On February 14, 2022 Oxilio, a pioneering drug development company repurposing existing drugs to address unmet needs in cancer treatment, reported that following successful formulation development it has commenced work on the clinical evaluation of its first novel formulation of OXL001 (Press release, Oxilio, FEB 14, 2022, View Source [SID1234621598]).

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

Oxilio signed a research agreement with TRx Biosciences in January 2021, to evaluate the performance of TRx Biosciences’ technology platform within Oxilio’s OXL001 programme. The TRx Biosciences technology offers the potential to address bioavailability and pharmacokinetic challenges in achieving and maintaining efficacious exposure whilst enhancing tumour uptake to maximise the utility of OXL001’s pharmacology.

As a result of successful formulation optimisation and encouraging preclinical evaluation, Oxilio and TRx Biosciences have begun work on the first human study for the clinical evaluation of the novel formulation of OXL001. It is anticipated that the first subject will be dosed later in 2022, with the study concluding by the end of the year.

Oxilio Limited Co-founder and Director, Dr Simon Yaxley said "Together with our colleagues at TRx Biosciences, we are excited and encouraged by what we have been able to achieve in formulation optimisation which has led to significant pharmacokinetic improvements in preclinical models. We look forward to taking this science forward into the clinic later this year which, if successful, offers tremendous near-term potential benefit to cancer patients.

TRx Biosciences Co-founder and CEO, Dr Robin Bannister said "Our work with Oxilio has enabled us to rapidly establish our underlying technology, both in terms of pharmacokinetics and pharmacodynamics and we are delighted to see the progression of OXL001 towards clinic, given its immense potential as a pan-cancer therapy. We will continue to closely support Oxilio throughout its clinical development activities, which will be equally transformative for TRx as the first clinical validation of our targeted oral delivery platform."

On February 14, 2022 Amgen (NASDAQ: AMGN) reported the presentation of efficacy and safety data from the CodeBreaK 100 Phase 1/2 trial in patients with KRAS G12C-mutated advanced pancreatic cancer who received LUMAKRAS (sotorasib)* (Press release, Amgen, FEB 14, 2022, View Source [SID1234608072]). The data will be presented at the monthly American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Plenary Series on Feb. 15, 2022. Data show encouraging and clinically meaningful anticancer activity and a positive benefit:risk profile.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

"Based on these exciting data, we are expanding CodeBreaK 100 to enroll more patients with pancreatic and other tumor types to better understand the efficacy and safety of LUMAKRAS in tumors outside of non-small cell lung and colorectal cancers," said David M. Reese, M.D., executive vice president of Research and Development at Amgen. "CodeBreaK is the largest and broadest global clinical trial program to date with one of the most robust, centrally reviewed datasets. As we learn more from the extensive data that we collect, we’ll continue to invest in the program by expanding cohorts and exploring new combinations so that we can help as many patients as possible."

LUMAKRAS demonstrated a centrally confirmed objective response rate (ORR) of 21% and disease control rate (DCR) of 84% across 38 heavily pre-treated advanced pancreatic cancer patients. Nearly 80% of patients received LUMAKRAS as a third-line or later therapy. Eight of the 38 patients achieved a confirmed partial response (PR) performed by a blinded independent central review (BICR). Two of the eight patients with PR have ongoing responses. Median duration of response was 5.7 months with a median follow-up of 16.8 months as of the data cutoff date of Nov. 1, 2021. The results also show a median progression free survival (PFS) of 4 months and a median overall survival (OS) of almost 7 months. No new safety signals were identified with this study of patients with advanced pancreatic cancers. Treatment-related adverse events (TRAEs) of any grade occurred in 16 (42%) patients with diarrhea (5%) and fatigue (5%) as the most common grade 3 TRAEs. No TRAEs were fatal or resulted in treatment discontinuation.

"After decades of research, current treatments for patients with pancreatic cancer provide limited survival benefit, illustrating the critical need for novel, safe and effective treatment options," said John Strickler, M.D. associate professor of medicine, Duke University School of Medicine and gastrointestinal oncologist. "In the largest dataset evaluating the efficacy and safety of a KRASG12C inhibitor in heavily pretreated advanced pancreatic cancer, sotorasib achieved a centrally confirmed response rate of 21% and a disease control rate of 84%. This is clinically meaningful for patients because there is not an established standard therapy for these patients once they get to a third-line of treatment."

