On February 14, 2022 ImmunityBio, Inc. (NASDAQ: IBRX), a clinical-stage immunotherapy company, reported positive data from the company’s late-stage bladder cancer trial (QUILT-3.032) (Press release, ImmunityBio, FEB 14, 2022, View Source [SID1234608075]). The data showed sustained complete response rates in patients with BCG-unresponsive non-muscle invasive carcinoma in situ (NMIBC CIS) bladder cancer (Cohort A) and with papillary disease (Cohort B). Of the 83 patients with BCG-unresponsive NMIBC CIS, 59 (71%) had a complete response with a median duration of response of 24.1 months—exceeding historical complete response rates of 41% and 18% for FDA-approved therapies pembrolizumab and valrubicin, respectively. In the papillary disease arm of the study (Cohort B), 57% of patients are disease free at 12 months and 53% at 18 months.

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"We are excited with these promising results," said Sam Chang, M.D., Urologic Surgery Chief Surgical Officer, Vanderbilt Ingram Cancer Center and trial investigator. "This study suggests that BCG induces trained immunity as the prime, while N-803 serves as a vital boost for innate immune memory. These results of high efficacy activity and excellent safety profile set a new bar for NMIBC treatment, and together with the familiar and favorable mode of administration, will advance our current standards of care for patients with bladder cancer."

The latest data from this trial exceeds AUA-FDA workshop benchmarks for both the magnitude of complete remission and the duration of complete response for new therapies for BCG-unresponsive bladder cancer. Indeed, the benchmark of 30% durable response at 18 to 24 months for a clinically meaningful therapy "is likely too high and may not be realistically achievable,"3 according to recommendations published in the Journal of Clinical Oncology. This "realistically unachievable" endpoint of 30% durable response at 18 months has in fact now been achieved and exceeded with the combination of Anktiva and BCG in this trial reported today. Taken together, the high rates of complete response, cystectomy avoidance, avoidance of progression to muscle invasive disease in the patients that responded, and the prolonged duration of complete response, as well as the favorable safety profile, places this novel immunotherapy combination at the forefront of both existing approved and potential treatments for bladder cancer patients.

"Trained immunity is a recently discovered immune system response triggered by BCG. Natural Killer (NK) and T cells are activated by BCG resulting in bladder cancer cell death. When an appropriate secondary stimulus is administered along with BCG, that trained immune response is enhanced to induce immune memory resulting in a prolonged duration of immunological response," said Patrick Soon-Shiong, M.D., Executive Chairman and Global Chief Scientific and Medical Officer of ImmunityBio. "N-803, our IL-15 superagonist which proliferates NK and T cells, serves as this enhancing secondary boost and augments the immunological response when given in combination with BCG. This mechanism of action of inducing trained innate immune memory, through the combination of N-803 and BCG, accounts for the prolonged 24-month durable complete response reported in this trial."

"These results support our hypothesis that immunogenic cell death can induce long-term memory and that N-803 increases the immunologic potential of BCG, even in patients who become unresponsive to BCG alone," Soon-Shiong said. "N-803 does this by stimulating proliferation and enhancing activity of tumor-killing Natural Killer (NK) cells and T cells, acting as a secondary stimulus or boost to the prime trained immunity induced by BCG."

The study results presented at ASCO (Free ASCO Whitepaper) GU are summarized below:

Cohort A (CIS)
Excellent safety and tolerability profile of N-803 + BCG for CIS

0% treatment-related SAEs
0% immune-related AE
0% grade 4 and 5 AE
71% Complete remission (CR) rate at anytime
24.1 Months median durable complete remission
96% Avoidance of bladder cancer progression at 24 months in responders
91% Avoidance of cystectomy at 24 months in responders
100% Bladder cancer specific overall survival at 24 months
Favorable & familiar dosing schedule with activity localized to the bladder
Cohort B (Papillary Disease)
Excellent safety and tolerability profile of N-803 + BCG for papillary disease

