On November 25, 2024 Astrazeneca reported that positive high-level results from the CAPItello-281 Phase III trial showed Truqap (capivasertib) in combination with abiraterone and androgen deprivation therapy (ADT) demonstrated a statistically significant and clinically meaningful improvement in the primary endpoint of radiographic progression-free survival (rPFS) versus abiraterone and ADT with placebo in patients with PTEN-deficient de novo metastatic hormone-sensitive prostate cancer (mHSPC) (Press release, AstraZeneca, NOV 25, 2024, View Source [SID1234648601]).

Overall survival (OS) data were immature at the time of this analysis; however, the Truqap combination showed an early trend towards an OS improvement versus abiraterone and ADT with placebo. The trial will continue as planned to further assess OS as a key secondary endpoint.

Prostate cancer is the second most prevalent cancer in men and the fifth leading cause of male cancer death globally.1 Only one third of patients with metastatic prostate cancer survive five years after diagnosis.2 Newly diagnosed mHSPC is an aggressive form of the disease associated with poor outcomes and survival.3,4 Approximately 200,000 patients are diagnosed with mHSPC each year, and one in four have PTEN-deficient tumours.5 Patients with a tumour biomarker of PTEN deficiency have a particularly poor prognosis.6

Karim Fizazi, MD, PhD, Institut Gustave Roussy, and University of Paris Saclay in Villejuif, France, and principal investigator for the trial said: "Patients with this aggressive form of prostate cancer with tumour PTEN deficiency currently face a particularly poor prognosis, and there is an urgent need for new treatments that improve upon current therapies. The results seen with capivasertib in combination with abiraterone-prednisone and androgen deprivation therapy in the CAPItello-281 trial represent a step forward for these patients."

Susan Galbraith, Executive Vice President, Oncology R&D, AstraZeneca, said: "These results show for the first time, that adding an AKT inhibitor to a standard-of-care therapy can provide benefit to patients with a biomarker of PTEN-deficient metastatic hormone-sensitive prostate cancer. By targeting a key driver of the disease, we have been able to improve upon current therapies and demonstrate the potential role of this combination in an area of critical unmet need. It will be important to see greater maturity in key secondary endpoints including overall survival."

The safety profile of Truqap in combination with abiraterone and ADT in CAPItello-281 was broadly consistent with the known profile of each medicine.

Data will be presented at a forthcoming medical meeting and shared with global regulatory authorities.

Notes

Prostate cancer
Prostate cancer is the second most prevalent cancer in men and the fifth leading cause of male cancer death globally, with an incidence of more than 1.4 million and approximately 397,000 deaths in 2022.1

Metastatic prostate cancer is associated with a significant mortality rate, with only one third of patients surviving five years after diagnosis.2 Development of prostate cancer is often driven by male sex hormones called androgens, including testosterone.7

Metastatic hormone-sensitive prostate cancer
In patients with mHSPC, also known as metastatic castration-sensitive prostate cancer (mCSPC), prostate cancer cells need high levels of androgens to drive cancer growth.4,7 Hormone therapies, such as ADT, are widely used to block the action of male sex hormones and lower the levels of androgens in the body.4,8 However, resistance to these therapies is common and there is a need to extend their use to delay disease progression and castration resistance, where the prostate cancer grows and spreads to other parts of the body despite the use of these therapies.3,4,8

In patients with de novo mHSPC, the cancer has spread to distant parts of the body at the time of first diagnosis.9

PTEN-loss or deficiency fuels the growth of cancer cells, leading to dysregulation of the PI3K/AKT pathway, and is associated with poor outcomes in patients with prostate cancer.6,10

CAPItello-281
CAPItello-281 is a Phase III, double-blind, randomised trial evaluating the efficacy and safety of Truqap in combination with abiraterone and ADT versus abiraterone and ADT in combination with placebo in the treatment of patients with PTEN-deficient de novo mHSPC.

The global trial enrolled 1,012 adult patients with histologically confirmed de novo hormone-sensitive prostate adenocarcinoma and PTEN deficiency as confirmed by central testing. The primary endpoint of the CAPItello-281 trial is rPFS as assessed by investigator, with OS as a secondary endpoint.

