On February 13, 2023 The Janssen Pharmaceutical Companies of Johnson & Johnson reported plans to present more than 20 abstracts featuring seven oncology therapies from its robust portfolio and pipeline at the annual American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Genitourinary (GU) Cancers Symposium, taking place in San Francisco on February 16-18 (Press release, Janssen Pharmaceutica, FEB 13, 2023, View Source [SID1234627128]). Building on more than a decade of leadership in the development of medicines for people diagnosed with GU cancers, Janssen will present data demonstrating its ambition to advance patient-centered treatment through precision medicine, real-world evidence and innovative development approaches across all stages of prostate and bladder cancer.
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"At Janssen, we are focused on early intervention in prostate and bladder cancer and optimizing outcomes through treatment approaches based on the genetic profiles of tumors," said Kiran Patel, M.D., Vice President, Clinical Development, Solid Tumors, Janssen Research & Development, LLC. "Data featured at this year’s ASCO (Free ASCO Whitepaper) GU reflect the cutting-edge therapies in our portfolio and pipeline and illustrate how Janssen’s science is advancing our vision to eliminate cancer."
"Despite advances in treatment over the past decade, we continue to see unmet needs across genitourinary cancers, especially for tumors with certain genetic mutations," said Luca Dezzani, M.D., U.S. Vice President, Medical Affairs, Solid Tumor, Janssen Scientific Affairs, LLC. "Presentations at this year’s ASCO (Free ASCO Whitepaper) GU underscore our continuing commitment to addressing the needs of patients living with prostate and bladder cancer at all stages of their disease."
Further information about these data and efforts across Janssen to advance the science of prostate and bladder cancer will be made available throughout ASCO (Free ASCO Whitepaper) GU via the Janssen Oncology Virtual Newsroom.
Key highlights from Janssen-sponsored studies to be presented at ASCO (Free ASCO Whitepaper) GU include:
Updated Data from the Phase 3 MAGNITUDE Study of Niraparib in Combination with Abiraterone Acetate Plus Prednisone (AAP) for the Treatment of Patients with BRCA-Positive Metastatic Castration-Resistant Prostate Cancer (mCRPC)
Rapid Oral Presentation: A presentation will highlight data from the second interim analysis of the Phase 3 MAGNITUDE study evaluating niraparib in combination with AAP for the treatment of patients with mCRPC with specific homologous recombination repair (HRR) gene alterations, in particular BRCA mutations (Abstract #170).1
Poster Presentation: An additional analysis from MAGNITUDE will review the impact of run-in treatment with AAP on the safety and efficacy of niraparib in combination with AAP to determine if the combination improved outcomes in patients with HRR genetic alterations, in particular BRCA mutations (Abstract #172).2
Latest ERLEADA (apalutamide) Data Includes Results from the Phase 3 PRESTO Study in High-Risk Biochemically Relapsed Prostate Cancer, a Post-Hoc Analysis from the Phase 3 SPARTAN Study Evaluating Treatment Sequencing in People with Advanced Disease and Multiple Real-World Evidence Presentations
Poster Presentation: New data from the collaborative Phase 3 PRESTO study will evaluate baseline factors associated with improved prostate-specific antigen (PSA) progression-free survival (PFS) when intensifying treatment beyond androgen deprivation therapy (ADT) with the addition of ERLEADA, with or without AAP in patients with high-risk biochemically relapsed prostate cancer (Abstract #208).3
Poster Presentation: A post-hoc analysis from the Phase 3 SPARTAN study will report the efficacy of subsequent therapies for mCRPC in patients with non-metastatic castration-resistant prostate cancer (nmCRPC) treated with ERLEADA (Abstract #157).4
Poster Presentations: Multiple real-world evidence data studies will evaluate the benefit of ERLEADA in patients across the prostate cancer spectrum including:
Real-world evidence data in patients with nmCRPC treated with ERLEADA assessed for PSA response and metastasis-free survival (MFS) (Abstract #69).5
A study describing time-to-castration resistance based on real-world evidence data for patients with metastatic castration-sensitive prostate cancer (mCSPC) who were treated with ERLEADA, abiraterone acetate or enzalutamide (Abstract #65).6
A retrospective study will examine real-world evidence data in patients with high-risk localized or locally advanced prostate cancer treated with external beam radiation therapy (Abstract # 330).7
Data from the Phase 1 TAR-200-102 Study Evaluating Safety and Efficacy of TAR-200, Real-World Evidence Data Evaluating Treatment Patterns and Adherence to Standard of Care in Patients with Non-Muscle Invasive Bladder Cancer (NMIBC), and a Trial-In-Progress Update from SunRISe-4 in Some Patients with Muscle-Invasive Bladder Cancer (MIBC)
Poster Presentation: New findings from the Phase 1 TAR-200-102 study will assess the safety and tolerability of TAR-200, a novel intravesical drug delivery system designed to provide a continuous, slow release of gemcitabine within the bladder, in patients with intermediate-risk NMIBC (Abstract #505).8
Poster Presentation: Real-world treatment patterns and adherence to Bacillus Calmette-Guerin (BCG) in the context of guideline recommendations for patients with NMIBC will help to emphasize the need for additional available treatment options that are safe, effective and tolerable (Abstract #470).9
Poster Presentation: Researchers will share a trial-in-progress update from the SunRISe-4 study of TAR-200 in combination with cetrelimab, an investigational programmed cell death receptor-1 (PD-1) monoclonal antibody, or cetrelimab alone in patients with MIBC who are ineligible or refuse neoadjuvant platinum-based chemotherapy (Abstract #TPS584).10
Data from the Phase 2 THOR-2 Study Evaluating the Safety and Efficacy of BALVERSA (erdafitinib) in High-Risk NMIBC and Intermediate-Risk NMIBC; TAR-210 Trial-in-Progress Update
Poster Presentation: Cohort 2 will assess patients with BCG-unresponsive high-risk NMIBC carcinoma in situ (CIS) with fibroblast growth factor receptor (FGFR) 3/2 genetic alterations. (Abstract #503).11
Poster Presentation: Cohort 3 will assess patients with intermediate-risk NMIBC and residual marker lesions with FGFR 3/2 genetic alterations. (Abstract #504).12
Poster Presentation: A trial-in-progress update from the open-label, multicenter Phase 1 TAR-210 study (Erdafitinib Intravesical Delivery System) will evaluate the safety and efficacy of TAR-210 in patients with NMIBC and MIBC harboring select FGFR genetic alterations (Abstract #TPS583).13
About Niraparib
Niraparib is an orally administered, highly selective poly (ADP-ribose) polymerase (PARP) inhibitor that is currently being studied by Janssen for the treatment of patients with prostate cancer.
Additional ongoing studies include the Phase 3 AMPLITUDE study evaluating the combination of niraparib and AAP in a biomarker-selected patient population with metastatic castration-sensitive prostate cancer (mCSPC).14
In April 2016, Janssen Biotech, Inc. entered a worldwide (except Japan) collaboration and license agreement with TESARO, Inc. (acquired by GlaxoSmithKline [GSK] in 2019) for exclusive rights to niraparib in prostate cancer. Niraparib is currently marketed by GSK as ZEJULA.15
About Abiraterone Acetate
Abiraterone acetate is an orally administered androgen biosynthesis inhibitor. In the United States, abiraterone acetate is indicated with prednisone for the treatment of mCRPC and high-risk mCSPC.16
About ERLEADA
ERLEADA (apalutamide) is an androgen receptor signaling inhibitor indicated for the treatment of patients with non-metastatic castration-resistant prostate cancer (nmCRPC) and for the treatment of patients with mCSPC.17 ERLEADA received U.S. Food and Administration (FDA) approval for nmCRPC in February 2018, and received U.S. FDA approval for mCSPC in September 2019.17 To date, more than 100,000 patients worldwide have been treated with ERLEADA.
For more information, visit www.ERLEADA.com.