0% treatment-related SAEs
0% immune-related AE
0% grade 4 and 5 AE
57% Disease free survival rate at 12 months
99% Overall bladder cancer specific survival
95% Cystectomy avoidance rate
Favorable & familiar dosing schedule with activity localized to the bladder
"When we began the QUILT trials across multiple tumor types, initiating our Cancer Moonshot program, the goal was to achieve a new paradigm in cancer care by activating the patient’s own immune system to induce NK and T cell memory with long-term complete remission in patients who have failed all current therapies," Soon-Shiong said. "With these results in bladder cancer, as well as our recently reported results in pancreatic cancer, we are one step closer to proving our hypothesis that delivering therapies that harness the patient’s own immune system is what will truly transform current standards of care."

The data will be announced on Friday, February 18 during an oral presentation at the 2022 ASCO (Free ASCO Whitepaper) Genitourinary Cancers Symposium titled Phase II/III clinical results of IL-15RαFc superagonist N-803 with BCG in BCG-unresponsive non-muscle invasive bladder cancer (NMIBC)

Incidence of Bladder Cancer

Bladder cancer has a high incidence worldwide; in 2020, an estimated 573,278 new cases were diagnosed and caused 212,536 deaths.4 In the United States, bladder cancer is the fourth most commonly-diagnosed solid malignancy in men and the twelfth for women; the American Cancer Society estimates there will be 83,730 new cases and 17,200 deaths from bladder cancer in 2021.5 Approximately 75–85% of bladder cancer patients present with a disease confined to the mucosa (stage Ta, carcinoma in situ) or submucosa (stage T1); these categories are grouped as non-muscle-invasive bladder cancer (NMIBC). Of these, approximately 70% present as stage Ta, 20% as T1, and 10% as CIS.6

For the last 30 years, BCG immunotherapy has been the standard for treating NMIBC. However, disease recurrence and progression rates remain unacceptably high. Standard-of-care recommendations include lifetime invasive surveillance and rapid treatment of recurrences, creating a substantial financial burden and drastic impact on quality of life. Of those patients who experience recurrence, approximately 30% will succumb to their disease over a 15-year period, and another 50% will undergo radical cystectomy of the bladder (surgical removal of the bladder that may require removing surrounding organs) in an attempt to control the disease.7

There is an urgent, unmet need to treat NMIBC and avoid cystectomy. Despite the advent of minimally-invasive procedures and robotic techniques, the 90-day mortality and morbidity rates in cystectomy patients remain unacceptably high at 3-6% and 28-64%, respectively.8&9 Based on this urgent need, the FDA published guidance in February 2018 to address BCG unresponsive NMIBC, stating that the goal of therapy in patients with BCG-unresponsive NMIBC is to avoid cystectomy.

About the Study and Breakthrough Designation

QUILT 3.032 is an open-label, three cohort, multicenter Phase 2/3 study of intravesical BCG plus Anktiva (N-803) in patients with BCG-unresponsive high-grade NMIBC (NCT03022825) and was opened in 2017. The primary endpoint for Cohort A of this Phase 2/3 study is incidence of complete response (CR) of CIS at any time. The FDA had granted Fast Track Designation to the pivotal trial based on Phase I data. In December 2019, the FDA granted ImmunityBio Breakthrough Therapy Designation based on interim Phase 2 data indicating the primary endpoint of the trial was already met.

ImmunityBio’s IL-15 superagonist Anktiva (N-803)

The cytokine interleukin-15 (IL-15) plays a crucial role in the immune system by affecting the development, maintenance, and function of the natural killer (NK) and T cells. N-803 is a novel IL-15 superagonist complex consisting of an IL-15 mutant (IL-15N72D) bound to an IL-15 receptor α/IgG1 Fc fusion protein. Its mechanism of action is direct specific stimulation of CD8+ T cells and NK cells through beta gamma T-cell receptor binding (not alpha) while avoiding T-reg stimulation. N-803 has improved pharmacokinetic properties, longer persistence in lymphoid tissues and enhanced anti-tumor activity compared to native, non-complexed IL-15 in vivo.

