ABSTRACT: CTO71

New data from the Phase III EMBRACA trial led by researchers at The University of Texas MD Anderson Cancer Center found the PARP inhibitor talazoparib did not demonstrate a statistically significant overall survival (OS) benefit for patients with metastatic HER2-negative breast cancer and mutations in the BRCA1/2 genes. Most patients included in the study went on to receive subsequent systemic therapies, which may have affected the survival outcome analysis. The research confirmed previous results showing talazoparib improved patient reported quality-of-life measures over available chemotherapies and had a tolerable safety profile.

The secondary endpoint results from the EMBRACA trial were presented today at the American Association for Cancer Research (AACR) annual meeting by Jennifer Litton, M.D., professor of Breast Medical Oncology. The primary analysis results previously were published in the New England Journal of Medicine and found that patients treated with talazoparib had significantly prolonged progression-free survival (PFS) when compared with chemotherapy, with a median PFS of 8.6 months versus 5.6 months, respectively. This led to Food and Drug Administration approval for talazoparib in 2018.

EMBRACA is the largest trial of PARP monotherapy to date in patients with germline BRCA-mutated HER2-negative advanced breast cancer. The final OS analysis was performed using the intent-to-treat population after 324 deaths had been observed. After a median follow-up of 44.9 months for talazoparib and 36.8 months for chemotherapy, 216 patients in the talazoparib group and 108 patients in the chemotherapy group had died. The effect of treatment with talazoparib also was similar regardless of BRCA status.

“Overall survival is always an important endpoint, but also a challenge for metastatic breast cancer patients as there are many treatment options available,” said Litton. “Many of these patients also received subsequent therapies, including PARP inhibitors and platinum-based therapies, which could have potentially influenced these results.”

Mutations in the BRCA1/2 genes, which account for 5 to 10% of all breast cancers, cause defects in normal DNA damage repair. PARP inhibitors block an additional DNA repair pathway, and the anti-tumor effects of PARP inhibitors can be intensified in patients with BRCA mutations. Talazoparib works by not only inhibiting the PARP enzyme, but by trapping the enzyme on DNA to further prevent DNA repair.

The international Phase III clinical trial, EMBRACA, enrolled 431 patients with locally advanced or metastatic and hereditary BRCA1/2 gene mutations. Patients with HER2-positive disease were excluded as there are approved targeted therapies for those cancers. Patients were allowed up to three previous chemotherapies, including platinum-based therapies.

Participants were randomized 2:1 to receive either talazoparib (287) or physician’s choice of treatment (PCT) of single-agent therapy (144), either capecitabine, eribulin, gemcitabine or vinorelbine. Fifty-four percent of participants had HR+ disease and 46% had triple negative breast cancer; BRCA1 and BRCA2 mutations were split at 45 and 55%, respectively.

Almost half of patients in the talazoparib group received a subsequent PARP inhibitor or platinum therapy compared with almost 60% of patients in the chemotherapy group. When looking at PARP inhibitors specifically, approximately a third of patients in the chemotherapy group received a subsequent PARP inhibitor, which became increasingly available to patients either through trials or commercially during the course of this trial, compared with only 4.5% of patients who received talazoparib.

Subsequent platinum therapy was received by around 46% of patients in the talazoparib group compared with approximately 42% of patients in the chemotherapy group.

Interpretation of the OS results may have been confounded by subsequent treatments, so two sensitivity analyses accounting for subsequent PARP inhibitor and/or platinum therapy were carried out.

The analysis suggests that the OS analysis underestimated the treatment benefit of talazoparib.

Patient-reported quality-of-life measures revealed a prolonged time to deterioration of overall health, 26.3 months in the talazoparib arm compared to 6.7 months for the chemotherapy arm.

“Talazoparib remains an option for patients with advanced breast cancer and a germline BRCA mutation due to its improvements in progression free survival,” said Litton “Other advantages include it being an oral once-daily option, as well as the demonstrated improvements in quality of life for metastatic breast cancer patients.”

