphorus homeostasis; calcification/mineralization of soft tissue or internal organs (except lymph node calcification or asymptomatic arterial calcification); evidence of corneal or retinal abnormality on ophthalmological evaluation.
• Primary endpoints: safety and tolerability; rate of pCR.
• Secondary endpoints: rate of MRD; partial response (PR); rate of organ-confined and specimen-confined disease.

Results

Patient Characteristics

• The baseline demographics and disease characteristics are described in Table: Patient Baseline Characteristics.

Efficacy

• All patients experienced biochemical response, with a PSA decrease of >95% in 5 patients before prostatectomy; no patient achieved a pCR or had MRD.
• Efficacy outcomes are described in Table: Efficacy Outcomes.
• Patients who tolerated BALVERSA for a longer duration had significantly lower residual tumor volume and decreased transcriptional markers of cell proliferation compared with those who had a shorter BALVERSA exposure.

Safety

• Grade 3 toxicities were reported in 6 patients; there were no grade 4-5 events.
• The most common AE was hyperphosphatemia reported in 8 patients, of whom 4 required phosphate binders. A summary of AEs occurring in ≥30% of patients is shown in Table: Adverse Events.
• Dose interruptions were reported in 3 patients (grade 2 bilateral central serous chorioretinopathy, n=1; grade 2 mucositis, n=2) followed by a dose reduction of BALVERSA from 9 mg to 8 mg once daily; recommencement of BALVERSA even at the lower dose led to its permanent discontinuation in all patients due to the relapse of symptoms, whereas ADT (4 months) was completed without interruption.
• Treatment with BALVERSA was discontinued in the remaining 3 patients due to intolerable grade 2 AEs.

Pant et al (2023)⁵ reported primary analysis results of the broad panel cohort of the RAGNAR study (NCT04083976; N=217), including patients with prostate cancer (n=2).

Study Design/Methods

• Ongoing phase 2, open-label, single-arm, global, multicenter study evaluating the efficacy and safety of BALVERSA PO once daily in adult and pediatric patients (children aged ≥6 years) with unresectable, locally advanced, or metastatic solid tumor malignancies (tumor agnostic), FGFR mutations or gene fusions, and documented disease progression.
• The primary cohort consisted of patients aged ≥12 years with unresectable, locally advanced or metastatic solid tumors (except urothelial carcinoma), predefined FGFR1-4 alterations (mutations/fusions), documented disease progression, who received ≥1 prior line of systemic therapy and no alternative standard therapy.
• Patients received BALVERSA PO once daily on a 21-day cycle until disease progression or intolerable toxicity.
  • Adult and adolescent patients (aged ≥15 to <18 years) were initiated with BALVERSA 8 mg with possible up-titration to 9 mg based on cycle 1 day 14 serum phosphate levels.
  • Adolescent patients (aged ≥12 to <15 years) were initiated with BALVERSA 5 mg with possible up-titration to 6 mg or further to 8 mg based on cycle 1 day 14 and cycle 2 day 7 serum phosphate levels.
• Efficacy for patients with non-central nervous system tumors was assessed using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1.
  • Primary endpoint: Independent review committee (IRC)-assessed ORR.
  • Secondary endpoints: Investigator-assessed ORR, duration of response (DOR), disease control rate (DCR), clinical benefit rate, progression-free survival (PFS), overall survival (OS), safety, health-related quality of life, and pharmacokinetics.

Results

Efficacy

• The primary cohort included 217 patients with 16 solid tumor types.
  • Median follow-up for efficacy was 17.9 months (interquartile range [IQR], 13.6-23.9), and median treatment duration was 4.3 months (IQR, 2.1-9.2).
  • IRC-assessed ORR was 30% (64/217; 95% confidence interval [CI], 24-36).
  • Investigator-assessed ORR was 25% (95% CI, 20-32), median DOR was 6.9 months (95% CI, 4.4-7.1; investigator-assessed median DOR, 7 months [95% CI, 5.5-8.5]), DCR was 74% (95% CI, 67-80), clinical benefit rate was 46% (95% CI, 39-53), median PFS was 4.2 months (95% CI, 4.1-5.5; PFS events, n=160), and median OS was 10.7 months (95% CI, 8.7-12.1).
• In patients with prostate cancer (n=2), no response to BALVERSA was observed. Median PFS was 1.3 months (95% CI, 1.2-not evaluable [NE]) and median OS was 7.1 months (95% CI, 3.5-NE).⁶

Safety

• Safety data were consistent with the known safety profile of BALVERSA in urothelial carcinoma. Safety was not separately evaluated for patients with prostate cancer.
• At a median treatment exposure of 4.3 months (IQR, 2.1-9.2), 99.5% (216/217) of patients experienced ≥1 TEAEs.
• BALVERSA-related grade ≥3 TEAEs occurred in 46% (100/217) of patients. The most common grade ≥3 TEAEs were stomatitis (12%), palmar-plantar erythrodysesthesia syndrome (6%), and hyperphosphatemia (5%).
• Serious TEAEs were reported in 39% (85/217) of patients. The most common grade ≥3 serious treatment-related adverse events (TRAEs) were stomatitis (4/217; 2%) and diarrhea (2/217; 1%).
• The most common TRAEs leading to discontinuation were palmar-plantar erythrodysesthesia syndrome and stomatitis (3/217; 2% each).
• Central serous retinopathy events were reported in 14% (31/217) of patients.
  • Grade 1-2: Chorioretinopathy (8/217; 4%), detachment of retinal pigment epithelium (7/217; 3%), and retinal detachment (6/217; 3%).
  • Grade 3: Retinal edema (<1%).
• TEAEs leading to death were reported in 4% (8/217) of patients (multiple organ dysfunction syndrome, pyrexia, coronavirus disease 2019 [COVID-19]), sepsis, pulmonary embolism, respiratory failure, cardiac arrest, and subdural hematoma); all were considered unrelated to BALVERSA by investigator assessment.

Literature Search

A literature search of MEDLINE^®, Embase^®, BIOSIS Previews^®, and Derwent Drug File (and/or other resources, including internal/external databases) was conducted on 13 January 2025.