Truqap
Truqap is a first-in-class, potent, adenosine triphosphate (ATP)-competitive inhibitor of all three AKT isoforms (AKT1/2/3). Truqap 400mg is administered twice daily according to an intermittent dosing schedule of four days on and three days off. This was chosen in early phase trials based on tolerability and the degree of target inhibition.

Truqap is approved in the US, EU, Japan and several other countries for the treatment of adult patients with HR-positive (or ER-positive), HER2-negative locally advanced or metastatic breast cancer with one or more biomarker alterations (PIK3CA, AKT1 or PTEN) following recurrence or progression on or after an endocrine-based regimen based on the results from the CAPItello-291 trial. Truqap is also approved in Australia for the treatment of adult patients with HR-positive, HER2-negative locally advanced or metastatic breast cancer following recurrence or progression on or after an endocrine based regimen based on these trial results.

Truqap is currently being evaluated in Phase III trials for the treatment of breast cancer (CAPItello-292) and prostate cancer (CAPItello-280 and CAPItello-281) in combination with established treatments.

Truqap was discovered by AstraZeneca subsequent to a collaboration with Astex Therapeutics (and its collaboration with the Institute of Cancer Research and Cancer Research Technology Limited).

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On November 25, 2024 Rakovina Therapeutics Inc. (TSX-V: RKV) ("Rakovina" or the "Company"), a biopharmaceutical company committed to advancing new cancer therapies based on novel DNA-damage response targeting technologies, reported the presentation of a poster showcasing initial results of its Deep Docking Artificial Intelligence (AI) drug discovery screening at the 29th Annual Meeting and Education Day of the Society for Neuro-Oncology (SNO), which was held November 21-24 in Houston, TX (Press release, Rakovina Therapeutics, NOV 25, 2024, View Source;utm_medium=rss&utm_campaign=rakovina-therapeutics-presents-ai-driven-drug-discovery-research-at-society-for-neuro-oncology-annual-meeting [SID1234648617]).

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The poster, titled "Utilizing Artificial Intelligence for the Discovery of Novel PARP1-Selective Inhibitors for Use Against Brain Tumors," highlighted a rapid virtual multi-billion compound screen to identify selective inhibitors of PARP-1, a key enzyme involved in DNA repair that plays a critical role in brain cancer progression. Inhibition of PARP-1 has shown promise in sensitizing cancer cells to treatment.

The poster provided insight into the compounds’ chemical properties affecting absorption, stability, and the ability to cross the blood-brain barrier. The poster also profiled candidates that are predicted to have similar or improved PARP-1 selectivity and central nervous system (CNS) exposure compared with AZD9574, a novel development-stage blood-brain barrier penetrant and selective inhibitor of PARP-1.

"Our team reached a significant milestone this fall with the initial results of our Deep Docking AI screening efforts, successfully evaluating billions of molecular structures within the projected timeframe described at the outset of the collaboration," said Jeffrey Bacha, Executive Chairman of Rakovina Therapeutics. "We were thrilled to present these preliminary findings to leading brain cancer researchers, clinicians, and potential pharmaceutical partners at the prestigious SNO conference. Our poster highlighted the transformative power of AI in accelerating the discovery of potential best-in-class drug candidates."

"Our innovative approach is not only improving the efficiency of drug discovery, but it is also enhancing the specificity and efficacy of potential therapeutics. Our novel class of PARP-1 selective inhibitors can offer hope for more effective treatments in the fight against primary brain tumors and cancers that have metastasized to the brain," he added. "The next step is to select a lead candidate molecule based on wet lab validation for target selectivity, metabolic and pharmacokinetic parameters, CNS penetration, and activity against cancer."

First-generation poly (ADP-ribose) polymerase (PARP) inhibitors have dramatically improved patient outcomes in certain mutated cancers but are limited in their utility to treat brain malignancies as they cannot pass through the blood-brain barrier. They also have adverse side effects that are possibly driven by the collateral inhibition of PARP-2. The successful development of a PARP-1 selective CNS penetrant inhibitor could reduce toxicity while providing a new therapeutic option for brain tumors.

Upcoming Video Conference Call

Rakovina Therapeutics will host a video conference call on Wednesday, November 27, 2024, at 10 am PST to further discuss the data presented at the Society for Neuro-Oncology Annual Meeting and discuss next steps and upcoming milestones in the PARP inhibitor and other development programs.