N-803 is currently being evaluated for adult patients in two clinical NMIBC trials. QUILT 2.005 is investigating use of N-803 in combination with BCG for patients with BCG-naïve NMIBC; QUILT 3.032 is studying N-803 in combination with BCG in patients with BCG-unresponsive NMIBC.

Mechanism of Action & Contribution of N-803 (Anktiva) and BCG for Bladder Cancer

Trained immunity10 is a recently discovered immune system response triggered by BCG. Natural Killer (NK) and T cells11 are activated by BCG resulting in bladder cancer cell death. When an appropriate secondary stimulus is administered along with BCG, that trained immune response is enhanced to induce immune memory resulting in a prolonged duration12 of immunological response. N-803, an IL-15 superagonist which proliferates NK and T cells13, serves as this enhancing secondary boost and augments the immunological response when given in combination with BCG. This mechanism of action of inducing trained innate immune memory, through the combination of N-803 and BCG, accounts for the prolonged 24-month durable complete response reported in this trial.

On February 14, 2022 Oakrum Pharma, LLC ("Oakrum Pharma"), in collaboration with ANI Pharmaceuticals (NASDAQ: ANIP), reported that the U.S. Food and Drug Administration (FDA) has approved the Abbreviated New Drug Application (ANDA) for a generic version of Cystadane1 (betaine anhydrous for oral solution) Powder in a 180 gm bottle and granted Competitive Generic Therapy (CGT) of 180 days of exclusivity (Press release, ANI Pharmaceuticals, FEB 14, 2022, View Source;powder-including-180-days-of-exclusivity-301481968.html [SID1234608093]). Shipments of the generic product began in early February, 2022.

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Marco Polizzi, CEO of Oakrum Pharma, stated, "This is the third generic orphan drug that we have launched since starting this business, and we remain committed to bringing rare disease patients affordable options of pharmaceutical products that currently have few or no generic options. Oakrum currently has licensing rights to seven additional ANDAs filed with the FDA and expects to file additional generic orphan drugs later this year."

"Our collaboration with Oakrum furthers ANI’s mission of bringing high-quality prescription pharmaceutical products to patients in need. Rare diseases are often overlooked, and we are especially pleased to continue identifying patient populations that are underserved and medicines that can help them. This approval with Competitive Generic Therapy status and resulting 180 days of exclusivity marks another milestone for ANI’s R&D engine as a leader in bringing limited competition products to market," stated Nikhil Lalwani, CEO of ANI Pharmaceuticals.

1 Cystadane is a licensed trademark of Recordati Rare Diseases Inc.

On February 14, 2022 Biodesix, Inc. (NASDAQ: BDSX) a leading data-driven diagnostic solutions company with a focus in lung disease, reported that the Company expects to report fourth quarter and record full-year 2021 preliminary unaudited total revenue of $7.2 million and $54.5 million, respectively (Press release, Biodesix, FEB 14, 2022, View Source [SID1234608060]). The strength in the full-year 2021 total revenue of $54.5 million compared to $45.6 million in 2020 was a result of growth in the Company’s core lung diagnostic testing and first half 2021 COVID-19 testing. The financial results included in this release pertaining to the fourth quarter and year ended December 31, 2021 are preliminary and unaudited and subject to final review and adjustments.

