On January 25, 2024 Blue Earth Diagnostics, a Bracco company and recognized leader in the development and commercialization of innovative positron emission tomography (PET) radiopharmaceuticals, reported results from a sub-analysis of data from the Phase 3 SPOTLIGHT trial (NCT04186845) which investigated the use of POSLUMA (flotufolastat F 18) PET in suspected biochemical recurrence of prostate cancer (Press release, Blue Earth Diagnostics, JAN 25, 2024, View Source [SID1234639489]). The sub-analysis assessed the impact of POSLUMA on treatment plans for patients with recurrent prostate cancer after curative-intent primary therapy. POSLUMA (flotufolastat F 18) injection (formerly referred to as 18F-rhPSMA-7.3) is indicated for positron emission tomography (PET) of prostate-specific membrane antigen (PSMA) positive lesions in men with prostate cancer with suspected metastasis who are candidates for initial definitive therapy or with suspected recurrence based on elevated serum prostate-specific antigen (PSA) level.

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Results highlights:

Flotufolastat F 18 PET imaging was positive for recurrent prostate cancer in 84% (81/97) of patients in the sub-analysis.
In 89% (86/97) of patients, management plans were changed following review of the flotufolastat F 18 PET scan results.
91% (78/86) of changes were considered major, defined as a change in the treatment modality.
75% (6/8) of patients whose plans were changed in favor of watchful waiting had a negative flotufolastat F 18 scan.
All patients with management plans that were revised from salvage therapy to non-curative systemic therapy had distant/extrapelvic flotufolastat F 18-avid lesions.
"Recurrent prostate cancer presents challenges, and the ability to determine the extent and location of recurrent disease to inform appropriate clinical management is key for physicians and their patients, as up to 40% of patients who undergo radical prostatectomy, and up to 50% of patients who undergo radiation therapy will develop local or distant recurrences within 10 years," said Przemyslaw Twardowski, MD, Saint John’s Cancer Institute at Providence Saint John’s Health Center, Santa Monica, Calif., on behalf of the SPOTLIGHT Study Group. "The SPOTLIGHT study investigated the diagnostic performance of POSLUMA PET imaging as a potential decision-making aid in assessing suspected biochemical recurrence of the disease. This sub-analysis further examined the impact of POSLUMA PET imaging on patients’ management plans. Results showed that POSLUMA identified recurrence sites in the majority of patients, frequently resulting in major changes to previously planned management plans. Patient treatment based on visualization of POSLUMA-avid lesions has the potential to facilitate optimal targeting of recurrence sites and help patients avoid futile salvage therapy."

"We are very pleased to present these results to the oncology community at ASCO (Free ASCO Whitepaper) GU," said David E. Gauden, D.Phil., Chief Executive Officer of Blue Earth Diagnostics. "POSLUMA represents a new class of high-affinity PSMA-targeted radiopharmaceuticals based on novel radiohybrid technology, and provides physicians with clinically useful information based on its performance at low PSA levels, PSMA binding and low urinary bladder activity. Our product has been added to nationally recognized clinical oncology guidelines for prostate cancer, alongside and for all the same categories as the other currently FDA-approved PSMA PET radiopharmaceuticals. POSLUMA is labeled with the radioisotope fluorine-18 (18F) to leverage high image quality and to enable broad, readily available geographic access for patients via the manufacturing and distribution network of our commercial U.S. manufacturer and distributor, PETNET Solutions Inc, A Siemens Healthineers Company."

The findings were discussed in a moderated poster presentation at the ASCO (Free ASCO Whitepaper) GU 2024 Genitourinary Cancers Symposium (ASCO GU) on January 25, 2024. "Impact of 18F-flotufolastat PET on management of patients with recurrent prostate cancer: Data from the SPOTLIGHT study," was presented by Przemyslaw Twardowski, MD, Saint John’s Cancer Institute at Providence Saint John’s Health Center, Santa Monica, Calif., on behalf of the SPOTLIGHT Study Group. Full session details are available in the ASCO (Free ASCO Whitepaper) GU online program here.

About the study

The sub-analysis of SPOTLIGHT data from the 389 patient study assessed the impact of flotufolastat F 18 on planned treatment after curative-intent primary therapy. The present analysis focused on patients who had a flotufolastat F 18 scan and sufficient data for management plan evaluation. Onsite investigators recorded patients’ management plans before and after flotufolastat F 18 PET. Plans were then categorized as "no change," "major change,"" other change," "additional information required" or "intended plan not valid." A "major change" was defined as a change in treatment modality (e.g., salvage radiation to systemic therapy), while "other change" represented a change within a modality (e.g., modified radiation therapy field). All imaging data were then submitted for blinded image evaluation by 3 central readers.

In total, 97 patients (median [range] PSA: 0.08 [0.09-134.6]] ng/mL) had an evaluable flotufolastat F 18 PET scan and sufficient data to evaluate management plan changes. Most patients, 86/97 (89%) had a change to their management plan post-scan. A "major change" was noted for 78 (80%) patients, while 8 (8.2%) had an "other change." Onsite imaging reads showed that both positive and negative flotufolastat F 18 scans influenced management planning. While 88% of revisions occurred after a positive scan, 75% of those whose management plans were revised to watchful waiting had negative scans. All patients with management plans revised from salvage therapy to non-curative systemic therapy had distant/extrapelvic flotufolastat F 18-avid lesions.
No serious adverse reactions were attributed to flotufolastat F 18 in the SPOTLIGHT study. Overall, 16/389 (4.1%) patients had at least one treatment-emergent adverse event that was considered possibly related/related to flotufolastat F 18. The most frequently reported events were: hypertension: 1.8% (n=7); diarrhea: 1.0% (n=4); injection site reaction: 0.5% (n=2), and headache: 0.5% (n=2).
About Radiohybrid Prostate-Specific Membrane Antigen (rhPSMA)

Radiohybrid Prostate-Specific Membrane Antigen (rhPSMA) compounds consist of a radiohybrid ("rh") Prostate-Specific Membrane Antigen-targeted receptor ligand which attaches to and is internalized by prostate cancer cells, and they may be radiolabeled with imaging isotopes for PET imaging, or with therapeutic isotopes for therapeutic use – providing the potential for creating a true theranostic technology. Radiohybrid technology and rhPSMA originated from the Technical University of Munich, Germany. Blue Earth Diagnostics acquired exclusive, worldwide rights to rhPSMA diagnostic imaging technology from Scintomics GmbH in 2018, and therapeutic rights in 2020, and sublicensed the therapeutic application to its sister company Blue Earth Therapeutics. Blue Earth Diagnostics received U.S. Food and Drug Administration approval for its radiohybrid PET diagnostic imaging product for use in prostate cancer in 2023. rhPSMA compounds for potential therapeutic use are investigational and have not received regulatory approval.