Grade 3-4 hematological adverse events (AEs) occurred in 56.6% of patients receiving talazoparib and 38.9% of those on chemotherapy. Most grade 3–4 AEs reported in the talazoparib group were hematologic and most were successfully managed by supportive care and dose modifications. The most common hematologic AE in patients receiving talazoparib was anemia, which was reported in 54.9% of patients receiving talazoparib compared with 19.0% of patients receiving chemotherapy.

Correlative studies currently are underway and analysis using the EMBRACA population to explore the effect of tumor BRCA zygosity and genomic loss-of-heterozygosity on efficacy outcomes also is being presented at AACR’s annual meeting by Lida Mina, M.D., associate director of Breast Programs at Banner MD Anderson Cancer Center.

The study was funded by Medivation, which was acquired by Pfizer in September 2016. Litton has research funding from Novartis, Pfizer, Genentech, GSK, EMD-Serono, AstraZeneca and Zenith Epigenetics, and she has served on advisory boards for AstraZeneca, Pfizer, and Ayala Pharmaceuticals, all uncompensated.

MD Anderson researchers have identified potential biomarkers for the response of high-grade serous ovarian cancers (HGSC) to surgical resection alone or to chemotherapy before surgery, providing new avenues to explore for improving ovarian cancer treatment.

Their ovarian cancer research findings, in collaboration with Inova Health System, were published today in Cell Reports.

HGSC accounts for nearly 90% of ovarian cancer deaths. Patients who undergo complete surgical resection (R0) have better outcomes, but it is unknown whether this survival benefit is due to the aggressive surgery or to the biology of resectable high-grade serous ovarian cancers.

“Our group was involved in the Cancer Genome Atlas (TCGA) efforts to discover molecular differences in ovarian cancers. However, these studies used only samples from patients undergoing surgical resection and did not account for the most aggressive tumors that need to be treated with chemotherapy first before surgery,” says Anil Sood, M.D., professor and vice chair for Translational Research in the departments of Gynecologic Oncology and Cancer Biology and senior author of the paper.

TCGA also did not conduct immune or cellular analyses and did not include samples from metastatic sites.

Search for biomarkers to guide ovarian cancer treatment

To understand the biology of these tumors in depth, Sood, first author Sanghoon Lee, Ph.D., assistant professor of Systems Biology, and colleagues, conducted extensive analyses, including high-pass whole-genome sequencing, targeted deep sequencing, RNA sequencing, reverse-phase protein array, mass spectrometry-based proteomics/phosphoproteomics, immune-profiling, and integrated data analyses. The team conducted this work through MD Anderson’s Ovarian Cancer Moon Shot.

“Most studies just perform RNA analysis or one or two types of analyses, but we wanted to carry out an all-out effort to find biomarkers that can be used for clinical decision-making,” Sood says.

This study used baseline primary and metastatic tumor samples from 30 patients triaged by a systematic algorithm to either surgical resection or neoadjuvant chemotherapy and surgery: 10 patients had no visible residual disease after primary surgery (R0), 10 underwent neoadjuvant therapy but had a poor response, and 10 underwent neoadjuvant therapy with an excellent response. The researchers found significant molecular and cellular differences between the R0 and neoadjuvant therapy groups.

Genetic differences may help determine high-grade serous ovarian cancer treatment

They found that tumor samples from the R0 group had significantly lower expression of the  NF1 gene, RNA, and protein than samples from the neoadjuvant therapy group. Previous studies have shown that NF1 helps in tumorigenesis and chemotherapy resistance in HGSC. Although the biological mechanisms are unknown, these findings suggest that NF1 may serve as a biomarker that could predict response to surgical resection versus neoadjuvant therapy for patients with high-grade serous ovarian cancer.

Compared to the neoadjuvant therapy samples, R0 samples also had fewer chromothripsis-like patterns, in which a chromosome shatters and is not reassembled correctly. R0 samples had fewer copy number switches, and the chromothripsis-like patterns were localized on chromosomes 6 and 19, whereas the chromothripsis-like patterns in the neoadjuvant tumors were enriched on chromosomes 8 and 17 (NF1 is located on chromosome 17).

The researchers did not find any significant genomic differences between primary tumors and metastatic tumors. This suggests that the genomic instability of HGSC, including copy number and structure variation, might occur at an early point in disease progression.