Cancer of the pancreas is a highly lethal malignancy. It is the fourth leading cause of cancer-related deaths in both men and women in the U.S. with a 5-year survival rate of approximately 10%.1 There is a high unmet need for patients with advanced pancreatic cancer that has progressed after first-line treatment, where FDA-approved second-line therapy has provided survival of about six months and a response rate of 16%.2 After progression on first- and second-line chemotherapy, there are no therapies with a demonstrated survival benefit.2,3 Despite advances in treatment, few improvements have been made to improve diagnosis and treatment of pancreatic cancer.

It is estimated that approximately 90% of patients with pancreatic cancer harbor a KRAS mutation with KRAS G12C accounting for approximately 1-2% of these mutations.4-5

ASCO Plenary Series Session
ASCO will host a livestream event on Tuesday, Feb. 15 at 3 p.m. ET featuring presentation of the abstract "First data for sotorasib in patients with pancreatic cancer with KRAS p.G12C mutation: A phase I/II study evaluating efficacy and safety" by Dr. John Strickler from Duke University. To participate in the free and open session, participants may register and login at View Source

*LUMAKRAS is marketed as LUMYKRAS (sotorasib) in the European Union and the United Kingdom.

About LUMAKRAS/LUMYKRAS (sotorasib)
Amgen took on one of the toughest challenges of the last 40 years in cancer research by developing LUMAKRAS/LUMYKRAS, a KRASG12C inhibitor.6 LUMAKRAS/LUMYKRAS has demonstrated a positive benefit-risk profile with rapid, deep and durable anticancer activity in patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring the KRAS G12C mutation with a once daily oral formulation.7

Amgen is progressing the largest and broadest global KRASG12C inhibitor development program with unparalleled speed and exploring more than 10 sotorasib combination regimens, including triplets, with clinical trial sites spanning five continents. To date, over 4,000 patients around the world have received LUMAKRAS/LUMYKRAS through the clinical development program and commercial use.

In May 2021, LUMAKRAS was the first KRASG12C inhibitor to receive regulatory approval anywhere in the world with its approval in the U.S., under accelerated approval. LUMAKRAS/LUMYKRAS is also approved in the United Arab Emirates, the European Union, Japan and Switzerland, and in Canada and Great Britain under the FDA’s Project Orbis. Through Project Orbis, Amgen also has Marketing Authorization Applications (MAAs) for sotorasib in review in Australia, Brazil, Singapore and Israel. Additionally, Amgen has submitted MAAs in South Korea, Turkey, Taiwan, Colombia, Thailand, Mexico, Hong Kong, Saudi Arabia, Argentina, Kuwait and Qatar.

LUMAKRAS/LUMYKRAS is also being studied in multiple other solid tumors.8

About CodeBreaK
The CodeBreaK clinical development program for Amgen’s drug sotorasib is designed to treat patients with an advanced solid tumor with the KRAS G12C mutation and address the longstanding unmet medical need for these cancers.

CodeBreaK 100, the Phase 1 and 2, first-in-human, open-label multicenter study, enrolled patients with KRAS G12C-mutant solid tumors.7.8 Eligible patients must have received a prior line of systemic anticancer therapy, consistent with their tumor type and stage of disease. The primary endpoint for the Phase 2 study was centrally assessed objective response rate. The Phase 2 trial in NSCLC enrolled 126 patients, 124 of whom had centrally evaluable lesions by RECIST at baseline.7 The Phase 2 trial in colorectal cancer (CRC) is fully enrolled and results have been published.9

CodeBreaK 200, the global Phase 3 randomized active-controlled study comparing sotorasib to docetaxel in KRAS G12C-mutated NSCLC completed enrollment of 345 patients. Eligible patients had previously treated (previous treatment with both platinum doublet chemotherapy and a checkpoint inhibitor), locally-advanced and unresectable or metastatic KRAS G12C-mutated NSCLC. The primary endpoint is progression-free survival and key secondary endpoints include overall survival, objective response rate, and patient-reported outcomes.