Indication and Important Safety Information About POSLUMA

INDICATION

POSLUMA (flotufolastat F 18) injection is indicated for positron emission tomography (PET) of prostate-specific membrane antigen (PSMA) positive lesions in men with prostate cancer

with suspected metastasis who are candidates for initial definitive therapy
with suspected recurrence based on elevated serum prostate-specific antigen (PSA) level
IMPORTANT SAFETY INFORMATION

Image interpretation errors can occur with POSLUMA PET. A negative image does not rule out the presence of prostate cancer and a positive image does not confirm the presence of prostate cancer. The performance of POSLUMA for imaging metastatic pelvic lymph nodes in patients prior to initial definitive therapy seems to be affected by serum PSA levels and risk grouping. The performance of POSLUMA for imaging patients with biochemical evidence of recurrence of prostate cancer seems to be affected by serum PSA levels. Flotufolastat F 18 uptake is not specific for prostate cancer and may occur in other types of cancer, in non-malignant processes, and in normal tissues. Clinical correlation, which may include histopathological evaluation, is recommended.
Risk of Image Misinterpretation in Patients with Suspected Prostate Cancer Recurrence: The interpretation of POSLUMA PET may differ depending on imaging readers, particularly in the prostate/prostate bed region. Because of the associated risk of false positive interpretation, consider multidisciplinary consultation and histopathological confirmation when clinical decision-making hinges on flotufolastat F 18 uptake only in the prostate/prostate bed region or only on uptake interpreted as borderline.
POSLUMA use contributes to a patient’s overall long-term cumulative radiation exposure. Long-term cumulative radiation exposure is associated with an increased risk for cancer. Advise patients to hydrate before and after administration and to void frequently after administration. Ensure safe handling to minimize radiation exposure to the patient and health care providers.
The adverse reactions reported in ≥0.4% of patients in clinical studies were diarrhea, blood pressure increase and injection site pain.
Drug Interactions: androgen deprivation therapy (ADT) and other therapies targeting the androgen pathway, such as androgen receptor antagonists, may result in changes in uptake of flotufolastat F 18 in prostate cancer. The effect of these therapies on performance of POSLUMA PET has not been established.
To report suspected adverse reactions to POSLUMA, call 1-844-POSLUMA (1-844-767-5862) or contact FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Full POSLUMA prescribing information is available at www.posluma.com/prescribing-information.pdf.

On January 25, 2024 Domain Therapeutics ("Domain" or "the Company"), a clinical-stage global biopharmaceutical company developing innovative drug candidates in immuno-oncology targeting G Protein-Coupled Receptors (GPCRs), reported that it has been awarded a grant as part of the Hospital-University Research in Health (RHU) SPRINT consortium (Press release, Domain Therapeutics, JAN 25, 2024, https://www.domaintherapeutics.com/domain-therapeutics-awarded-hospital-university-research-in-health-rhu-sprint-consortium-grant-to-progress-its-proprietary-ccr8-antibody-candidate-to-the-clinic/ [SID1234639474]). The €30 million consortium project will be supported by a nearly €10 million grant from the Agence Nationale de la Recherche (ANR) as part of the France2030 investment plan, shared between the academic and private partners to progress precision medicines, including moving Domain’s DT-7012 to the clinic.

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The SPRINT project aims to revolutionize the management of patients with CTCL and deliver a new cure paradigm as a standard-of-care. CTCL affects about one in 100,000 adults worldwide each year, nearly tripling in last 30 years. The impact on the quality of life of patients is severe, and the median overall survival rate is less than 5 years in the advanced stages. There is no clear understanding of the underlying factors guiding disease progression.

The multidisciplinary SPRINT consortium gathers internationally renowned physicians and researchers as well as drug discovery and artificial intelligence specialists to investigate the immune tumor microenvironment (TME) of CTCL, understand the mechanism of immuno-resistance, develop a non-invasive prognostic tool and bring new innovative therapeutic solutions to the clinic. The group includes five world-class academics:
UPCité, INSERM, Hospices Civils de Lyon, AP-HP, CHU Bordeaux, two highly innovating companies (Domain Therapeutics and TheraPanacea), while being endorsed by Medicen, the European Reference Network for Rare Hematological Diseases (EuroBloodNet), the French Study Group on Cutaneous Lymphomas (GFELC) – a national network supported by the French National Cancer Institute (INCa), and the patients association ELLyE

Domain and the SPRINT consortium will utilize a triad approach, building upon previous discoveries of extensive investigation into the TME in CTCL, including:

Implementation of an innovative strategy to improve treatment-agnostic early prognostication, through an effective synergy of domain-driven and data-driven artificial intelligence
Validation of a molecular signature of response to mAbs
Innovative drug development targeting tumor cells and the TME in the mechanisms of resistance with mAbs to provide long-term responses
Dr. Stephan Schann, Vice-President of Research at Domain Therapeutics, commented: "Cutaneous T-cell lymphoma is a rare type of cancer, and is largely considered an incurable disease with only few patients responding to current treatments. The grant that we have been awarded by the RHU SPRINT consortium will support the progress of DT-7012, an anti-CCR8 monoclonal antibody which has incredible potential as a best-in-class therapeutic, into the clinic. We are proud to take part in the RHU SPRINT consortium as we aim to turn more non-responder patients into responders."

Professor Adèle de Masson, RHU SPRINT Project Coordinator at Saint-Louis Hospital, Paris, said: "I would like to thank the Agence Nationale de la Recherche (ANR) for this significant support. There is a need for new treatments to address the severe impact on quality of life that cutaneous T-cell lymphoma has on patients, ranging from skin damage to secondary infections, pain, and fatigue, and survival rates. I am hopeful that Domain Therapeutics and the other recipients of the RHU SPRINT consortium grants will help improve the lives of CTCL patients worldwide and I look forward to the outcomes."

Dr Anthony Johnson, President and CEO, Domain Therapeutics, said: "We are extremely pleased for the support and further validation from the RHU for our GPCR targeting immuno-oncology pipeline. Domain was already awarded a first RHU grant, RHU CONDOR for Sarcoma, in the previous campaign, leveraging another proprietary asset. Being successful two consecutive years is unique and highlights the excellence of our science and collaborators. We are excited to work with the government and our partners in this second consortium, RHU SPRINT."

Domain previously announced the nomination of novel drug candidate DT-7012, an anti-CCR8 monoclonal antibody depleting tumor-infiltrating regulatory T cells (Tregs), with best-in-class potential in CTCL and solid tumors. Domain’s target is a highly strategic approach to derive efficient novel immunotherapies that increase the clinical success rate of treatments in non-responding patients with cancer, and the Company expects to start a Phase I study of DT-7012 by mid-2025.

On January 25, 2024 Natera, Inc. (NASDAQ: NTRA), a global leader in cell-free DNA testing, reported the publication of two new studies in Nature Medicine evaluating Natera’s personalized and tumor-informed molecular residual disease (MRD) test, Signatera (Press release, Natera, JAN 25, 2024, View Source [SID1234639490]).

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The first study shows results from the single-arm, phase I AMPLIFY-201 trial evaluating the ELI-002 cancer vaccine. The study enrolled a total of 25 patients (20 pancreatic, 5 colorectal), 21 of whom were Signatera-positive after locoregional treatment. Signatera dynamics were also used as a secondary endpoint to assess tumor biomarker response, together with serum tumor antigens. This study is the first of its kind to have utilized circulating tumor DNA (ctDNA)-positivity in conjunction with other tumor biomarkers for enrollment, highlighting the use of Signatera for detecting early evidence of anti-tumor activity of a drug candidate to help assess for a dose response.

The study reported that tumor biomarker responses were observed in 21/25 patients (84%), and ctDNA clearance was observed in 6/25 patients (24%). In contrast, serum tumor antigens declined but did not clear, highlighting the potential utility of ctDNA to be used as a reliable surrogate biomarker for treatment efficacy.

"We are excited about our partnership with Natera, which has resulted in a successful prospective, phase I clinical trial focused on trial enrichment by enrolling Signatera-positive patients and monitoring therapy response in patients receiving a cancer vaccine," said Christopher Haqq, MD, PhD, Elicio Therapeutic, Inc’s executive vice president, head of research and development, and chief medical officer. "We are optimistic about the potential for this study to improve outcomes for patients with pancreatic and colorectal cancer, who face clinical challenges and are often incurable when ctDNA is detected after treatment."

A second study published in Nature Medicine, called PANDA, is a single-arm, open-label, phase II study that investigated preoperative atezolizumab plus chemotherapy in patients with resectable, non-metastatic gastric and gastroesophageal junction adenocarcinoma. The study included 20 patients who underwent surgery and were evaluated for safety, pathologic response, and survival endpoints, and Signatera was used to detect and monitor ctDNA dynamics in all 20 patients.