About TAR-200
TAR-200 is an investigational drug delivery system, enabling controlled release of gemcitabine into the bladder, increasing dwell time and local drug exposure. The safety and efficacy of TAR-200 are being evaluated in Phase 2 and Phase 3 studies in patients with muscle-invasive bladder cancer (MIBC) and non-muscle invasive bladder cancer (NMIBC).
About Cetrelimab
Cetrelimab is an investigational programmed cell death receptor-1 (PD-1) monoclonal antibody being studied to treat bladder cancer, prostate cancer, melanoma and multiple myeloma as part of a combination treatment. Cetrelimab is also being evaluated in multiple other combination regimens across the Janssen Oncology portfolio.
About BALVERSA
BALVERSA (erdafitinib) is a once-daily, oral FGFR kinase inhibitor for the treatment of adults with locally advanced or metastatic urothelial carcinoma (mUC) that has susceptible FGFR3 or FGFR2 genetic alterations and has progressed during or following at least one line of platinum-containing chemotherapy, including within 12 months of neoadjuvant or adjuvant platinum-containing chemotherapy and received U.S. FDA approval in April 2019.18 Patients are selected for therapy based on an FDA-approved companion diagnostic for BALVERSA. This indication is approved under accelerated approval based on tumor response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.18,19 BALVERSA is the only approved treatment option for patients with FGFR-mutated mUC.
In 2008, Janssen Pharmaceutica NV entered into an exclusive worldwide license and collaboration agreement with Astex Pharmaceuticals to develop and commercialize BALVERSA.
For more information, visit www.BALVERSA.com.
About TAR-210
TAR-210 is an intravesical drug delivery system designed to provide local, continuous release of erdafitinib within the bladder. The safety and efficacy of TAR-210 is being evaluated in a Phase 1 study in patients with muscle-invasive bladder cancer (MIBC) and non-muscle invasive bladder cancer (NMIBC).
ERLEADA IMPORTANT Safety Information17
WARNINGS AND PRECAUTIONS
Cerebrovascular and Ischemic Cardiovascular Events — In a randomized study (SPARTAN) of patients with nmCRPC, ischemic cardiovascular events occurred in 3.7% of patients treated with ERLEADA and 2% of patients treated with placebo. In a randomized study (TITAN) in patients with mCSPC, ischemic cardiovascular events occurred in 4.4% of patients treated with ERLEADA and 1.5% of patients treated with placebo. Across the SPARTAN and TITAN studies, 4 patients (0.3%) treated with ERLEADA and 2 patients (0.2%) treated with placebo died from an ischemic cardiovascular event. Patients with history of unstable angina, myocardial infarction, congestive heart failure, stroke, or transient ischemic attack within 6 months of randomization were excluded from the SPARTAN and TITAN studies.
In the SPARTAN study, cerebrovascular events occurred in 2.5% of patients treated with ERLEADA and 1% of patients treated with placebo. In the TITAN study, cerebrovascular events occurred in 1.9% of patients treated with ERLEADA and 2.1% of patients treated with placebo. Across the SPARTAN and TITAN studies, 3 patients (0.2%) treated with ERLEADA, and 2 patients (0.2%) treated with placebo died from a cerebrovascular event.
Cerebrovascular and ischemic cardiovascular events, including events leading to death, occurred in patients receiving ERLEADA. Monitor for signs and symptoms of ischemic heart disease and cerebrovascular disorders. Optimize management of cardiovascular risk factors, such as hypertension, diabetes, or dyslipidemia. Consider discontinuation of ERLEADA for Grade 3 and 4 events.
Fractures — In a randomized study (SPARTAN) of patients with nmCRPC, fractures occurred in 12% of patients treated with ERLEADA and in 7% of patients treated with placebo. In a randomized study (TITAN) of patients with mCSPC, fractures occurred in 9% of patients treated with ERLEADA and in 6% of patients treated with placebo. Evaluate patients for fracture risk. Monitor and manage patients at risk for fractures according to established treatment guidelines and consider use of bone-targeted agents.