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Fourth Quarter and Full-Year 2021 Financial Highlights

•Total quarterly revenue of $6.8 million, excluding COVID-19 testing revenue, increased $1.2 million or 22% for the fourth quarter 2021 compared to the same period in 2020 and $0.8 million or 13% for the fourth quarter 2021 compared to the third quarter 2021; and
•Total annual revenue of $24.3 million, excluding COVID-19 testing revenue, increased $7.1 million or 41% for the year ended December 31, 2021 compared to the same period in 2020.
•Cash and cash equivalents as of December 31, 2021 of $32.7 million.
"We are pleased to see the continued growth in our core lung diagnostic business throughout 2021 despite the challenges created by the ongoing pandemic," stated Scott Hutton, Chief Executive Officer. "With the launch of our new IQLung Treatment Guidance Testing Strategy, which includes the new GeneStrat NGS test and provides for both early and advanced stage lung cancer testing results, our Nodify Lung testing for lung nodule risk assessment, as well as the broad array of tests that we perform on behalf of our biopharmaceutical partners, we are very well positioned to continue to drive growth in our core business in 2022. As we said in our third quarter earnings call, given our current financial position, including covenants under our current debt facility, we will continue to explore paths to greater liquidity, including raising capital through additional equity and/or debt as the markets continue to evolve, and through partnering opportunities."

On February 14, 2022 The Janssen Pharmaceutical Companies of Johnson & Johnson reported new real-world evidence data showing the initiation of ERLEADA (apalutamide) results in high rates of rapid and deep prostate-specific antigen (PSA) response among patients with metastatic castration-sensitive prostate cancer (mCSPC) (Press release, Johnson & Johnson, FEB 14, 2022, View Source [SID1234608094]). In a separate post-hoc analysis of the registrational Phase 3 SPARTAN and TITAN studies, rapid and deep PSA responses with ERLEADA were associated with improvement in patient-reported outcomes (PROs) related to quality of life, physical wellbeing, pain, and fatigue intensity. These findings will be presented during the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper)’s Genitourinary (ASCO GU) Cancers Symposium, taking place in San Francisco and virtually from February 17-19, 2022.

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The real-world evidence study evaluating PSA response (Abstract 43, Poster B9) included data from 186 patients treated with ERLEADA and 165 treated with enzalutamide from 69 community urology practices in the United States. By six months, 69.3 percent of patients with mCSPC initiated on ERLEADA attained PSA90 response and 55.6 percent for enzalutamide (HR=1.56; p=0.014). PSA90 response is defined as the patient’s earliest attainment of ≥90 percent decline in PSA relative to their baseline PSA at treatment initiation. At nine months and by the end of follow-up, 70.4 percent of patients treated with ERLEADA achieved PSA90 and 62.5 percent for enzalutamide (HR=1.49; p=0.024). The median time to PSA90 response was 3.1 months for patients treated with ERLEADA and to 5.2 months for enzalutamide.1*

"Deep PSA response is an important early prognostic factor for achieving longer radiographic progression-free survival and overall survival in patients with metastatic castration-sensitive prostate cancer," said Benjamin Lowentritt, M.D., Director Prostate Cancer Care Program, Chesapeake Urology, and Past President, AUA, Mid-Atlantic Region, and lead study investigator.** "These real-world data are consistent with and reinforce the benefit of ERLEADA as reported in the clinical trial setting, providing prescribers with important insights regarding time to and durability of PSA90 responses for commonly prescribed mCSPC medications."

Patients included in the analysis had at least 12 months of clinical activity to assess baseline characteristics and were classified into treatment cohorts based on their first filled prescription for ERLEADA or enzalutamide after Dec. 16, 2019. Patients were followed from their first filled prescription date until the earliest of one of the following events: regimen discontinuation, treatment switch, end of clinical activity or end of data availability (March 5, 2021).

A separate ERLEADA poster presentation evaluating PROs data (Abstract 73, Poster D1) demonstrated an association between rapid and deep PSA decline and improved health-related quality of life PROs as reported from the Phase 3 SPARTAN and TITAN studies. Patient-reported outcomes were assessed using tools including the Functional Assessment of Cancer Therapy-Prostate (FACT-P; TITAN and SPARTAN), Brief Pain Inventory-Short Form (BPI-SF; TITAN only), and Brief Fatigue Inventory (BFI; TITAN only):