The PANDA study found that ctDNA clearance after neoadjuvant therapy correlated with pathologic response in 11/11 patients, while 3/6 patients with poor pathologic response remained ctDNA-positive (P=0.029). None of the patients with complete pathologic response (pCR) were ctDNA-positive, and among the nonresponders who were ctDNA negative (n=3), the study reported superior long-term outcomes. Additionally, ctDNA-positivity at the MRD and follow-up time points was associated with a recurrence rate of 100%.

"We’re pleased to see these excellent results from the PANDA study which demonstrate the strong correlation between ctDNA and pathologic response pre-surgery and the therewith associated recurrence risk, highlighting the potential utility of Signatera in gastric and gastroesophageal cancers," said Myriam Chalabi MD, PhD, medical oncologist, Netherlands Cancer Institute, and principal investigator of the PANDA study.

"PANDA and AMPLIFY-201 add to the growing number of studies supporting the use of Signatera across various GI indications, showing the promise of tumor-informed ctDNA testing to help personalize treatment strategies," said Alexey Aleshin, general manager of oncology and early cancer detection at Natera. "These studies also point to the valuable insights longitudinal ctDNA monitoring can provide in the evaluation of novel therapies."

About Signatera

Signatera is a personalized, tumor-informed, molecular residual disease test for patients previously diagnosed with cancer. Custom-built for each individual, Signatera uses circulating tumor DNA to detect and quantify cancer left in the body, identify recurrence earlier than standard-of-care tools, and help optimize treatment decisions. The test is available for clinical and research use and is covered by Medicare for patients with colorectal cancer, breast cancer (stage IIb and higher) and muscle invasive bladder cancer, as well as for immunotherapy monitoring of any solid tumor. Signatera has been clinically validated across multiple cancer types and indications, with published evidence in more than 50 peer-reviewed papers.

On January 25, 2024 Exelixis, Inc. (Nasdaq: EXEL) reported detailed results from CONTACT-02, a phase 3 pivotal study evaluating cabozantinib (CABOMETYX) in combination with atezolizumab compared with a second novel hormonal therapy (NHT) in patients with metastatic castration-resistant prostate cancer (mCRPC) and measurable extra-pelvic soft tissue disease who have progressed on one prior NHT (Press release, Exelixis, JAN 25, 2024, View Source [SID1234639475]). The detailed findings are being presented during Oral Abstract Session A: Prostate Cancer at 7:55 a.m. PST on January 25 at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) 2024 Genitourinary Cancers Symposium (ASCO GU).

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"Patients with metastatic castration-resistant prostate cancer with prior progression on a novel hormone therapy and who have measurable soft tissue metastasis experience the worst outcomes among advanced prostate cancer patients and have limited treatment options," said Neeraj Agarwal, M.D., FASCO, Senior Director for Clinical Research at Huntsman Cancer Institute at the University of Utah and the global lead investigator of the trial. "CONTACT-02 is the only phase 3 study evaluating a tyrosine kinase inhibitor and an immune checkpoint inhibitor to show a statistically significant improvement in progression-free survival and a trend for overall survival in these patients. I am encouraged by these results and the potential for cabozantinib plus atezolizumab to be a widely available treatment option for our patients."

As announced in August 2023, CONTACT-02 met one of its primary endpoints, demonstrating a statistically significant improvement in progression-free survival (PFS) as assessed by a blinded independent radiology committee (BIRC) and per RECIST 1.1. The PFS analysis was conducted in the first 400 randomized patients in the intent-to-treat (PFS ITT) population and per protocol. Similar results were observed for all patients.

Detailed results presented at ASCO (Free ASCO Whitepaper) GU show that at a median follow-up of 14.3 months for the PFS ITT population, the hazard ratio (HR) was 0.65 (95% confidence interval [CI]: 0.50-0.84; p=0.0007); the median PFS (mPFS) was 6.3 months for cabozantinib in combination with atezolizumab compared with 4.2 months for second NHT. This was nearly identical to the PFS for the ITT population (n=507): HR was 0.64 (95% CI: 0.50-0.81, p=0.0002); mPFS was 6.3 months for cabozantinib in combination with atezolizumab and was 4.2 months for second NHT. At a median follow-up of 12.0 months for the ITT population, the median overall survival (OS) was 16.7 months for cabozantinib in combination with atezolizumab compared with 14.6 months for second NHT (HR: 0.79; 95% CI: 0.58-1.07; p=0.13). While a trend toward OS improvement was observed, the data were immature and did not meet the threshold for statistical significance. The study will continue to the next analysis of OS, anticipated in 2024.

The PFS benefit and the trend for an OS benefit were observed across subgroups of high-risk populations, as presented in Table 1.

TABLE 1

Liver metastasis

Prior docetaxel for mCSPC

Bone metastasis

Cabozantinib +
atezolizumab

Second NHT

Cabozantinib +
atezolizumab

Second NHT

Cabozantinib +
atezolizumab

Second NHT

Median PFS
per BIRC, months
(95% CI)

6.2
(4.0-9.1)

2.1
(2.0-2.3)

8.8
(6.2-9.2)

4.1
(2.3-4.3)

6.3
(6.0-8.8)

4.1
(2.8-5.7)

Patients, n

51

48

45

44

162

155

PFS HR
(95% CI)

0.43
(0.27-0.68)

0.57
(0.34-0.97)

0.67
(0.50-0.88)

Median OS,
months
(95% CI)

16.4
(8.3-NE)

9.8
(5.5-11.3)

20.9
(10.1-NE)

11.3
(9.0-NE)

16.4
(11.4-18.8)

11.4
(10.4-14.6)

Patients, n

59

60

57

58

206

196

OS HR
(95% CI)

0.60
(0.35-1.02)

0.56
(0.29-1.08)

0.74
(0.54-1.02)

BIRC = blinded independent radiology committee; CI = confidence interval; HR = hazard ratio; mCSPC = metastatic castration-sensitive prostate cancer; NE = not evaluable; NHT = novel hormone therapy; OS = overall survival; PFS = progression-free survival

Treatment-emergent adverse events (AEs) occurred in 97% of patients treated with cabozantinib in combination with atezolizumab (n=248) compared with 87% of patients treated with a second NHT (n=253), 48% and 23% of which were grade 3/4, respectively. Grade 5 treatment-emergent AEs occurred in 8% of patients treated with the combination regimen compared with 12% of patients treated with a second NHT; no grade 5 treatment-related AEs occurred in either arm. Treatment-related AEs led to the discontinuation of any treatment component in 13% of patients treated with the combination regimen and 2% of patients treated with a second NHT. For all treatment components, the treatment-related AEs leading to discontinuation were 5% vs. 2%, respectively.

"Given there are limited options after progression on novel hormonal therapy, we recognize the need for a regimen that can delay disease progression, that has an acceptable tolerability profile and that is widely available to patients who may not have the means or desire to travel to specialized centers for other therapies," said Amy Peterson, M.D., Executive Vice President, Product Development & Medical Affairs, and Chief Medical Officer, Exelixis. "Our decision to conduct CONTACT-02, based upon a signal we observed in COMET-01, underscores our commitment to patients with advanced prostate cancer and to improving their standard of care. We look forward to discussing these important results with the U.S. Food and Drug Administration, and to learning more in the next analysis of overall survival, anticipated this year."