Amgen also has several Phase 1b studies investigating sotorasib monotherapy and sotorasib combination therapy across various advanced solid tumors (CodeBreaK 101) open for enrollment. A Phase 2 randomized study will evaluate sotorasib in patients with stage IV KRAS G12C-mutated NSCLC in need of first-line treatment (CodeBreaK 201). For information, please visit www.hcp.codebreaktrials.com.

LUMAKRAS (sotorasib) U.S. Indication
LUMAKRAS is indicated for the treatment of adult patients with KRAS G12C-mutated locally advanced or metastatic non-small cell lung cancer (NSCLC), as determined by an FDA-approved test, who have received at least one prior systemic therapy.

This indication is approved under accelerated approval based on overall response rate (ORR) and duration of response (DOR). Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).

LUMAKRAS (sotorasib) Important U.S. Safety Information

Hepatotoxicity

LUMAKRAS can cause hepatotoxicity, which may lead to drug-induced liver injury and hepatitis.
Among 357 patients who received LUMAKRAS in CodeBreaK 100, hepatotoxicity occurred in 1.7% (all grades) and 1.4% (Grade 3). A total of 18% of patients who received LUMAKRAS had increased alanine aminotransferase (ALT)/increased aspartate aminotransferase (AST); 6% were Grade 3 and 0.6% were Grade 4. In addition to dose interruption or reduction, 5% of patients received corticosteroids for the treatment of hepatotoxicity.
Monitor liver function tests (ALT, AST and total bilirubin) prior to the start of LUMAKRAS every 3 weeks for the first 3 months of treatment, then once a month or as clinically indicated, with more frequent testing in patients who develop transaminase and/or bilirubin elevations.
Withhold, dose reduce or permanently discontinue LUMAKRAS based on severity of adverse reaction.
Interstitial Lung Disease (ILD)/Pneumonitis

LUMAKRAS can cause ILD/pneumonitis that can be fatal. Among 357 patients who received LUMAKRAS in CodeBreaK 100, ILD/pneumonitis occurred in 0.8% of patients, all cases were Grade 3 or 4 at onset, and 1 case was fatal. LUMAKRAS was discontinued due to ILD/pneumonitis in 0.6% of patients.
Monitor patients for new or worsening pulmonary symptoms indicative of ILD/pneumonitis (e.g., dyspnea, cough, fever). Immediately withhold LUMAKRAS in patients with suspected ILD/pneumonitis and permanently discontinue LUMAKRAS if no other potential causes of ILD/pneumonitis are identified.
Most Common Adverse Reactions

The most common adverse reactions ≥ 20% were diarrhea, musculoskeletal pain, nausea, fatigue, hepatotoxicity and cough.
Drug Interactions

Advise patients to inform their healthcare provider of all concomitant medications, including prescription medicines, over-the-counter drugs, vitamins, dietary and herbal products.
Inform patients to avoid proton pump inhibitors and H2 receptor antagonists while taking LUMAKRAS.
If coadministration with an acid-reducing agent cannot be avoided, inform patients to take LUMAKRAS 4 hours before or 10 hours after a locally acting antacid.

On February 14, 2022 Stablix, Inc., a biopharmaceutical company pioneering targeted protein stabilization (TPS) as a novel therapeutic modality, reported the appointment of Tony Kingsley as Chief Executive Officer (Press release, Stablix Therapeutics, FEB 14, 2022, View Source [SID1234608089]). Mr. Kingsley replaces interim CEO Dr. Carlo Rizzuto, partner at founding investor Versant Ventures, who remains on Stablix’s board of directors.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

Mr. Kingsley is an experienced biotech CEO with a track record leading and building organizations across multiple scientific disciplines, therapeutic areas and stages of drug development. He most recently was president and CEO of Scholar Rock. Prior to that, he was president and CEO of TarisBio, president and COO of The Medicines Company, and the head of global commercial at Biogen.

Earlier in his career, Mr. Kingsley held leadership roles in the medical device and diagnostics industries and was a partner at McKinsey & Company. He received his undergraduate degree from Dartmouth College and an MBA from Harvard Business School.