Falls — In a randomized study (SPARTAN), falls occurred in 16% of patients treated with ERLEADA compared with 9% of patients treated with placebo. Falls were not associated with loss of consciousness or seizure. Falls occurred in patients receiving ERLEADA with increased frequency in the elderly. Evaluate patients for fall risk.
Seizure — In two randomized studies (SPARTAN and TITAN), 5 patients (0.4%) treated with ERLEADA and 1 patient treated with placebo (0.1%) experienced a seizure. Permanently discontinue ERLEADA in patients who develop a seizure during treatment. It is unknown whether anti-epileptic medications will prevent seizures with ERLEADA. Advise patients of the risk of developing a seizure while receiving ERLEADA and of engaging in any activity where sudden loss of consciousness could cause harm to themselves or others.
Severe Cutaneous Adverse Reactions — Fatal and life-threatening cases of severe cutaneous adverse reactions (SCARs), including Stevens Johnson syndrome/toxic epidermal necrolysis (SJS/TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS) occurred in patients receiving ERLEADA.
Monitor patients for the development of SCARs. Advise patients of the signs and symptoms of SCARs (e.g., a prodrome of fever, flu-like symptoms, mucosal lesions, progressive skin rash, or lymphadenopathy). If a SCAR is suspected, interrupt ERLEADA until the etiology of the reaction has been determined. Consultation with a dermatologist is recommended. If a SCAR is confirmed, or for other Grade 4 skin reactions, permanently discontinue ERLEADA [see Dosage and Administration (2.2)].
Embryo-Fetal Toxicity — The safety and efficacy of ERLEADA have not been established in females. Based on findings from animals and its mechanism of action, ERLEADA can cause fetal harm and loss of pregnancy when administered to a pregnant female. Advise males with female partners of reproductive potential to use effective contraception during treatment and for 3 months after the last dose of ERLEADA [see Use in Specific Populations (8.1, 8.3)].
ADVERSE REACTIONS
The most common adverse reactions (≥10%) that occurred more frequently in the ERLEADA-treated patients (≥2% over placebo) from the randomized placebo-controlled clinical trials (TITAN and SPARTAN) were fatigue, arthralgia, rash, decreased appetite, fall, weight decreased, hypertension, hot flush, diarrhea, and fracture.
Laboratory Abnormalities — All Grades (Grade 3-4)
Hematology — In the TITAN study: white blood cell decreased ERLEADA 27% (0.4%), placebo 19% (0.6%). In the SPARTAN study: anemia ERLEADA 70% (0.4%), placebo 64% (0.5%); leukopenia ERLEADA 47% (0.3%), placebo 29% (0%); lymphopenia ERLEADA 41% (1.8%), placebo 21% (1.6%).
Chemistry — In the TITAN study: hypertriglyceridemia ERLEADA 17% (2.5%), placebo 12% (2.3%). In the SPARTAN study: hypercholesterolemia ERLEADA 76% (0.1%), placebo 46% (0%); hyperglycemia ERLEADA 70% (2%), placebo 59% (1.0%); hypertriglyceridemia ERLEADA 67% (1.6%), placebo 49% (0.8%); hyperkalemia ERLEADA 32% (1.9%), placebo 22% (0.5%).
Rash — In 2 randomized studies (SPARTAN and TITAN), rash was most commonly described as macular or maculopapular. Adverse reactions of rash were 26% with ERLEADA vs 8% with placebo. Grade 3 rashes (defined as covering >30% body surface area [BSA]) were reported with ERLEADA treatment (6%) vs placebo (0.5%).
The onset of rash occurred at a median of 83 days. Rash resolved in 78% of patients within a median of 78 days from onset of rash. Rash was commonly managed with oral antihistamines, topical corticosteroids, and 19% of patients received systemic corticosteroids. Dose reduction or dose interruption occurred in 14% and 28% of patients, respectively. Of the patients who had dose interruption, 59% experienced recurrence of rash upon reintroduction of ERLEADA.