About CONTACT-02

CONTACT-02 is a global, multicenter, randomized, phase 3, open-label study that randomized 507 patients 1:1 to the experimental arm of cabozantinib in combination with atezolizumab and the control arm of a second NHT (either abiraterone and prednisone or enzalutamide). The two primary endpoints of the trial are PFS and OS. The study included patients with mCRPC who have measurable extra-pelvic soft tissue metastasis and who have progressed on one prior NHT. The secondary endpoint is objective response rate per BIRC. The trial is sponsored by Exelixis and co-funded by Ipsen, Roche and Takeda Pharmaceutical Company Limited (Takeda). Takeda is conducting the trial in Japan. More information about CONTACT-02 is available at ClinicalTrials.gov.

About CRPC

According to the American Cancer Society, approximately 299,000 new cases of prostate cancer will be diagnosed in the U.S., and over 35,000 people will die from the disease in 2024.1 Prostate cancer that has spread beyond the prostate and does not respond to androgen-suppression therapies – a common treatment for prostate cancer – is known as mCRPC.2 Men diagnosed with mCRPC often have a poor prognosis, with an estimated survival of 1-2 years.3,4

About CABOMETYX (cabozantinib)

In the U.S., CABOMETYX tablets are approved for the treatment of patients with advanced renal cell carcinoma (RCC); for the treatment of patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib; for patients with advanced RCC as a first-line treatment in combination with nivolumab; and for adult and pediatric patients 12 years of age and older with locally advanced or metastatic differentiated thyroid cancer (DTC) that has progressed following prior VEGFR-targeted therapy and who are radioactive iodine-refractory or ineligible. CABOMETYX tablets have also received regulatory approvals in the European Union and additional countries and regions worldwide. In 2016, Exelixis granted Ipsen Pharma SAS exclusive rights for the commercialization and further clinical development of cabozantinib outside of the U.S. and Japan. In 2017, Exelixis granted exclusive rights to Takeda for the commercialization and further clinical development of cabozantinib for all future indications in Japan. Exelixis holds the exclusive rights to develop and commercialize cabozantinib in the U.S.

CABOMETYX in combination with atezolizumab is not indicated as a treatment for mCRPC.

IMPORTANT SAFETY INFORMATION

WARNINGS AND PRECAUTIONS

Hemorrhage: Severe and fatal hemorrhages occurred with CABOMETYX. The incidence of Grade 3 to 5 hemorrhagic events was 5% in CABOMETYX patients in RCC, HCC, and DTC studies. Discontinue CABOMETYX for Grade 3 or 4 hemorrhage and prior to surgery as recommended. Do not administer CABOMETYX to patients who have a recent history of hemorrhage, including hemoptysis, hematemesis, or melena.

Perforations and Fistulas: Fistulas, including fatal cases, occurred in 1% of CABOMETYX patients. Gastrointestinal (GI) perforations, including fatal cases, occurred in 1% of CABOMETYX patients. Monitor patients for signs and symptoms of fistulas and perforations, including abscess and sepsis. Discontinue CABOMETYX in patients who experience a Grade 4 fistula or a GI perforation.

Thrombotic Events: CABOMETYX increased the risk of thrombotic events. Venous thromboembolism occurred in 7% (including 4% pulmonary embolism) and arterial thromboembolism in 2% of CABOMETYX patients. Fatal thrombotic events occurred in CABOMETYX patients. Discontinue CABOMETYX in patients who develop an acute myocardial infarction or serious arterial or venous thromboembolic events that require medical intervention.

Hypertension and Hypertensive Crisis: CABOMETYX can cause hypertension, including hypertensive crisis. Hypertension was reported in 37% (16% Grade 3 and <1% Grade 4) of CABOMETYX patients. Do not initiate CABOMETYX in patients with uncontrolled hypertension. Monitor blood pressure regularly during CABOMETYX treatment. Withhold CABOMETYX for hypertension that is not adequately controlled with medical management; when controlled, resume at a reduced dose. Permanently discontinue CABOMETYX for severe hypertension that cannot be controlled with anti-hypertensive therapy or for hypertensive crisis.

Diarrhea: Diarrhea occurred in 62% of CABOMETYX patients. Grade 3 diarrhea occurred in 10% of CABOMETYX patients. Monitor and manage patients using antidiarrheals as indicated. Withhold CABOMETYX until improvement to ≤ Grade 1, resume at a reduced dose.

Palmar-Plantar Erythrodysesthesia (PPE): PPE occurred in 45% of CABOMETYX patients. Grade 3 PPE occurred in 13% of CABOMETYX patients. Withhold CABOMETYX until improvement to Grade 1 and resume at a reduced dose for intolerable Grade 2 PPE or Grade 3 PPE.

Hepatotoxicity: CABOMETYX in combination with nivolumab can cause hepatic toxicity with higher frequencies of Grades 3 and 4 ALT and AST elevations compared to CABOMETYX alone.

Monitor liver enzymes before initiation of and periodically throughout treatment. Consider more frequent monitoring of liver enzymes than when the drugs are administered as single agents. For elevated liver enzymes, interrupt CABOMETYX and nivolumab and consider administering corticosteroids.

With the combination of CABOMETYX and nivolumab, Grades 3 and 4 increased ALT or AST were seen in 11% of patients. ALT or AST >3 times ULN (Grade ≥2) was reported in 83 patients, of whom 23 (28%) received systemic corticosteroids; ALT or AST resolved to Grades 0-1 in 74 (89%). Among the 44 patients with Grade ≥2 increased ALT or AST who were rechallenged with either CABOMETYX (n=9) or nivolumab (n=11) as a single agent or with both (n=24), recurrence of Grade ≥2 increased ALT or AST was observed in 2 patients receiving CABOMETYX, 2 patients receiving nivolumab, and 7 patients receiving both CABOMETYX and nivolumab. Withhold and resume at a reduced dose based on severity.

Adrenal Insufficiency: CABOMETYX in combination with nivolumab can cause primary or secondary adrenal insufficiency. For Grade 2 or higher adrenal insufficiency, initiate symptomatic treatment, including hormone replacement as clinically indicated. Withhold CABOMETYX and/or nivolumab and resume CABOMETYX at a reduced dose depending on severity.

Adrenal insufficiency occurred in 4.7% (15/320) of patients with RCC who received CABOMETYX with nivolumab, including Grade 3 (2.2%), and Grade 2 (1.9%) adverse reactions. Adrenal insufficiency led to permanent discontinuation of CABOMETYX and nivolumab in 0.9% and withholding of CABOMETYX and nivolumab in 2.8% of patients with RCC.

Approximately 80% (12/15) of patients with adrenal insufficiency received hormone replacement therapy, including systemic corticosteroids. Adrenal insufficiency resolved in 27% (n=4) of the 15 patients. Of the 9 patients in whom CABOMETYX with nivolumab was withheld for adrenal insufficiency, 6 reinstated treatment after symptom improvement; of these, all (n=6) received hormone replacement therapy and 2 had recurrence of adrenal insufficiency.

Proteinuria: Proteinuria was observed in 8% of CABOMETYX patients. Monitor urine protein regularly during CABOMETYX treatment. For Grade 2 or 3 proteinuria, withhold CABOMETYX until improvement to ≤ Grade 1 proteinuria; resume CABOMETYX at a reduced dose. Discontinue CABOMETYX in patients who develop nephrotic syndrome.

Osteonecrosis of the Jaw (ONJ): ONJ occurred in <1% of CABOMETYX patients. ONJ can manifest as jaw pain, osteomyelitis, osteitis, bone erosion, tooth or periodontal infection, toothache, gingival ulceration or erosion, persistent jaw pain, or slow healing of the mouth or jaw after dental surgery. Perform an oral examination prior to CABOMETYX initiation and periodically during treatment. Advise patients regarding good oral hygiene practices. Withhold CABOMETYX for at least 3 weeks prior to scheduled dental surgery or invasive dental procedures, if possible. Withhold CABOMETYX for development of ONJ until complete resolution, resume at a reduced dose.

