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.

On February 14, 2022 Arvinas, Inc. (Nasdaq: ARVN), a clinical-stage biotechnology company creating a new class of drugs based on targeted protein degradation, reported the presentation of new data showing that bavdegalutamide (also known as ARV-110), a novel PROTAC protein degrader targeting the androgen receptor (AR), continues to provide evidence of anti-tumor activity and patient benefit in metastatic castration-resistant prostate cancer (mCRPC) (Press release, Arvinas, FEB 14, 2022, View Source [SID1234608077]). These data show that bavdegalutamide reduced prostate-specific antigen (PSA) levels greater than or equal to 50% (PSA50) in 46% of patients with tumors harboring AR T878X/H875Y (T878X = T878A or T878S) mutations. Updated Phase 1 and interim Phase 2 ARDENT data will be presented in both a rapid abstract session and a poster session on February 17, 2022, at the 2022 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Genitourinary (ASCO GU) Cancers Symposium.

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"These results are very encouraging and reinforce our conviction that bavdegalutamide has the potential to provide meaningful clinical benefit to patients with mCRPC who have progressed after treatment with novel hormonal agents and for whom few treatment options exist," said John Houston, Ph.D., president and chief executive officer of Arvinas. "With particularly robust activity in a molecularly defined patient population, we believe there is a clear path forward to developing this novel treatment as a precision medicine and plan to initiate a pivotal trial by year end 2022."

Highlights from the bavdegalutamide abstract (data cut-off date August 26, 2021):

Across 140 biomarker-evaluable patients with ≥1 month of PSA follow-up in the completed Phase 1 dose escalation and ongoing Phase 2 ARDENT expansion cohort:

Evidence of anti-tumor activity and patient benefit, including:
PSA50 rate of 46% in patients with AR T878X/H875Y tumor mutations (n=26)
Two confirmed RECIST (Response Evaluation Criteria in Solid Tumors) partial responses out of seven RECIST-evaluable patients with AR T878X/H875Y tumor mutations
PSA50 rate of 26% (five of 19) in evaluable patients in the subgroup defined as "less pretreated" (having received only one prior novel hormonal agent and no prior chemotherapy). The "less pretreated" subgroup had a similar circulating tumor DNA molecular profile to the more pretreated, biomarker-defined subgroups in the ARDENT trial; a majority of patients with PSA50 declines in this group had tumors with the AR T878X/H875Y mutations
Bavdegalutamide had a manageable tolerability profile at the recommended Phase 2 dose (RP2D) of 420 mg. The majority of treatment-related adverse events (TRAEs) were Grade 1/2 and there were no Grade ≥4 TRAEs in the 113 patients treated at the RP2D.
The most common TRAEs of any grade at the RP2D across Phase 1 and the ongoing phase 2 ARDENT expansion cohort were nausea (Grade 1/2: 42%; Grade 3: 1%), fatigue (Grade 1/2: 27%; Grade 3: 1%), vomiting (Grade 1/2: 23%; Grade 3: 1%), decreased appetite (Grade 1/2: 19%; Grade 3: 0), diarrhea (Grade 1/2: 15%; Grade 3: 2%), and alopecia (Grade 1/2: 11%).
"Novel hormonal agents have become standard of care in castration-sensitive prostate cancer and there is a need for novel AR therapies with the potential to provide benefit for patients with mCRPC and tumors that have developed resistance," said Ron Peck, M.D., chief medical officer at Arvinas. "As an oncologist, I’m particularly excited by a precision medicine approach with the potential to identify patients who are most likely to respond to bavdegalutamide."

Additional data from the completed Phase 1 and interim results from the ongoing Phase 2 ARDENT trial will be presented on Thursday, February 17, 2022. The cut-off date for data in the rapid abstract session and the poster session was December 20, 2021.