"I am incredibly excited by the opportunities I see in Stablix’s proprietary scientific approach," said Mr. Kingsley. "Targeted protein stabilization represents a whole new therapeutic platform technology with applications across a wide range of important diseases with high unmet need. I look forward to working with the remarkable scientific team, the board, and our investors to build a leading company."

"We are thrilled that Tony is joining the company at this pivotal time," said Dr. Rizzuto. "His breadth of experience in drug development, strategy, partnering and company building will help us accelerate our efforts to create a powerful scientific platform and world-class organization."

On February 14, 2022 Kinnate Biopharma Inc. (Nasdaq: KNTE) ("Kinnate"), a biopharmaceutical company focused on the discovery and development of small molecule kinase inhibitors for difficult-to-treat, genomically defined cancers, reported that it has been selected to deliver an oral presentation of preclinical data from its KIN-2787 program at the upcoming virtual IASLC 2022 Targeted Therapies of Lung Cancer meeting taking place February 22-26, 2022 (Press release, Kinnate Biopharma, FEB 14, 2022, View Source [SID1234608057]). The presentation will be delivered by study collaborator and presenting author Tadashi Manabe, M.D., Ph.D., Postdoctoral Scholar-Fellow, Department of Medicine, Division of Hematology and Oncology at the University of California, San Francisco (UCSF).

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

"We continue to make progress in our clinical trial of KIN-2787 and expect initial data in the third quarter of 2022," said Richard Williams, MBBS, Ph.D., Chief Medical Officer at Kinnate. "Among other indications, KIN-2787 is being developed for the treatment of patients with non-small cell lung cancer driven by BRAF Class II or Class III alterations and we are looking forward to sharing preclinical data on its antitumor activity at this upcoming IASLC meeting."

In this study, KIN-2787 activity was assessed by suppression of downstream MAPK pathway signaling and subsequent cell growth inhibition across BRAF-altered and/or RAS-altered versus wild type panels of human non-small cell lung cancer (NSCLC) cell lines. In contrast to approved therapies, targeting Class I BRAF alterations, KIN-2787 was most active in Class II and Class III BRAF-altered NSCLC cells. KIN-2787 also inhibited cellular proliferation in BRAF alteration-positive human NSCLC cell lines. Additionally, KIN-2787 was active in in vitro cell growth inhibition assays against a parental BRAF Class I-driven NSCLC cell line and retained activity in an experimentally acquired vemurafenib-resistant BRAF p61 splice variant-expressing derived cell line. In vivo, KIN-2787 efficacy was evaluated using a BRAF-alteration driven human NSCLC cell line and patient-derived xenograft models. The ongoing KN-8701 trial (NCT# 04913285) of KIN-2787 is actively enrolling patients across multiple centers in the United States.

"Together, Class II and III alterations represent as many as 65% of all oncogenic BRAF alterations in NSCLC. While there are approved RAF inhibitors being used in combination treatment of BRAF Class I-altered NSCLC, there are currently no RAF-targeted therapies for the treatment of NSCLC patients with tumors driven by BRAF Class II or III alterations, which is likely a contributing factor in the inferior clinical outcomes often seen with these patients," said Dr. Manabe. "I am pleased to share findings from this study which show that KIN-2787 is a potent and selective pan-RAF inhibitor with demonstrated capabilities in overcoming well-characterized resistance mechanisms."

"KIN-2787 is a promising next-generation RAF inhibitor with unique properties that has shown potent activity against a variety of oncogenic BRAF-driven lung cancers in preclinical studies. The preclinical data are exciting, and I have great enthusiasm for its continued clinical development as a potential new targeted therapy that could help address the current unmet needs for oncogene-driven lung cancer patients," added Trever Bivona, M.D., Ph.D., study collaborator and Professor, Hematology and Oncology, at UCSF.