Register for the webinar or access the live stream here:

View Source

About the Society for Neuro-Oncology (SNO) Annual Meeting

The SNO Annual Meeting is the premier global event in neuro-oncology, bringing together over 2,600 researchers, clinicians, and scientists from more than 40 countries to advance the field of neuro-oncology. This influential conference features leading experts in oncology, providing a platform for the latest research, treatments, and innovations. The 2024 meeting took place at the George R. Brown Convention Center in Houston, Texas, from November 21-24. For more information, visit: View Source

On November 25, 2024 Natera, Inc. (NASDAQ: NTRA), a global leader in cell-free DNA and genetic testing, reported that it will present new SignateraTM data at the San Antonio Breast Cancer Symposium (SABCS), taking place Dec. 10-13 in San Antonio, TX (Press release, Natera, NOV 25, 2024, View Source [SID1234648634]). Natera and its collaborators will present a total of six abstracts.

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"We are proud to share this new data on Signatera at SABCS that underscores our commitment to generating evidence on the clinical utility of Signatera for patients with breast cancer," said Angel Rodriguez, M.D., senior medical director at Natera.

The full list of abstracts with selected highlights are as follows:

ZEST Clinical Trial
Oral Presentation #GS3-01 | Dec. 13 | Presenter: Nicholas Turner, MD, PhD, FRCP, FMedSci
Circulating tumor DNA surveillance in ZEST, a randomized, phase 3, double-blind study of niraparib or placebo in patients with triple-negative breast cancer or HR+ HER2− BRCA-mutated breast cancer with molecular residual disease after definitive therapy

ZEST was a randomized, phase III, double-blind trial, sponsored by GSK, that evaluated whether niraparib can enhance disease-free survival in patients with breast cancer who are ctDNA-positive after completion of curative intent therapy and without evidence of radiographic recurrence. A total of 2,746 patients were pre-screened. Of patients who were ctDNA-positive, 40 were enrolled and randomized (niraparib, 18; placebo, 22); 36 patients (90%) had Triple Negative Breast Cancer (TNBC), and 4 patients (10%) had BRCA-mutated HR+ disease. An analysis of outcomes among randomized patients showed a median disease-free survival of 11.4 months in the niraparib arm versus 5.4 months in the placebo group (hazard ratio, 0.64; 95% CI, 0.30–1.39).

Clinical Genomics Database Experience
Poster Spotlight #PS9-01 | Dec. 12 | Presenter: Marla Lipsyc-Sharf, MD
Actionable Genomic Alterations in Localized Hormone Receptor Positive (HR+) Breast Cancer and Impact on Clinical Outcomes: Results from Comprehensive Whole Exome Sequencing (WES) and Tumor-Informed circulating tumor DNA (ctDNA) analysis

This real-world analysis evaluated the association of targetable tumor genomic alterations with ctDNA detection and distant recurrence-free survival (DRFS) in early-stage breast cancer. In the study, 44% of patients (127/287) who were Signatera-positive had at least one targetable genomic alternation, including 34.5% with the PIK3CA mutation. In addition, of patients with ctDNA-positivity within 2 years, those with mutated PIK3CA had an inferior DRFS (HR: 36.9), compared to patients with wild-type PIK3CA (HR=16.3).

Patient-Reported Outcomes
Four abstracts to be presented at SABCS evaluated patient reported outcomes when testing for circulating tumor DNA (ctDNA). The data indicates that ctDNA testing can provide valuable information for treatment planning while not causing increased anxiety in patients.

Poster #P2-03-21 | Dec. 11 | Presenter: Neil Carleton
Longitudinal Monitoring of ctDNA to Facilitate Surgical De-Escalation and Disease Surveillance in Older Women with ER+ Breast Cancer on Primary Endocrine Therapy: A Prospective, Pragmatic, Hybrid-Decentralized Trial with Correlative Analyses

Poster #P4-03-29 | Dec. 12 | Presenter: Devora Isseroff, MD
Patient (Pt) reported anxiety levels during ctDNA surveillance in early-stage triple negative (TNBC) and hormone receptor positive (HR+) breast cancer (BC)

Poster #P3-01-22 | Dec. 12 | Presenter: Mrinalini Ramesh, DO
Pilot feasibility study of ctDNA testing in breast cancer and its association with pain, stress and anxiety

Poster #P5-12-19 | Dec. 13 | Presenter: Mridula George, MD
Patient-reported outcomes from the CIPHER study

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, ovarian cancer, 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 100 peer-reviewed papers.