Impaired Wound Healing: Wound complications occurred with CABOMETYX. Withhold CABOMETYX for at least 3 weeks prior to elective surgery. Do not administer CABOMETYX for at least 2 weeks after major surgery and until adequate wound healing. The safety of resumption of CABOMETYX after resolution of wound healing complications has not been established.

Reversible Posterior Leukoencephalopathy Syndrome (RPLS): RPLS, a syndrome of subcortical vasogenic edema diagnosed by characteristic findings on MRI, can occur with CABOMETYX. Evaluate for RPLS in patients presenting with seizures, headache, visual disturbances, confusion, or altered mental function. Discontinue CABOMETYX in patients who develop RPLS.

Thyroid Dysfunction: Thyroid dysfunction, primarily hypothyroidism, has been observed with CABOMETYX. Based on the safety population, thyroid dysfunction occurred in 19% of patients treated with CABOMETYX, including Grade 3 in 0.4% of patients.

Patients should be assessed for signs of thyroid dysfunction prior to the initiation of CABOMETYX and monitored for signs and symptoms of thyroid dysfunction during CABOMETYX treatment. Thyroid function testing and management of dysfunction should be performed as clinically indicated.

Hypocalcemia: CABOMETYX can cause hypocalcemia. Based on the safety population, hypocalcemia occurred in 13% of patients treated with CABOMETYX, including Grade 3 in 2% and Grade 4 in 1% of patients. Laboratory abnormality data were not collected in CABOSUN.

In COSMIC-311, hypocalcemia occurred in 36% of patients treated with CABOMETYX, including Grade 3 in 6% and Grade 4 in 3% of patients.

Monitor blood calcium levels and replace calcium as necessary during treatment. Withhold and resume at reduced dose upon recovery or permanently discontinue CABOMETYX depending on severity.

Embryo-Fetal Toxicity: CABOMETYX can cause fetal harm. Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Verify the pregnancy status of females of reproductive potential prior to initiating CABOMETYX and advise them to use effective contraception during treatment and for 4 months after the last dose.

ADVERSE REACTIONS

The most common (≥20%) adverse reactions are:

CABOMETYX as a single agent: diarrhea, fatigue, PPE, decreased appetite, hypertension, nausea, vomiting, weight decreased, and constipation.

CABOMETYX in combination with nivolumab: diarrhea, fatigue, hepatotoxicity, PPE, stomatitis, rash, hypertension, hypothyroidism, musculoskeletal pain, decreased appetite, nausea, dysgeusia, abdominal pain, cough, and upper respiratory tract infection.

DRUG INTERACTIONS

Strong CYP3A4 Inhibitors: If coadministration with strong CYP3A4 inhibitors cannot be avoided, reduce the CABOMETYX dosage. Avoid grapefruit or grapefruit juice.

Strong CYP3A4 Inducers: If coadministration with strong CYP3A4 inducers cannot be avoided, increase the CABOMETYX dosage. Avoid St. John’s wort.

USE IN SPECIFIC POPULATIONS

Lactation: Advise women not to breastfeed during CABOMETYX treatment and for 4 months after the final dose.

Hepatic Impairment: In patients with moderate hepatic impairment, reduce the CABOMETYX dosage. Avoid CABOMETYX in patients with severe hepatic impairment.

Please see accompanying full Prescribing Information
View Source

You are encouraged to report negative side effects of prescription drugs to the FDA.

Visit www.FDA.gov/medwatch or call 1-800-FDA-1088.

On January 24, 2024 Johnson & Johnson reported new clinical and real-world evidence data will be featured in 18 abstracts at this year’s ASCO (Free ASCO Whitepaper) GU Symposium (San Francisco, January 25-27), highlighting the Company’s commitment to transform the science of genitourinary (GU) cancers (Press release, Johnson & Johnson, JAN 24, 2024, View Source;johnson-highlights-ambition-to-transform-the-treatment-of-prostate-cancer-and-bladder-cancer-through-data-presentations-at-asco-gu-302042441.html [SID1234639457]). Key presentations will include new real-world evidence data adding to the strong and differentiated clinical profile of ERLEADA (apalutamide) in the treatment of various stages of prostate cancer, patient-reported outcomes data from the Phase 3 MAGNITUDE study of niraparib plus abiraterone acetate given with prednisone, and updates on targeted releasing systems TAR-200 and TAR-210.

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"We are applying our GU expertise to advance the science of prostate cancer and bladder cancer," said Kiran Patel, M.D., Vice President, Clinical Development, Solid Tumors, Johnson & Johnson Innovative Medicine. "A recent FDA approval of new labelling for ERLEADA reinforces the impact of this standard-of-care treatment on reducing PSA to undetectable levels when added to androgen deprivation therapy. With the addition of new analyses presented at ASCO (Free ASCO Whitepaper) GU, we are progressing in our ambition to address unmet patient needs through earlier treatment intervention with the goal of improving and extending patients’ lives."

"Our data across six different mechanisms of action underscore the breadth and depth of J&J’s GU portfolio and our commitment to redefine treatment paradigms and pioneer new therapeutic advances for people with prostate and bladder cancers," said Luca Dezzani, M.D., U.S. Vice President, Medical Affairs, Solid Tumors, Johnson & Johnson Innovative Medicine. "In addition to traditional endpoints like overall survival, we are committed to assessing patients’ well-being and investing in studies and real-world analyses based on patient populations that reflect everyday clinical practice."

Delivering patient-centric innovation in prostate cancer

With a deep legacy in the treatment of prostate cancer, J&J is committed to improve outcomes in metastatic disease, while defining new standards of care for patients at all stages of disease. New data at ASCO (Free ASCO Whitepaper) GU build on the strong clinical profile of ERLEADA with real-world evidence supporting its impact on survival and PSA responses. Additional presentations highlight the company’s commitment to advance equity in clinical trials.

Key presentations include:

Real-world survival rates as presented in the ROME (Abstract #57) and ROMA (Abstract #58) studies, which reviewed patients in an oncology database with metastatic castration-sensitive prostate cancer (mCSPC) who were treated with ERLEADA or enzalutamide (ROME) or ERLEADA or abiraterone acetate (ROMA).
U.S. real-world evidence comparing PSA90 response in patients with mCSPC six months after initiating ERLEADA or enzalutamide (Abstract #51).
A first look at the design of the LIBERTAS study, the first Phase 3 trial evaluating ERLEADA plus intermittent vs continuous androgen deprivation therapy (ADT) in patients with mCSPC, inclusive of all gender identities (Abstract #TPS236).
Patient-reported outcomes from the Phase 3 MAGNITUDE study evaluating niraparib with abiraterone acetate plus prednisone in patients with BRCA-positive metastatic castration-resistant prostate cancer (mCRPC) (Abstract #105).
Data from the ongoing Phase 3 PRIMORDIUM study, including baseline characteristics of PSMA-PET positive and negative high-risk patients with biochemical recurrence after radical prostatectomy (Abstract #119).
Working to transform bladder cancer treatment with novel drug delivery technology and precision therapies

Data in bladder cancer underscore J&J’s vision to advance the treatment paradigm and address unmet patient needs through bladder-sparing and Bacillus Calmette-Guérin (BCG)-free therapies in earlier-stage disease, and precision medicine for patients with specific genetic mutations. ASCO (Free ASCO Whitepaper) GU presentations showcase innovative targeted releasing systems TAR-200 and TAR-210, and new real-world evidence data on the proportion and prognosis of fibroblast growth factor receptors (FGFR) alterations in Japan.