Immune response differences

R0 tumors and tumors with excellent response to neoadjuvant therapy had significantly higher levels of neoantigens than the tumors with poor response to neoadjuvant therapy, and the R0 tumors had significantly more strong-binding neoantigens. These high levels of neoantigens also were associated with a better immune profile, such as more infiltration of tumor immune cells and fewer macrophages. These tumor-associated neoantigens might be good immunotherapeutic targets that could spare healthy cells.

Chemotherapy response markers

Compared to tumors that had poor response to neoadjuvant therapy, those with excellent response had significantly lower expression levels of phosphosites of LCK and YES1, Src-family kinases. These phosphosites have been implicated in T cell development and migration signaling, and these differences could serve as biomarkers to predict chemotherapy response in HGSC.

Next steps for high-grade serous ovarian cancer research

Because this in-depth analysis of high-grade serous ovarian cancer used baseline tumor samples before treatment, the research team plans to study tumor samples from patients after treatment. They also will look at promising biomarkers identified in this study to see if these genetic differences could be used for clinical decision-making or as therapeutic targets.

“Patients with high-grade serous ovarian cancer that does not respond to neoadjuvant therapy have the worst outcomes; we’d like to identify molecular/cellular targets and design drugs that can improve these patients’ outcomes,” Sood says.  “Accurate biomarkers could help us tailor precise treatment strategies for all patients with HGSC.”

ABSTRACT: DDT01-03

In a first-time disclosure of IPN60090, a small-molecule inhibitor of the metabolic enzyme glutaminase (GLS1), researchers from The University of Texas MD Anderson Cancer Center’s Therapeutics Discovery division and Ipsen Biopharmaceuticals reported the preclinical discovery and early-stage clinical development of this novel drug. IPN60090, now under investigation in a Phase I trial, may hold benefit for certain patients with lung and ovarian cancers.

MD Anderson’s GLS1 program was initiated and advanced by a team of scientists in the Institute for Applied Cancer Science (IACS) and Translational Research to Advance Therapeutics and Innovation in Oncology (TRACTION) platforms, both engines within Therapeutics Discovery. Development of the program continues in collaboration with Ipsen, which licensed the therapeutic in 2018.

Findings and information about the ongoing trial will be presented today at the 2020 American Association for Cancer Research Virtual Annual Meeting I by Jeffrey Kovacs, Ph.D., institute group leader with TRACTION and co-leader of the GLS1 program.

“This effort is a great example of our strategy within Therapeutics Discovery, taking a comprehensive approach to personalized medicine,” said Kovacs. “Our preclinical data suggest that IPN60090 may be effective in underserved groups of patients who need better treatment options, and we look forward to results from our ongoing clinical trials.”

Dysregulation of cellular metabolism is a hallmark of cancer development, and the GLS1 enzyme plays a key role in many metabolic processes. Thus, it makes an attractive target for cancer therapy, explained Kovacs.

IACS drug-discovery scientists identified IPN60090 as a potent and selective inhibitor of GLS1 suitable for clinical trials, and translational researchers in TRACTION demonstrated its activity against subsets of lung and ovarian cancer preclinical models.

Further analysis revealed biomarkers of response, which have been leveraged to identify patients most likely to benefit. In lung cancers, mutations in the KEAP1 and NFE2L2 genes, which regulate response to oxidative stress, sensitize cells to treatment with IPN60090. Similarly, low expression of the metabolic protein asparagine synthetase (ASNS) in ovarian cancers predicts response to IPN60090 in preclinical models.

“Identifying these putative predictive biomarkers of response is critical for our ongoing clinical efforts to ensure that we’re able to offer patients the most relevant therapies,” said Timothy A. Yap, M.B.B.S., Ph.D., F.R.C.P., associate professor of Investigational Cancer Therapeutics and medical director of IACS. “These patient groups in particular, which represent distinct niches within those cancer types, are in need of more effective treatment options.”

For example, patients with lung cancers harboring KEAP1/NRF2 mutations have not benefited from treatment with immune checkpoint inhibitors and have poorer outcomes overall, explained Yap, who leads the IPN60090 clinical trial at MD Anderson.