A landmark analysis at three months after treatment initiation evaluated the association between deep PSA decline (≤ 0.2 ng/mL) and delay in deterioration in PROs (defined as decrease ≥ 10 points FACT-P total, ≥ 3 points Physical Wellbeing, ≥ 30 percent baseline for BPI-SF worst pain, or ≥ 2 points for BFI worst fatigue).2
Patients in both studies who achieved a deep PSA decline maintained FACT-P total (SPARTAN: HR=0.83; TITAN: HR=0.54) or FACT-P Physical Wellbeing (SPARTAN: HR=0.70; TITAN: HR=0.63) levels longer.2
Patients in TITAN who achieved a deep PSA decline had a lower risk of increasing pain or worsening fatigue; as assessed by the BPI-SF worst pain intensity progression (HR=0.70) or BFI worst fatigue intensity progression (HR=0.76), respectively.2
"This analysis demonstrates that the rapid and deep PSA responses shown in the SPARTAN and TITAN pivotal studies translate into improved quality of life for patients," said Tracy McGowan, M.D., Therapeutic Area Head, U.S. Medical Affairs, Janssen Scientific Affairs, LLC. "We are dedicated to continually expanding the body of research for ERLEADA by providing important information that may help patients and their physicians make treatment decisions that work best for them."

To date, published results on ERLEADA include data from more than 2,000 patients across three Phase 3 clinical studies. ERLEADA has shown a statistically significant improvement in overall survival with a consistent safety profile, while maintaining patients’ health-related quality of life in both approved indications of mCSPC and non-metastatic castration resistant prostate cancer (nmCRPC).3 ERLEADA is currently approved in more than 74 countries.

About ERLEADA
ERLEADA is an androgen receptor inhibitor indicated for the treatment of patients with nmCRPC and for the treatment of patients with mCSPC.4 ERLEADA received U.S. Food and Drug Administration (FDA) approval for nmCRPC on February 14, 2018 and was approved for mCSPC on September 17, 2019.4 To date, more than 50,000 patients worldwide have been treated with ERLEADA. ERLEADA is taken orally, once daily, with or without food.4 The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Prostate Cancer include apalutamide (ERLEADA) with continued androgen deprivation therapy**† as a Category 1 Preferred treatment option for patients with non-metastatic (M0) castration-resistant prostate cancer and a PSADT ≤10 months.4 The NCCN Clinical Practice Guidelines also include apalutamide (ERLEADA) with androgen deprivation**† as a Category 1 Preferred treatment option for patients with metastatic (M1) castration-naive prostate cancer.‡5 The American Urological Association (AUA) Guidelines for Castration-Resistant Prostate Cancer (CRPC) recommend clinicians offer apalutamide (ERLEADA) with continued androgen deprivation therapy (ADT) as one of the treatment options for patients with nmCRPC at high risk for developing metastatic disease (Standard; Evidence Level Grade A).***5 ERLEADA is being further studied in two ongoing Phase 3 clinical trials.

For more information about ERLEADA, visit www.ERLEADA.com.

*© National Comprehensive Cancer Network, Inc. 2020. All rights reserved. Accessed December 11, 2020. To view the most recent and complete version of the NCCN Guidelines, go online to NCCN.org. NCCN makes no warranties of any kind whatsoever regarding their content, use, or application, and disclaims any responsibility for their application or use in any way.

**Orchiectomy, LHRH agonist, or LHRH antagonist

†Use of an LHRH agonist plus a first-generation antiandrogen is an option for patients receiving ADT alone, but is not an option for patients receiving apalutamide.

‡The term "castration-naive" is used to define patients who are not on ADT at the time of progression. The NCCN Prostate Cancer Panel uses the term "castration-naive" even when patients have had neoadjuvant, concurrent, or adjuvant ADT as part of radiation therapy provided they have recovered testicular function.

***Standard: Directive statement that an action should (benefits outweigh risks/burdens) or should not (risks/burdens outweigh benefits) be taken based on Grade A or B evidence.