Poster presentation:

Poster Title: Phase 1/2 study of ARV-110, an androgen receptor (AR) PROTAC degrader, in metastatic castration-resistant prostate cancer (mCRPC)
Session: Poster Session A: Prostate Cancer
Date: Thursday, February 17, 2022
Time: 2:30 – 4:00 p.m. ET
Rapid abstract session (7:45 – 8:45 p.m. ET):

Rapid Abstract Title: Rapid Abstract Session A: Prostate Cancer
Date: Thursday, February 17, 2022
Time: 7:55 – 8:00 p.m. ET
The full abstract can be found at the official ASCO (Free ASCO Whitepaper) Genitourinary Cancers Symposium website here.

Arvinas Webcast Investor Meeting
Arvinas will host a conference call and webcast Thursday, February 17, 2022, at 8:30 a.m. ET, to discuss the completed Phase 1 dose escalation data and interim data from the Phase 2 ARDENT trial presented at ASCO (Free ASCO Whitepaper) GU. Participants are invited to listen by dialing (844) 467-7654 (domestic) or (602) 563-8497 (international) five minutes prior to the start of the call and providing the passcode 1085203.

Supporting materials for the conference call and webcast will be available on the Arvinas’ website at www.arvinas.com under Events + Presentations. A replay of the webcast will be archived on the Arvinas website following the presentation.

About Bavdegalutamide (ARV-110)

Bavdegalutamide is an investigational orally bioavailable PROTAC protein degrader designed to selectively target and degrade the androgen receptor (AR). Bavdegalutamide is being developed as a potential treatment for men with metastatic castration-resistant prostate cancer.

Bavdegalutamide has demonstrated activity in preclinical models of AR mutation or overexpression, both common mechanisms of resistance to currently available AR-targeted therapies.

On February 14, 2022 The Janssen Pharmaceutical Companies of Johnson & Johnson reported initial results from the Phase 3 MAGNITUDE study evaluating the investigational use of niraparib, a selective poly-ADP ribose polymerase (PARP) inhibitor, in combination with abiraterone acetate plus prednisone in patients with metastatic castration-resistant prostate cancer (mCRPC) with or without specific homologous recombination repair (HRR) gene alterations (Press release, Johnson & Johnson, FEB 14, 2022, View Source [SID1234608095]). At the final analysis for radiographic progression-free survival (rPFS), the treatment combination of niraparib and abiraterone acetate plus prednisone demonstrated a statistically significant improvement in patients with HRR gene alterations. Results will be featured in a late-breaking oral presentation (Abstract #12; Oral Abstract Session A) at 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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MAGNITUDE (NCT03748641) is a Phase 3, randomized, double-blind, placebo-controlled, multicenter study evaluating the safety and efficacy of the combination of niraparib and abiraterone acetate plus prednisone as a first-line therapy in patients with mCRPC. The MAGNITUDE study was intentionally designed with two independent cohorts to assess treatment effect in patients with and without HRR gene alterations (including ATM, BRCA1, BRCA2, BRIP1, CDK12, CHEK2, FANCA, HDAC2, PALB2 alterations) versus standard of care. The cohort of patients with prospectively-identified HRR gene alterations enrolled 423 patients, with patients randomized to receive the combination of niraparib and abiraterone acetate plus prednisone (combination arm [n=212]) or placebo and abiraterone acetate plus prednisone (control arm [n=211]). At 18.6-month median follow-up, patients in the combination arm of the cohort with HRR gene alterations showed a significant improvement in rPFS, with a reduction in the risk of progression or death of 27 percent (hazard ratio [HR] 0.73; p=0.022). This improvement was most pronounced in patients with BRCA1/2 gene alterations, where a 47 percent risk reduction was observed for rPFS (HR 0.53; p=0.001), as analyzed by blinded independent central review (BICR). A consistent but greater improvement was observed in investigator-assessed rPFS, which showed an overall 36 percent risk reduction in patients with HRR gene alterations (HR: 0.64; p=0.002), and a 50 percent risk reduction in patients with BRCA1/2 gene alterations (HR: 0.50; p=0.0006).1

The cohort without HRR gene alterations (n=233) met the predefined futility criteria in August 2020, showing no benefit from the treatment combination (HR>1) in the HRR biomarker negative population.1 Enrollment into this cohort was stopped at the time of futility at the recommendation of the Independent Data Monitoring Committee. Investigators and patients were unblinded and given the opportunity to continue treatment with niraparib and abiraterone acetate plus prednisone or receive only abiraterone acetate plus prednisone at the discretion of the study investigator.