Hypothyroidism — In 2 randomized studies (SPARTAN and TITAN), hypothyroidism was reported for 8% of patients treated with ERLEADA and 1.5% of patients treated with placebo based on assessments of thyroid-stimulating hormone (TSH) every 4 months. Elevated TSH occurred in 25% of patients treated with ERLEADA and 7% of patients treated with placebo. The median onset was at the first scheduled assessment. There were no Grade 3 or 4 adverse reactions. Thyroid replacement therapy, when clinically indicated, should be initiated or dose adjusted.
DRUG INTERACTIONS
Effect of Other Drugs on ERLEADA — Co-administration of a strong CYP2C8 or CYP3A4 inhibitor is predicted to increase the steady-state exposure of the active moieties. No initial dose adjustment is necessary; however, reduce the ERLEADA dose based on tolerability [see Dosage and Administration (2.2)].
Effect of ERLEADA on Other Drugs
CYP3A4, CYP2C9, CYP2C19, and UGT Substrates — ERLEADA is a strong inducer of CYP3A4 and CYP2C19, and a weak inducer of CYP2C9 in humans. Concomitant use of ERLEADA with medications that are primarily metabolized by CYP3A4, CYP2C19, or CYP2C9 can result in lower exposure to these medications. Substitution for these medications is recommended when possible or evaluate for loss of activity if medication is continued. Concomitant administration of ERLEADA with medications that are substrates of UDP-glucuronosyl transferase (UGT) can result in decreased exposure. Use caution if substrates of UGT must be co-administered with ERLEADA and evaluate for loss of activity.
P-gp, BCRP, or OATP1B1 Substrates — Apalutamide is a weak inducer of P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), and organic anion transporting polypeptide 1B1 (OATP1B1) clinically. Concomitant use of ERLEADA with medications that are substrates of P-gp, BCRP, or OATP1B1 can result in lower exposure of these medications. Use caution if substrates of P-gp, BCRP, or OATP1B1 must be co-administered with ERLEADA and evaluate for loss of activity if medication is continued.
Please see the full Prescribing Information for ERLEADA.
BALVERSA IMPORTANT SAFETY INFORMATION18
WARNINGS AND PRECAUTIONS
Ocular Disorders – BALVERSA can cause ocular disorders, including central serous retinopathy/retinal pigment epithelial detachment (CSR/RPED) resulting in visual field defect.
CSR/RPED was reported in 25% of patients treated with BALVERSA, with a median time to first onset of 50 days. Grade 3 CSR/RPED, involving central field of vision, was reported in 3% of patients. CSR/RPED resolved in 13% of patients and was ongoing in 13% of patients at the study cutoff. CSR/RPED led to dose interruptions and reductions in 9% and 14% of patients, respectively, and 3% of patients discontinued BALVERSA. Dry eye symptoms occurred in 28% of patients during treatment with BALVERSA and were Grade 3 in 6% of patients. All patients should receive dry eye prophylaxis with ocular demulcents as needed.
Perform monthly ophthalmological examinations during the first 4 months of treatment and every 3 months afterwards, and urgently at any time for visual symptoms. Ophthalmological examination should include assessment of visual acuity, slit lamp examination, fundoscopy, and optical coherence tomography. Withhold BALVERSA when CSR occurs and permanently discontinue if it does not resolve within 4 weeks or if Grade 4 in severity. For ocular adverse reactions, follow the dose modification guidelines [see Dosage and Administration (2.3)].
Hyperphosphatemia and Soft Tissue Mineralization – BALVERSA can cause hyperphosphatemia leading to soft tissue mineralization, cutaneous calcinosis, non-uremic calciphylaxis and vascular calcification. Increases in phosphate levels are a pharmacodynamic effect of BALVERSA [see Pharmacodynamics (12.2)]. Hyperphosphatemia was reported as adverse reaction in 76% of patients treated with BALVERSA. The median onset time for any grade event of hyperphosphatemia was 20 days (range: 8–116) after initiating BALVERSA. Thirty-two percent of patients received phosphate binders during treatment with BALVERSA. Cutaneous calcinosis, non-uremic calciphylaxis and vascular calcification have been observed in 0.3% of patients treated with BALVERSA.