***Evidence Level: A designation indicating the certainty of the results as high, moderate, or low (A, B, or C, respectively) based on AUA nomenclature and methodology.

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.

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.

On February 14, 2022 Taiho Pharmaceutical Co., Ltd. reported that it has submitted to the Japanese Ministry of Health, Labour and Welfare, an application for the additional indication of "postoperative adjuvant chemotherapy in breast cancer" for its oral anticancer agent TS-1 (Press release, Taiho, FEB 14, 2022, View Source [SID1234608061]).

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This application is based on the results of an investigator-initiated study, Postoperative Therapy with TS-1 for oestrogen receptor-positive, HER2-negative breast cancer (POTENT study). According to the results of the POTENT study, the combination of TS-1 with endocrine therapy showed a clinically significant extension of invasive disease-free survival (iDFS) among patients with oestrogen receptor-positive, HER2-negative breast cancer with an intermediate or higher risk of recurrence. The safety profile was similar to that of TS-1 reported in the past, and no new concerns were identified in the POTENT study.

Taiho Pharmaceutical will continue to prepare for the delivery of this treatment option to patients with breast cancer, aiming to obtain approval as quickly as possible.

About the POTENT Study
POTENT is an investigator-initiated study conducted since March 25, 2011, under the designation of advanced medical care (Specific Clinical Research jRCTs051180057，UMIN000003969). The principal investigator, Masakazu Toi, M.D., Ph.D., Professor of Breast Surgery at Kyoto University’s Graduate School of Medicine and Faculty of Medicine, had submitted a study application to the Japanese Ministry of Health, Labour and Welfare under the former Advanced Medical Care Program. On January 25, 2011, the Advanced Medical Care Assessment Council approved the study with the advanced medical care name, "Postoperative Therapy with TS-1 for oestrogen receptor-positive, HER2-negative breast cancer."

The purpose of the study was to verify any increase in the effect on prevention of recurrence through a randomized comparative Phase III study in postoperative adjuvant therapy for oestrogen receptor-positive, HER2-negative breast cancer. The control group was treated with endocrine therapy (5 years), the standard treatment method, with the study group treated with endocrine therapy (5 years) in combination with TS-1 (1 year). The study endpoints included invasive disease-free survival, overall survival, safety, etc. The study enrolled 1,959 women from 139 breast cancer facilities across Japan during the registration period from February 2012 to February 2016.1

Public Health Research Center, contracted to serve as the study management office, received funding from Taiho Pharmaceutical and this study was conducted with such funding.
.

1 Toi M et al., Lancet Oncol 2021; 22: 74–84.

For more information of the POTENT study, please refer to
View Source
View Source (in Japanese only)

About Primary Breast Cancer
According to the Japan Breast Cancer Society’s Annual Report of the Japanese Breast Cancer Registry for 2017,2 94,612 women in Japan are affected by breast cancer annually. It is reported that 75.3% of these cases are oestrogen receptor-positive, HER2-negative breast cancer. In cases of early-stage breast cancer, perioperative chemotherapy and postoperative endocrine therapy are given as standard treatments in addition to surgery, considering the risk of recurrence.

2 Hayashi N et al., Breast Cancer 2020; 27:803–809.

About TS-1
A member of the fluoropyrimidine class of anticancer agents, TS-1 is a combination of three pharmacological compounds: tegafur, an antimetabolite agent that, after absorption, is converted into the anticancer agent fluorouracil (5-FU); gimeracil (5-chloro-2, 4-dihydroxypyridine, or CDHP), which decreases the degradation of 5-FU in the liver; and oteracil (Oxo), which decreases 5-FU phosphorylation in the gastrointestinal tract. Developed as a gastric cancer treatment, TS-1 was first approved in Japan in 1999 and has become a standard of care for the treatment of gastric cancer. TS-1 has been approved in Japan for the treatment of gastric, colorectal, head and neck, non-small cell lung, inoperable or recurrent breast, pancreatic, and biliary tract cancers.