"When choosing a treatment plan for patients with prostate cancer, physicians must consider individual needs, particularly for patients with mCRPC with HRR gene alterations who face a poor prognosis," said Dr. Kim Chi, Medical Oncologist at BC Cancer – Vancouver and principal investigator of the MAGNITUDE study.* "The MAGNITUDE data provide important context about the subgroup of patients with prostate cancer who may benefit from treatment with niraparib in combination with abiraterone acetate plus prednisone in the first-line setting, as well as those who may be better served by other treatment options."

In patients with HRR gene alterations, clinically relevant improvements in outcomes were also seen at this first interim analysis for secondary endpoints including time to initiation of cytotoxic chemotherapy, time to symptomatic progression and time to PSA progression. Additionally, objective response rate was improved by the combination of niraparib and abiraterone acetate plus prednisone. Overall survival data were immature at this interim analysis and follow-up will continue for all secondary endpoints.1

"These data suggest clinically meaningful improvements in outcomes in patients with prostate with HRR gene alterations who may derive benefit from this combination regimen, highlighting the importance of biomarkers to guide the patient selection process," said Mary Guckert, RN, MSN, Vice President, Development Leader, Prostate Cancer, Janssen Research & Development, LLC. "The design of this trial aligns with the real-world setting as it includes patients with prostate cancer who were able to start first-line standard of care treatment, while awaiting HRR biomarker results, and shows the need to prospectively test for and identify patients most likey to benefit from the combination of niraparib and abiraterone acetate with prednisone."

The observed safety profile of the combination of niraparib and abiraterone acetate plus prednisone was consistent with the known safety profile of each agent. Of the patients with HRR gene alterations, 67 percent experienced Grade 3 adverse events (AEs) and 46.4 percent experienced Grade 4 AEs, largely driven by anemia and fatigue. Discontinuation rates for the combination arm and control arm were 10.8 percent and 4.7 percent respectively. The combination of niraparib and abiraterone acetate plus prednisone also maintained overall quality of life in comparison with placebo and abiraterone acetate plus prednisone as measured on the Functional Assessment of Cancer Therapy–Prostate (FACT-P) scale.1

Patients with HRR gene alterations, such as BRCA1/2, are at an increased risk of developing prostate cancer, and BRCA-related prostate cancer is usually aggressive.2 Long-term survival is low for patients with mCRPC and those who have HRR gene alterations face a worse prognosis, driving a significant unmet medical need for novel therapies in this disease.3,4

About MAGNITUDE
MAGNITUDE is a Phase 3 randomized, double-blind, placebo-controlled, multicenter clinical study evaluating the safety and efficacy of the combination of niraparib and abiraterone acetate plus prednisone as a first-line therapy for patients with mCRPC, with or without certain HRR gene alterations. The study includes two cohorts in which patients were randomized to receive either niraparib and abiraterone acetate plus prednisone or abiraterone acetate (placebo) plus prednisone cohorts: one cohort of patients with predefined HRR gene alterations (including ATM, BRCA1, BRCA2, BRIP1, CDK12, CHEK2, FANCA, HDAC2, PALB2 alterations) and one cohort of patients without HRR gene alterations. In a third, open-label cohort, all patients received a combination tablet of niraparib and abiraterone and a separate tablet of prednisone. The primary endpoint of the MAGNITUDE trial is rPFS. Secondary endpoints include time-to-initiation of cytotoxic chemotherapy, time to symptomatic progression, and overall survival.