On November 25, 2024 Bicycle Therapeutics plc (NASDAQ: BCYC), a pharmaceutical company pioneering a new and differentiated class of therapeutics based on its proprietary bicyclic peptide (Bicycle) technology, reported that the company will present data showing the enhanced anti-tumor activity of zelenectide pevedotin monotherapy in triple-negative breast cancer (TNBC) patients with NECTIN4 gene amplification at the 2024 San Antonio Breast Cancer Symposium (SABCS) taking place December 10-13 in San Antonio, Texas (Press release, Bicycle Therapeutics, NOV 25, 2024, View Source [SID1234648602]).

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In conjunction with the SABCS poster presentation, Bicycle Therapeutics will also announce topline combination data for zelenectide pevedotin plus pembrolizumab in previously untreated (first-line) cisplatin-ineligible patients with metastatic urothelial cancer, and topline monotherapy data for zelenectide pevedotin in non-small cell lung cancer patients with NECTIN4 gene amplification. The company will host a conference call and webcast for analysts and investors to review the updated data for zelenectide pevedotin.

Poster Presentation:
Title: Enhanced anti-tumor activity of zelenectide pevedotin in triple negative breast cancer (TNBC) patients (pts) with NECTIN4 gene amplification (amp)
Session Number: 4
Date and Time: Thursday, Dec. 12, at 5:30-7 p.m. CT
Presentation Number: P4-10-21
Lead Author: Niklas Klümper, M.D., University Hospital Bonn

Conference Call and Webcast Information
Bicycle Therapeutics will host a conference call and webcast on Friday, Dec. 13, at 7 a.m. CT to review the data updates for zelenectide pevedotin. To access the call, please dial +1-833-816-1408 (U.S.) or +1-412-317-0501 (international) and ask to join the Bicycle Therapeutics call. A live webcast and replay of the conference call will be available in the Investor section of the company’s website, www.bicycletherapeutics.com.

On November 25, 2024 Replimune Group, Inc. (Nasdaq: REPL), a clinical stage biotechnology company pioneering the development of novel oncolytic immunotherapies, reported a proposed public offering of $125 million of shares of its common stock and pre-funded warrants to purchase shares of common stock (Press release, Replimune, NOV 25, 2024, View Source [SID1234648618]). All securities in the offering will be offered by Replimune. In addition, Replimune intends to grant the underwriter a 30-day option to purchase up to an additional $18.75 million of securities from Replimune at the public offering price, less the underwriting discounts and commissions.

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Leerink Partners is acting as sole bookrunning manager for the proposed offering. The proposed offering is subject to market and other customary closing conditions, and Replimune cannot assure you as to whether or when the proposed offering may be completed.

The proposed offering will be made only by means of a preliminary prospectus supplement and the accompanying prospectus. A copy of the preliminary prospectus supplement and the accompanying prospectus relating to the proposed offering will be filed with the Securities and Exchange Commission (the "SEC") and may be obtained, when available, by visiting EDGAR on the SEC website at www.sec.gov. Alternatively, copies of the preliminary prospectus supplement and the accompanying prospectus, when available, may be obtained from Leerink Partners LLC, Attention: Syndicate Department, 53 State Street, 40th Floor, Boston, Massachusetts 02109, by telephone at (800) 808-7525, ext. 6105, or by email at [email protected]. The final terms of the proposed offering will be disclosed in a final prospectus supplement to be filed with the SEC.

The securities described above are being offered by Replimune pursuant to its shelf registration statement on Form S-3, including a base prospectus, that was previously filed by Replimune with the SEC on August 3, 2023, as amended by the Post-Effective Amendment No. 1 filed with the SEC on May 16, 2024 and as further amended by the Post-Effective Amendment No. 2 filed with the SEC on May 16, 2024, and declared effective by the SEC on July 22, 2024. This press release shall not constitute an offer to sell or the solicitation of an offer to buy, nor shall there be any sale of securities, in any state or jurisdiction in which such an offer, solicitation or sale would be unlawful prior to registration or qualification under the securities laws of any such state or jurisdiction.