Monitor for hyperphosphatemia throughout treatment. In all patients, restrict phosphate intake to 600–800 mg daily. If serum phosphate is above 7.0 mg/dL, consider adding an oral phosphate binder until serum phosphate level returns to <5.5 mg/dL. Withhold, dose reduce, or permanently discontinue BALVERSA based on duration and severity of hyperphosphatemia [see Dosage and Administration (2.3), Table 2: Dose Modifications for Adverse Reactions].
Embryo-fetal Toxicity –Based on the mechanism of action and findings in animal reproduction studies, BALVERSA can cause fetal harm when administered to a pregnant woman. In a rat embryo-fetal toxicity study, erdafitinib was embryotoxic and teratogenic at exposures less than the human exposures at all doses studied. Advise pregnant women of the potential risk to the fetus. Advise female patients of reproductive potential to use effective contraception during treatment with BALVERSA and for one month after the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with BALVERSA and for one month after the last dose [see Use in Specific Populations (8.1, 8.3) and Clinical Pharmacology (12.1)].
Most common adverse reactions including laboratory abnormalities ≥20%:
Phosphate increased (76%), stomatitis (56%), fatigue (54%), creatinine increased (52%), diarrhea (47%), dry mouth (45%), nail disorder (45%), alanine aminotransferase increased (41%), alkaline phosphatase increased (41%), sodium decreased (40%), decreased appetite (38%), albumin decreased (37%), dysgeusia (37%), hemoglobin decreased (35%), dry skin (34%), aspartate aminotransferase increased (30%), magnesium decreased (30%), dry eye (28%), alopecia (26%), palmar-plantar erythrodysesthesia syndrome (26%), constipation (28%), phosphate decreased (24%), abdominal pain (23%), calcium increased (22%), nausea (21%), and musculoskeletal pain (20%). The most common Grade 3 or greater adverse reactions (>1%) were stomatitis (9%), nail dystrophy*, palmar-plantar erythrodysesthesia syndrome (6%), paronychia (3%), nail disorder (10%), keratitis†, and hyperphosphatemia (1%).
*Included within onycholysis. †Included within dry eye.
An adverse reaction with a fatal outcome in 1% of patients was acute myocardial infarction.
Serious adverse reactions occurred in 41% of patients, including eye disorders (10%).
Permanent discontinuation due to an adverse reaction occurred in 13% of patients. The most frequent reasons for permanent discontinuation included eye disorders (6%).
Dosage interruptions occurred in 68% of patients. The most frequent adverse reactions requiring dosage interruption included hyperphosphatemia (24%), stomatitis (17%), eye disorders (17%), and palmar-plantar erythrodysesthesia syndrome (8%).
Dose reductions occurred in 53% of patients. The most frequent adverse reactions for dose reductions included eye disorders (23%), stomatitis (15%), hyperphosphatemia (7%), palmar-plantar erythrodysesthesia syndrome (7%), paronychia (7%), and nail dystrophy (6%).
Drug Interactions
Moderate CYP2C9 or strong CYP3A4 Inhibitors: Consider alternative agents or monitor closely for adverse reactions. (7.1)
Strong CYP2C9 or CYP3A4 inducers: Avoid concomitant use with BALVERSA. (7.1)
Moderate CYP2C9 or CYP3A4 inducers: Increase BALVERSA dose up to 9 mg. (7.1)
Serum phosphate level-altering agents: Avoid concomitant use with agents that can alter serum phosphate levels before the initial dose modification period. (2.3, 7.1)
CYP3A4 substrates: Avoid concomitant use with sensitive CYP3A4 substrates with narrow therapeutic indices. (7.2)
OCT2 substrates: Consider alternative agents or consider reducing the dose of OCT2 substrates based on tolerability. (7.2)
P-gp substrates: Separate BALVERSA administration by at least 6 hours before or after administration of P-gp substrates with narrow therapeutic indices. (7.2)