Details of the meeting presentation are as follows:

Abstract title: Antitumor Activity of KIN-2787, a Next-Generation Pan-RAF Inhibitor, in Preclinical Models of Human BRAF-Alteration Driven Non-Small Cell Lung Cancer (NSCLC)
Session: Best Fellows Oral Abstract Session
Session date and time: Wednesday, February 23, 2022 at 4:15pm ET
Additional information on the virtual IASLC 2022 Targeted Therapies of Lung Cancer meeting is available at: View Source

On February 14, 2022 AstraZeneca reported that Positive results from the PROpel Phase III trial showed and MSD’s Lynparza (olaparib) in combination with abiraterone demonstrated a statistically significant and clinically meaningful improvement in radiographic progression-free survival (rPFS) versus current standard-of-care abiraterone as a 1st-line treatment for patients with metastatic castration-resistant prostate cancer (mCRPC) with or without homologous recombination repair (HRR) gene mutations (Press release, AstraZeneca, FEB 14, 2022, View Source [SID1234608073]).

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

These results will be presented on 17 February at the 2022 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Genitourinary Cancers Symposium.

Prostate cancer is the second most common cancer in male patients, causing approximately 375,000 deaths in 2020.1 Patients with advanced prostate cancer have a particularly poor prognosis and the five-year survival rate remains low.1,2,3 Approximately half of patients with mCRPC receive only one line of active treatment, with diminishing benefit of subsequent therapies.4,5,6,7 HRR gene mutations occur in approximately 20-30% of patients with mCRPC.8

Fred Saad, Professor and Chairman of Urology and Director of Genitourinary Oncology at the University of Montreal Hospital Center and principal investigator in the trial, said: "It is clear to me that the prognosis for metastatic castration resistant prostate cancer (mCRPC) is extremely poor, and many patients are only able to receive one line of effective therapy. The results of the PROpel trial, which showed that olaparib in combination with abiraterone significantly delayed disease progression versus abiraterone by more than eight months, demonstrate the potential for this combination to become a new standard of care option in mCRPC if approved."

Susan Galbraith, Executive Vice President, Oncology R&D, AstraZeneca, said: "This Lynparza combination has the potential to afford first-line patients more time without disease progression while also maintaining their quality of life. The PROpel results are impressive because active comparator trials set a high bar and, in this trial, Lynparza plus abiraterone showed a significant clinical improvement when compared to an active standard of care in patients with metastatic castration-resistant prostate cancer, regardless of whether they have an HRR gene mutation."

Roy Baynes, Senior Vice President and Head of Global Clinical Development, Chief Medical Officer, MSD Research Laboratories, said: "Results from the PROpel trial showed that Lynparza in combination with abiraterone plus prednisone reduced the risk of disease progression or death by a third compared to abiraterone plus prednisone in the first-line setting for patients with metastatic castration-resistant prostate cancer, regardless of their biomarker status. We look forward to discussing these important results with global health authorities as quickly as possible. We thank the patients, caregivers and health care providers for participating in this study."

In a predefined interim analysis, Lynparza in combination with abiraterone reduced the risk of disease progression or death by 34% versus abiraterone alone (based on a hazard ratio [HR] of 0.66; 95% confidence interval [CI] 0.54-0.81; p<0.0001). Median rPFS was 24.8 months for Lynparza plus abiraterone versus 16.6 for abiraterone alone.

Results also showed a favourable trend towards improved overall survival (OS) with Lynparza plus abiraterone versus abiraterone alone, however the difference did not reach statistical significance at the time of this data cut-off (analysis at 29% data maturity). The trial will continue to assess OS as a key secondary endpoint.

Additional data from efficacy endpoints such as time to first subsequent therapy (TFST), second progression-free survival (PFS2), objective response rate (ORR), as well as prostate-specific antigen levels and circulating-tumour-cell counts further support the treatment benefit of Lynparza and abiraterone compared to abiraterone alone in the overall trial population.

The safety and tolerability of Lynparza in combination with abiraterone was in line with that observed in prior clinical trials and the known profiles of the individual medicines. There was no increase in the rate of discontinuation of abiraterone in patients treated with Lynparza in combination with abiraterone, and no detrimental effect on health-related quality of life versus those treated with abiraterone alone (FACT-P (Functional Assessment of Cancer Therapy-Prostate) questionnaire).