Highlights include:

Insights on the reasons for refusal or ineligibility for radical cystectomy from an analysis of the SunRISe-1 study evaluating TAR-200, a gemcitabine-containing targeted releasing system being studied in patients with BCG-unresponsive high-risk non-muscle-invasive bladder cancer (HR-NMIBC) (Abstract #701).
Preliminary results evaluating a novel urine-based screening assay to detect FGFR alterations and select patients who may respond to TAR-210, an erdafitinib-containing targeted releasing system being studied in patients with NMIBC with select FGFR alterations (Abstract #676).
Data describing the proportion and prognosis of Japanese patients with fibroblast growth factor receptor 2 or 3 (FGFR2 or 3) altered advanced or metastatic urothelial cancer (Abstract #647).
The complete list of Company-sponsored abstracts follows:

Prostate Cancer

ERLEADA (apalutamide)

Poster Session

Abstract #51

Real-world comparison of prostate-specific antigen (PSA) response in
patients with metastatic castration-sensitive prostate cancer (mCSPC)
treated with apalutamide (APA) or enzalutamide (ENZ)

Abstract #57

Real-world survival of men with metastatic castration-sensitive prostate
cancer (mCSPC) initiated on apalutamide (APA) or enzalutamide (ENZ)
in an oncology database: ROME study

Abstract #58

Analysis of real-world survival for patients with metastatic castration-sensitive
prostate cancer (mCSPC) treated with apalutamide (APA) or abiraterone
acetate (ABI) in an oncology database: ROMA study

Abstract #65

Treatment of metastatic castration-sensitive prostate cancer (mCSPC):
Impact of starting treatment on real-world clinical outcomes

Abstract #119

Baseline characteristics of PSMA-PET positive and negative patients with
high-risk biochemical recurrence (BCR) after radical prostatectomy (RP) in
the ongoing Phase 3 PRIMORDIUM study

Abstract #223

Phase 3 TITAN OS Extrapolation: Estimating median overall survival of
apalutamide compared to placebo in metastatic hormone-sensitive prostate
cancer (mHSPC) populations: statistical extrapolations of the TITAN study

Abstract #294

Influential factors impacting treatment decision-making (TDM) and decision
regret (DR) in patients with localized or locally advanced prostate cancer
(LPC/LAPC)

Abstract #316

Impact of a rash management guide on incidence and severity of rash with
apalutamide: experience from the APA-RP study in high-risk localized prostate
cancer

Abstract #53D

Prostate-specific antigen (PSA) response among patients with metastatic
castration-sensitive prostate cancer (mCSPC) initiated on apalutamide (APA)
or abiraterone acetate (ABI) in real-world urology practices

Abstract #TPS236

Apalutamide (APA) plus intermittent versus continuous androgen-deprivation
therapy (ADT) in participants with metastatic castration-sensitive prostate
cancer (mCSPC): LIBERTAS Phase 3 study design

AKEEGA (niraparib)

Poster Session

Abstract #52

Real-world treatment patterns in patients with BRCA 1/2-positive (BRCA+)
metastatic castration-resistant prostate cancer (mCRPC) initiating first-line
(1L) therapy

Abstract #64

Real-world economic burden of patients with metastatic castration-sensitive
prostate cancer (mCSPC)

Abstract #105

Patient-reported outcomes in patients with BRCA 1/2-altered metastatic
castration-resistant prostate cancer (mCRPC) receiving niraparib (NIRA)
with abiraterone acetate and prednisone: results from the MAGNITUDE study

Early Development

Poster Session

Abstract #202

Preclinical characterization of human kallikrein 2 as a novel target for the
treatment of prostate cancer

Bladder Cancer

BALVERSA (erdafitinib)

Poster Session

Abstract #647

Real-world experience of FGFR gene alterations and clinical outcomes in
advanced/metastatic urothelial cancer in Japan: MONSTAR-SCREEN
database study

Bladder (TAR-200)

Poster Session

Abstract #699

Population based trends in intravesical gemcitabine use among patients with
high-risk non-muscle-invasive bladder cancer

Abstract #701

Reasons for refusal of or ineligibility for radical cystectomy in patients with
Bacillus Calmette-Guérin-unresponsive high-risk non-muscle-invasive
bladder cancer from the SunRISe-1 study

Bladder (TAR-210)

Poster Session

Abstract # 676

Urine-based testing for patient selection and genomic characterization of
patients with FGFR alteration-positive non-muscle-invasive bladder cancer
treated with TAR-210

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 metastatic castration-sensitive prostate cancer (mCSPC). ERLEADA received U.S. FDA approval for nmCRPC in February 2018, and received U.S. FDA approval for mCSPC in September 2019. To date, more than 150,000 patients worldwide have been treated with ERLEADA. Additional ongoing Phase 3 studies include ATLAS, evaluating ERLEADA for patients with localized prostate cancer with radiation therapy, and PROTEUS, evaluating ERLEADA for patients with localized prostate cancer treatment after radical prostatectomy.

For more information, visit www.ERLEADA.com.

About AKEEGA

AKEEGA is a combination, in the form of a dual-action tablet (DAT), of niraparib, a highly selective poly (ADP-ribose) polymerase (PARP) inhibitor, and abiraterone acetate, a CYP17 inhibitor. AKEEGA together with prednisone or prednisolone was approved in April 2023 by the European Medicines Agency, and in August 2023 by the U.S. FDA, for the treatment of patients with BRCA-mutated metastatic castration-resistant prostate cancer (mCRPC). Additional marketing authorization applications are under review across a number of countries globally.

Additional ongoing studies include the Phase 3 AMPLITUDE study, evaluating AKEEGA with prednisone or prednisolone in a biomarker-selected patient population with metastatic castration-sensitive prostate cancer (mCSPC).

For more information, visit www.AKEEGA.com.

About BALVERSA

BALVERSA (erdafitinib) is a once-daily, oral FGFR kinase inhibitor indicated for the treatment of adult patients with locally advanced or metastatic urothelial carcinoma (mUC) with susceptible fibroblast growth factor receptor 3 (FGFR3) genetic alterations whose disease progressed on or after at least one line of prior systemic therapy. BALVERSA is not recommended for the treatment of patients who are eligible for and have not received prior PD-1 or PD-(L)1 inhibitor therapy.1 Patients are selected for therapy based on an FDA-approved companion diagnostic for BALVERSA. Information on FDA-approved tests for the detection of FGFR genetic alterations in urothelial cancer is available at: View Source

BALVERSA received Breakthrough Therapy Designation from the U.S. FDA in 2018 and received accelerated approval in 2019 for the treatment of adults with locally advanced or mUC which has susceptible FGFR3 or FGFR2 genetic alterations and who have progressed during or following at least one line of prior platinum-containing chemotherapy, including within 12 months of neoadjuvant or adjuvant platinum-containing chemotherapy.2

The Company submitted a marketing authorization application to the European Medicines Agency in September 2023 for BALVERSA as a treatment for adult patients with FGFR3-altered, locally advanced unresectable or metastatic urothelial carcinoma that has progressed following therapy with a PD-(L)1 inhibitor.

In 2008, Janssen Pharmaceuticals 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-200

TAR-200 is an investigational targeted releasing system designed to provide controlled release of gemcitabine into the bladder, sustaining local drug exposure for weeks at a time. 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) in SunRISe-2 and SunRISe-4 and non-muscle-invasive bladder cancer (NMIBC) in SunRISe-1 and SunRISe-3.

About TAR-210

TAR-210 is an investigational targeted releasing system designed to provide controlled release of erdafitinib into the bladder. The safety and efficacy of TAR-210 is being evaluated in a Phase 1 study in patients with MIBC and NMIBC (NCT05316155).

About Cetrelimab

Cetrelimab is an investigational anti-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 Johnson & Johnson portfolio.