About Niraparib
Niraparib is an orally administered, selective poly-ADP ribose polymerase (PARP) inhibitor, that is currently being studied by Janssen for the treatment of patients with prostate cancer. Additional ongoing studies include the Phase 3 AMPLITUDE study evaluating the combination of niraparib and abiraterone acetate plus prednisone in a biomarker-selected patient population with metastatic castration-sensitive prostate cancer and QUEST, a Phase 1b/2 study of niraparib combination therapies for the treatment of mCRPC.

In April 2016, Janssen Biotech, Inc. entered a worldwide (except Japan) collaboration and license agreement with TESARO, Inc. (acquired by GSK in 2018), for exclusive rights to niraparib in prostate cancer. In the U.S., niraparib is indicated for the maintenance treatment of adult patients with advanced epithelial ovarian, fallopian tube or primary peritoneal cancer who are in a complete or partial response to first-line platinum-based chemotherapy; for the maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer who are in a complete or partial response to platinum-based chemotherapy; for the treatment of adult patients with advanced ovarian, fallopian tube or primary peritoneal cancer who have been treated with three or more prior chemotherapy regimens and whose cancer is associated with homologous recombination deficiency (HRD) positive status defined by either: a deleterious or suspected deleterious BRCA mutation, or genomic instability and who have progressed more than six months after response to the last platinum-based chemotherapy. Niraparib is currently marketed by GSK as ZEJULA.5

About Metastatic Castration-Resistant Prostate Cancer
Metastatic castration-resistant prostate cancer characterizes cancer that no longer responds to androgen deprivation therapy and has spread to other parts of the body. The most common metastatic sites are bones, followed by lymph nodes, lungs and liver.6 Prostate cancer is the second most common cancer in men worldwide, behind lung cancer.2 More than one million men around the world are diagnosed with prostate cancer each year.7 Patients with mCRPC and HRR gene alterations have a worse prognosis than those without HRR alterations.8

On February 14, 2022 Roivant Sciences reported that has spawned another Vant (Press release, Roivant Sciences, FEB 14, 2022, View Source [SID1234608336]). The latest addition to the clan is Hemavant, a biotech that starts life with a former Eisai drug and plans to start a study in patients with myelodysplastic syndromes (MDS) this year.

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Hemavant is developing RVT-2001, the small-molecule modulator of splicing factor 3B subunit 1 that Roivant licensed from Eisai late last year. Eisai, working with its H3 Biomedicine subsidiary, took the oral candidate into a phase 1 clinical trial in 2016 but saw no complete or partial responses in the first 84 patients enrolled in the study of patients with MDS and other blood cancers.

Work stalled on the candidate after the 2019 data drop, with Roivant saying in January that the number of subjects treated with RVT-2001 still stands at "over 80." Yet, Roivant sees promise in some of the data generated by Eisai, leading it to license the asset and narrow the focus of the program.

Eisai enrolled patients with acute myeloid leukemia, chronic myelomonocytic leukemia and lower- and higher-risk MDS in its phase 1 study. In that population, the lack of responses was a blow, but Roivant has zeroed in on another endpoint that suggests RVT-2001 may have a future in lower-risk, transfusion-dependent MDS patients.

RELATED: Roivant ditches plan to reacquire Immunovant, invests $200M

Thirty percent of the 19 lower-risk MDS patients treated with RVT-2001, formerly known as H3B 8800, gained red blood cell transfusion independence. Most of the patients had previously received Bristol Myers Squibb’s Revlimid, hypomethylating agents or both therapies.

Based on the signal, Hemavant is developing RVT-2001 as an oral therapy for transfusion-dependent anemia in patients with lower-risk MDS. A phase 1/2 clinical trial is set to start in the first half of the year.

Roivant has paid Eisai $8 million in cash and $7 million in stock for the global rights to the candidate. As RVT-2001 advances, Roivant will pay up to $65 million in development and regulatory milestones in the first indication plus up to $18 million in additional indications. The deal also features up to $295 million in commercial milestones and a tiered high single-digit to sub-teens royalty.