Summary of PROpel results

Lynparza + abiraterone

(n=399)

Placebo + abiraterone

(n=397)

rPFS by Investigator 1

Number of patients with events (%)

168 (42)

226 (57)

Median PFS (in months)

24.8

16.6

HR (95% CI)

p-value

0.66 (0.54, 0.81)

<0.0001

rPFS by BICR2

Number of patients with events (%)

157 (39)

218 (55)

Median PFS (in months)

27.6

16.4

HR (95% CI)

p-value5

0.61 (0.49, 0.74)

<0.0001

OS3

Number of patients with events (%)

107 (27)

121 (30)

Median OS (in months)

NC4

NC

HR (95% CI)

p-value

0.86 (0.66, 1.12)

0.2923

PFS2

Number of patients with events (%)

70 (18)

94 (24)

Median (in months)

NC

NC

HR (95% CI)

p-value5

0.69 (0.51, 0.94)

0.0184

TFST

Number of patients with events (%)

183 (46)

221 (56)

Median (95% CI) (in months)

25.0 (22.2, NC)

19.9 (17.1, 22.0)

HR (95% CI)

p-value5

0.74 (0.61, 0.90)

0.0040

Objective Response Rate

Number of evaluable patients6

161

160

Number of patients with responses (%)

94 (58)

77 (48)

Odds ratio (95% CI)

1.60 (1.02, 2.53)

p-value5

0.0409

rPFS by HRR gene mutation status7

HRRm

Number of patients randomized

111

115

Number of patients with events (%)

43 (39)

73 (63)

Median (in months)

NC

13.9

HR (95% CI)

0.50 (0.34, 0.73)

Non-HRRm

Number of patients randomized

279

273

Number of patients with events (%)

119 (43)

149 (55)

Median (95% CI) (in months)

24.1 (19.6, 27.6)

19.0 (14.3, 21.9)

HR (95% CI)

0.76 (0.60, 0.97)

1. Investigator-assessed PFS data; Interim analysis with 50% maturity (394 events in 796 patients)

2. Assessed by blinded independent central review (BICR)

3. OS analysis was done at 29% maturity (228 events in 796 patients) and boundary for significance 0.001 (2-sided); statistical significance not reached. Survival follow up continues and further analyses were planned.

4. Not calculable

5. Nominal

6. Patients with measurable disease at baseline as per RECIST 1.1 criteria, investigator assessment.

7. Exploratory subgroup analysis by HRR status. The HRRm status of patients in PROpel was determined retrospectively using results from tumour tissue and plasma ctDNA HRRm tests. Patients were classified as HRRm if (one or more) HRR gene mutation was detected by either test; patients were classified as non-HRRm if no HRR gene mutation was detected by either test; 18 patients did not have a valid HRR testing result from either a tumour tissue or ctDNA test and were excluded from this subgroup analysis. The analysis was performed using a Cox proportional hazards model including terms for treatment group, the subgroup factor, and a treatment by subgroup interaction.

The most common adverse events (AEs) (greater than or equal to 20% of patients) were anaemia (45%), nausea (28%) and fatigue (28%). Grade 3 or higher AEs were anaemia (15%), hypertension (4%), urinary tract infection (2%), fatigue (1%), decreased appetite (1%), vomiting (1%), asthenia (1%), back pain (1%), diarrhoea (1%). Approximately 86% of patients treated with Lynparza in combination with abiraterone who experienced AEs remained on treatment at the time of data cut-off.

In September 2021 at a planned interim analysis, the Independent Data Monitoring Committee concluded that the PROpel trial met the primary endpoint of rPFS.

Lynparza is approved in the US for patients with HRR gene-mutated mCRPC (BRCA-mutated and other HRR gene mutations); and in the EU, Japan and China for patients with BRCA-mutated mCRPC.

Notes

Metastatic castration-resistant prostate cancer
Metastatic prostate cancer is associated with a significant mortality rate.3 Development of prostate cancer is often driven by male sex hormones called androgens, including testosterone.9

In patients with mCRPC, their prostate cancer grows and spreads to other parts of the body despite the use of androgen-deprivation therapy to block the action of male sex hormones.10 Approximately 10-20% of patients with advanced prostate cancer will develop castration-resistant prostate cancer (CRPC) within five years, and at least 84% of these patients will have metastases at the time of CRPC diagnosis.10

Of patients with no metastases at CRPC diagnosis, 33% are likely to develop metastases within two years.11 Despite the advances in mCRPC treatment in the past decade with taxane and new hormonal agent (NHA) treatment, once patients failed first line therapy, the treatment effect of second line anti-cancer therapy diminished significantly hence there is high unmet medical need in this population.10,12,13,14

PROpel
PROpel is a randomised, double-blind, multi-centre Phase III trial testing the efficacy, safety, and tolerability of Lynparza versus placebo when given in addition to abiraterone in men with mCRPC who had not received prior chemotherapy or NHAs in the 1st-line setting.