AKEEGA IMPORTANT SAFETY INFORMATION
WARNINGS AND PRECAUTIONS

The safety population described in the WARNINGS and PRECAUTIONS reflect exposure to AKEEGA in combination with prednisone in BRCAm patients in Cohort 1 (N=113) of MAGNITUDE.

Myelodysplastic Syndrome/Acute Myeloid Leukemia

AKEEGA may cause myelodysplastic syndrome/acute myeloid leukemia (MDS/AML).

MDS/AML, including cases with fatal outcome, has been observed in patients treated with niraparib, a component of AKEEGA.

All patients treated with niraparib who developed secondary MDS/cancer-therapy-related AML had received previous chemotherapy with platinum agents and/or other DNA-damaging agents, including radiotherapy.

For suspected MDS/AML or prolonged hematological toxicities, refer the patient to a hematologist for further evaluation. Discontinue AKEEGA if MDS/AML is confirmed.

Myelosuppression

AKEEGA may cause myelosuppression (anemia, thrombocytopenia, or neutropenia).

In MAGNITUDE Cohort 1, Grade 3-4 anemia, thrombocytopenia, and neutropenia were reported, respectively in 28%, 8%, and 7% of patients receiving AKEEGA. Overall, 27% of patients required a red blood cell transfusion, including 11% who required multiple transfusions. Discontinuation due to anemia occurred in 3% of patients.

Monitor complete blood counts weekly during the first month of AKEEGA treatment, every two weeks for the next two months, monthly for the remainder of the first year and then every other month, and as clinically indicated. Do not start AKEEGA until patients have adequately recovered from hematologic toxicity caused by previous therapy. If hematologic toxicities do not resolve within 28 days following interruption, discontinue AKEEGA and refer the patient to a hematologist for further investigations, including bone marrow analysis and blood sample for cytogenetics.

Hypokalemia, Fluid Retention, and Cardiovascular Adverse Reactions

AKEEGA may cause hypokalemia and fluid retention as a consequence of increased mineralocorticoid levels resulting from CYP17 inhibition. In post-marketing experience, QT prolongation and Torsades de Pointes have been observed in patients who develop hypokalemia while taking abiraterone acetate, a component of AKEEGA. Hypertension and hypertensive crisis have also been reported in patients treated with niraparib, a component of AKEEGA.

In MAGNITUDE Cohort 1, which used prednisone 10 mg daily in combination with AKEEGA, Grades 3-4 hypokalemia was detected in 2.7% of patients on the AKEEGA arm and Grades 3-4 hypertension were observed in 14% of patients on the AKEEGA arm.

The safety of AKEEGA in patients with New York Heart Association (NYHA) Class II to IV heart failure has not been established because these patients were excluded from MAGNITUDE.

Monitor patients for hypertension, hypokalemia, and fluid retention at least weekly for the first two months, then once a month. Closely monitor patients whose underlying medical conditions might be compromised by increases in blood pressure, hypokalemia, or fluid retention, such as those with heart failure, recent myocardial infarction, cardiovascular disease, or ventricular arrhythmia. Control hypertension and correct hypokalemia before and during treatment with AKEEGA.

Discontinue AKEEGA in patients who develop hypertensive crisis or other severe cardiovascular adverse reactions.

Hepatotoxicity

AKEEGA may cause hepatotoxicity.

Hepatotoxicity in patients receiving abiraterone acetate, a component of AKEEGA, has been reported in clinical trials. In post-marketing experience, there have been abiraterone acetate-associated severe hepatic toxicity, including fulminant hepatitis, acute liver failure, and deaths.

In MAGNITUDE Cohort 1, Grade 3-4 ALT or AST increases (at least 5 x ULN) were reported in 1.8% of patients. The safety of AKEEGA in patients with moderate or severe hepatic impairment has not been established as these patients were excluded from MAGNITUDE.

Measure serum transaminases (ALT and AST) and bilirubin levels prior to starting treatment with AKEEGA, every two weeks for the first three months of treatment and monthly thereafter. Promptly measure serum total bilirubin, AST, and ALT if clinical symptoms or signs suggestive of hepatotoxicity develop. Elevations of AST, ALT, or bilirubin from the patient’s baseline should prompt more frequent monitoring and may require dosage modifications.

Permanently discontinue AKEEGA for patients who develop a concurrent elevation of ALT greater than 3 x ULN and total bilirubin greater than 2 x ULN in the absence of biliary obstruction or other causes responsible for the concurrent elevation, or in patients who develop ALT or AST ≥20 x ULN at any time after receiving AKEEGA.

Adrenocortical Insufficiency

AKEEGA may cause adrenal insufficiency.

Adrenocortical insufficiency has been reported in clinical trials in patients receiving abiraterone acetate, a component of AKEEGA, in combination with prednisone, following interruption of daily steroids and/or with concurrent infection or stress. Monitor patients for symptoms and signs of adrenocortical insufficiency, particularly if patients are withdrawn from prednisone, have prednisone dose reductions, or experience unusual stress. Symptoms and signs of adrenocortical insufficiency may be masked by adverse reactions associated with mineralocorticoid excess seen in patients treated with abiraterone acetate. If clinically indicated, perform appropriate tests to confirm the diagnosis of adrenocortical insufficiency. Increased doses of corticosteroids may be indicated before, during, and after stressful situations.

Hypoglycemia

AKEEGA may cause hypoglycemia in patients being treated with other medications for diabetes.

Severe hypoglycemia has been reported when abiraterone acetate, a component of AKEEGA, was administered to patients receiving medications containing thiazolidinediones (including pioglitazone) or repaglinide.

Monitor blood glucose in patients with diabetes during and after discontinuation of treatment with AKEEGA. Assess if antidiabetic drug dosage needs to be adjusted to minimize the risk of hypoglycemia.

Increased Fractures and Mortality in Combination with Radium 223 Dichloride

AKEEGA with prednisone is not recommended for use in combination with Ra-223 dichloride outside of clinical trials.

The clinical efficacy and safety of concurrent initiation of abiraterone acetate plus prednisone/prednisolone and radium Ra 223 dichloride was assessed in a randomized, placebo-controlled multicenter study (ERA-223 trial) in 806 patients with asymptomatic or mildly symptomatic castration-resistant prostate cancer with bone metastases. The study was unblinded early based on an Independent Data Monitoring Committee recommendation.

At the primary analysis, increased incidences of fractures (29% vs 11%) and deaths (39% vs 36%) have been observed in patients who received abiraterone acetate plus prednisone/prednisolone in combination with radium Ra 223 dichloride compared to patients who received placebo in combination with abiraterone acetate plus prednisone.

It is recommended that subsequent treatment with Ra-223 not be initiated for at least five days after the last administration of AKEEGA, in combination with prednisone.

Posterior Reversible Encephalopathy Syndrome

AKEEGA may cause Posterior Reversible Encephalopathy Syndrome (PRES).

PRES has been observed in patients treated with niraparib as a single agent at higher than the recommended dose of niraparib included in AKEEGA.

Monitor all patients treated with AKEEGA for signs and symptoms of PRES. If PRES is suspected, promptly discontinue AKEEGA and administer appropriate treatment. The safety of reinitiating AKEEGA in patients previously experiencing PRES is not known.

Embryo-Fetal Toxicity

The safety and efficacy of AKEEGA have not been established in females. Based on animal reproductive studies and mechanism of action, AKEEGA can cause fetal harm and loss of pregnancy when administered to a pregnant female.

Niraparib has the potential to cause teratogenicity and/or embryo-fetal death since niraparib is genotoxic and targets actively dividing cells in animals and patients (e.g., bone marrow).

In animal reproduction studies, oral administration of abiraterone acetate to pregnant rats during organogenesis caused adverse developmental effects at maternal exposures approximately ≥0.03 times the human exposure (AUC) at the recommended dose.

Advise males with female partners of reproductive potential to use effective contraception during treatment and for 4 months after the last dose of AKEEGA. Females who are or may become pregnant should handle AKEEGA with protection, e.g., gloves.

Based on animal studies, AKEEGA may impair fertility in males of reproductive potential.

ADVERSE REACTIONS

The safety of AKEEGA in patients with BRCAm mCRPC was evaluated in Cohort 1 of MAGNITUDE.

The most common adverse reactions (≥10%), including laboratory abnormalities, are decreased hemoglobin, decreased lymphocytes, decreased white blood cells, musculoskeletal pain, fatigue, decreased platelets, increased alkaline phosphatase, constipation, hypertension, nausea, decreased neutrophils, increased creatinine, increased potassium, decreased potassium, increased AST, increased ALT, edema, dyspnea, decreased appetite, vomiting, dizziness, COVID-19, headache, abdominal pain, hemorrhage, urinary tract infection, cough, insomnia, increased bilirubin, weight decreased, arrhythmia, fall, and pyrexia.

Serious adverse reactions reported in >2% of patients included COVID-19 (7%), anemia (4.4%), pneumonia (3.5%), and hemorrhage (3.5%). Fatal adverse reactions occurred in 9% of patients who received AKEEGA, including COVID-19 (5%), cardiopulmonary arrest (1%), dyspnea (1%), pneumonia (1%), and septic shock (1%).

DRUG INTERACTIONS

Effect of Other Drugs on AKEEGA

Avoid coadministration with strong CYP3A4 inducers.

Abiraterone is a substrate of CYP3A4. Strong CYP3A4 inducers may decrease abiraterone concentrations, which may reduce the effectiveness of abiraterone.

Effects of AKEEGA on Other Drugs

Avoid coadministration unless otherwise recommended in the Prescribing Information for CYP2D6 substrates for which minimal changes in concentration may lead to serious toxicities. If alternative treatments cannot be used, consider a dose reduction of the concomitant CYP2D6 substrate drug.

Abiraterone is a CYP2D6 moderate inhibitor. AKEEGA increases the concentration of CYP2D6 substrates, which may increase the risk of adverse reactions related to these substrates.

Monitor patients for signs of toxicity related to a CYP2C8 substrate for which a minimal change in plasma concentration may lead to serious or life-threatening adverse reactions. Abiraterone is a CYP2C8 inhibitor. AKEEGA increases the concentration of CYP2C8 substrates, which may increase the risk of adverse reactions related to these substrates.

Please see the full Prescribing Information for AKEEGA.

ERLEADA IMPORTANT SAFETY INFORMATION
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 (eg, 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 INFORMATION
WARNINGS AND PRECAUTIONS

The safety population described in the Warnings and Precautions reflect a pooled safety population of 479 patients with advanced urothelial cancer and FGFR alterations who received BALVERSA.

Ocular Disorders – BALVERSA can cause ocular disorders, including central serous retinopathy/retinal pigment epithelial detachment (CSR/RPED) resulting in visual field defect.

CSR/RPED occurred in 22% of patients treated with BALVERSA, with a median time to first onset of 46 days. In 104 patients with CSR, 40% required dose interruptions and 56% required dose reductions; 2.9% of BALVERSA-treated patients required permanent discontinuation for CSR. Of the 24 patients who restarted BALVERSA after dose interruption with or without dose reduction, 67% had recurrence and/or worsening of CSR after restarting. CSR was ongoing in 41% of the 104 patients at the time of last evaluation.

Dry eye symptoms occurred in 26% of BALVERSA-treated 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 or permanently discontinue BALVERSA based on severity and/or ophthalmology exam findings.

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. Increased phosphate occurred in 73% of BALVERSA-treated patients. The median onset time of increased phosphate was 16 days (range: 8–421) after initiating BALVERSA. Twenty-four percent of patients received phosphate binders during treatment with BALVERSA. Vascular calcification was observed in 0.2% of patients treated with BALVERSA.

Monitor for hyperphosphatemia throughout treatment. In all patients, restrict phosphate intake to 600-800 mg daily and avoid concomitant use of agents that may increase serum phosphate levels. If serum phosphate is above 7.0 mg/dL, consider adding an oral phosphate binder until serum phosphate level returns to <7.0 mg/dL. Withhold, dose reduce, or permanently discontinue BALVERSA based on duration and severity of hyperphosphatemia.

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 female. In a rat embryo-fetal toxicity study, erdafitinib caused malformations and embryo-fetal death at maternal exposures that were less than the human exposures at the maximum human recommended dose based on AUC. Advise pregnant patients 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.

ADVERSE REACTIONS

In the pooled safety population described in Warnings and Precautions, the median duration of treatment was 4.8 months (range: 0.1 to 43 months). The most common (³20%) adverse reactions were: increased phosphate, nail disorders, stomatitis, diarrhea, increased creatinine, increased alkaline phosphatase, increased alanine aminotransferase, decreased hemoglobin, decreased sodium, increased aspartate aminotransferase, fatigue, dry mouth, dry skin, decreased phosphate, decreased appetite, dysgeusia, constipation, increased calcium, dry eye, palmar-plantar erythrodysesthesia syndrome, increased potassium, alopecia, and central serous retinopathy.

In Cohort 1 of the BLC3001 study:

Serious adverse reactions occurred in 41% of patients who received BALVERSA. Serious reactions in >2% of patients included urinary tract infection (4.4%), hematuria (3.7%), hyponatremia (2.2%), and acute kidney injury (2.2%). Fatal adverse reactions occurred in 4.4% of patients who received BALVERSA, including sudden death (1.5%), pneumonia (1.5%), renal failure (0.7%), and cardiorespiratory arrest (0.7%).
Permanent discontinuation of BALVERSA due to an adverse reaction occurred in 14% of patients. Adverse reactions which resulted in permanent discontinuation of BALVERSA in >2% of patients included nail disorders (3%) and eye disorders (2.2%).
Dosage interruptions of BALVERSA due to an adverse reaction occurred in 72% of patients. Adverse reactions which required dosage interruption in >4% of patients included nail disorders (22%), stomatitis (19%), eye disorders (16%), palmar-plantar erythrodysesthesia syndrome (15%), diarrhea (10%), hyperphosphatemia (7%), increased aspartate aminotransferase (6%), and increased alanine aminotransferase (5%).
Dose reductions of BALVERSA due to an adverse reaction occurred in 69% of patients. Adverse reactions which required dose reductions in >4% of patients included nail disorders (27%), stomatitis (19%), eye disorders (17%), palmar-plantar erythrodysesthesia syndrome (12%), diarrhea (7%), dry mouth (4.4%), and hyperphosphatemia (4.4%).
Clinically relevant adverse reactions in <15% of patients who received BALVERSA included nausea (15%), pyrexia (15%), epistaxis (13%), vomiting (10%), and arthralgia (10%).
DRUG INTERACTIONS

Effects of Other Drugs on BALVERSA

Moderate CYP2C9 or Strong CYP3A4 Inhibitors: Consider alternative agents; however, if co-administration is unavoidable monitor closely for adverse reactions.
Strong CYP3A4 Inducers: Avoid co-administration with BALVERSA.
Moderate CYP3A4 inducers: If co-administration is required at the start of BALVERSA treatment, administer BALVERSA at a dose of 9 mg daily.
Serum phosphate level-altering agents: Avoid co-administration use with agents that can alter serum phosphate levels before the initial dose increase period based on serum phosphate levels.
Effect of BALVERSA on Other Drugs

P-gp substrates: If co-administration is unavoidable, separate BALVERSA administration by at least 6 hours before or after administration of P-gp substrates with narrow therapeutic indices.
Please click here to see full BALVERSA Prescribing Information.