Men in both treatment groups will also receive either prednisone or prednisolone twice daily. The primary endpoint is rPFS and secondary endpoints include OS, PFS2, and TFST.

For more information about the trial please visit ClinicalTrials.gov.

Lynparza
Lynparza (olaparib) is a first-in-class PARP inhibitor and the first targeted treatment to block DNA damage response (DDR) in cells/tumours harbouring a deficiency in HRR, such as those with mutations in BRCA1 and/or BRCA2, or those where deficiency is induced by other agents (such as NHAs).

Inhibition of PARP proteins with Lynparza leads to the trapping of PARP bound to DNA single-strand breaks, stalling of replication forks, their collapse and the generation of DNA double-strand breaks and cancer cell death. In the PROpel Phase III trial, Lynparza is combined with abiraterone, an NHA which targets the androgen receptor (AR) pathway.

Androgen receptor signalling engages a transcriptional programme that is critical for tumour cell growth & survival in prostate cancer.15,16 Preclinical models have identified interactions between PARP signalling and the AR pathway which support the observation of a combined anti-tumour effect of Lynparza and NHAs, like abiraterone, in both HRR deficient and HRR proficient prostate cancer.17,18,19

The PARP1 protein has been reported to be required for the transcriptional activity of androgen receptors; therefore inhibiting PARP with Lynparza may impair the expression of androgen receptor target genes and enhance the activity of NHAs.15,18,20 Additionally, it is thought that abiraterone may alter/inhibit the transcription of some HRR genes which may induce HRR deficiency and increase sensitivity to PARP inhibition.17,19,21,22

Lynparza is currently approved in a number of countries across PARP-dependent tumour types with defects and dependencies in the DDR pathway. It is approved for the maintenance treatment of platinum-sensitive relapsed ovarian cancer as a monotherapy and in combination with bevacizumab for the 1st-line maintenance treatment of BRCA-mutated (BRCAm) and homologous recombination deficiency (HRD) positive advanced ovarian cancer, respectively.

Lynparza is also approved for BRCAm, HER2-negative metastatic breast cancer (in the EU this includes locally advanced breast cancer); for germline BRCAm metastatic pancreatic cancer, and for HRR gene-mutated metastatic castration-resistant prostate cancer (BRCAm only in the EU and Japan).

Lynparza, which is being jointly developed and commercialised by AstraZeneca and MSD, is the foundation of AstraZeneca’s industry-leading portfolio of potential new medicines targeting DDR mechanisms in cancer cells.

The AstraZeneca and MSD strategic oncology collaboration
In July 2017, AstraZeneca and Merck & Co., Inc., Kenilworth, NJ, US, known as MSD outside the US and Canada, announced a global strategic oncology collaboration to co-develop and co-commercialise Lynparza (olaparib), the world’s first PARP inhibitor, and Koselugo (selumetinib), a mitogen-activated protein kinase (MEK) inhibitor, for multiple cancer types.

Working together, the companies will develop Lynparza and Koselugo in combination with other potential new medicines and as monotherapies. Independently, the companies will develop Lynparza and Koselugo in combination with their respective PD-L1 and PD-1 medicines.

AstraZeneca in oncology
AstraZeneca is leading a revolution in oncology with the ambition to provide cures for cancer in every form, following the science to understand cancer and all its complexities to discover, develop and deliver life-changing medicines to patients.

The Company’s focus is on some of the most challenging cancers. It is through persistent innovation that AstraZeneca has built one of the most diverse portfolios and pipelines in the industry, with the potential to catalyse changes in the practice of medicine and transform the patient experience.

AstraZeneca has the vision to redefine cancer care and, one day, eliminate cancer as a cause of death.