IPN60090 currently is under investigation in a Phase I dose-escalation and dose-expansion study for patients with advanced solid tumors that harbor KEAP1/NFE2L2 mutations or have low ASNS levels. The team has developed novel CLIA-certified assays to identify patients likely to benefit and monitor how effectively the drug is acting. Initial data from the clinical trial indicate that IPN60090 is effectively inhibiting GLS1 activity in peripheral blood mononuclear cells from patients.

Future trial cohorts plan to investigate IPN60090 in combination with checkpoint inhibitors, chemotherapy and targeted therapies identified by the researchers as having potential synergistic benefits with GLS1 inhibition.

The ongoing research is supported by Ipsen through a global licensing and development agreement. The research is managed according to MD Anderson’s Institutional Conflict of Interest Management and Monitoring Plan. Kovacs is a co-inventor on material and method-of-use patent applications related to IPN60090. The Therapeutics Discovery division is supported in part by MD Anderson’s Moon Shots Program.

Although metastatic castration-resistant prostate cancer (mCRPC) typically has limited response to immunotherapy, a subset of patients with pretreatment evidence of active T-cell responses in their tumors experienced prolonged survival following treatment with ipilimumab in a Phase II trial at The University of Texas MD Anderson Cancer Center.

The results, published today in Science Translational Medicine, suggest that certain patients with mCRPC may benefit from immune checkpoint inhibitors and provide biomarkers for identifying this subgroup.

“Our results indicate that immune checkpoint blockade can instigate T-cell responses to tumor neoantigens despite a low tumor mutational burden in prostate cancer,” said lead author Sumit Subudhi, M.D., Ph.D., assistant professor of Genitourinary Medical Oncology. “We found specific markers among a subset of patients with the greatest benefit, such as T-cell density and interferon-γ signaling, that may help improve our ability to select patients for treatment with checkpoint blockade.”

Cancers with the strongest responses to immune checkpoint inhibitors, such as melanoma or lung cancer, tend to have high levels of underlying gene mutations, which leads to production of mutation proteins, or neoantigens, that can be recognized as abnormal by the immune system. Prostate cancers have relatively low mutation levels and fewer neoantigens present.

However, small groups of mCRPC patients within larger Phase III trials have seen favorable outcomes to checkpoint inhibitors, explained Subudhi, which drove the researchers to ask whether effective immune responses could be stimulated by checkpoint blockade in tumors with low mutation levels.

To investigate this question, the research team launched the Phase II trial in collaboration with MD Anderson’s immunotherapy platform, which is co-led by corresponding author Padmanee Sharma, M.D., Ph.D., professor of Genitourinary Medical Oncology and Immunology. The platform is part of the institution’s Moon Shots Program^®, a collaborative effort to accelerate the development of scientific discoveries into clinical advances that save patient’s lives.

The trial enrolled 30 MD Anderson patients with mCRPC between January 2015 and May 2018. Of those, 29 received at least one dose of ipilimumab and were able to be included in the final analysis. Median follow-up after the first treatment was 45.5 months.

Across all patients, median progression-free survival (PFS) according to radiographic imaging was 3 months, and median overall survival (OS) was 24.3 months. Eight patients (28%) experienced grade 3 toxicities, the most common of which were dermatitis and diarrhea, and none experienced grade 4 or 5 toxicities.

The researchers noted a “favorable” cohort of nine patients with PFS greater than six months and OS greater than one year, and an “unfavorable” cohort of ten patients with PFS less than six months and OS less than one year. At the time of analysis, six (67%) patients from the “favorable” cohort were alive, with survival ranging between 33 and 54 months.

By comparing pretreatment samples from these two cohorts, the researchers identified markers associated with improved responses to checkpoint blockade. Those in the “favorable” cohort had a higher density of cytotoxic and memory T cells in the tumor as well as increased expression of interferon (IFN)-γ signaling.

Further, the researchers showed that T cells isolated from patients in the “favorable” cohort were capable of recognizing and responding to the neoantigens present in their tumor, whereas T cells from patients in the “unfavorable” group did not appear to have the same responses.

“We were encouraged to see that prostate cancers with a low mutational burden do in fact express neoantigens that elicit T-cell responses that lead to favorable clinical outcomes,” said Sharma. “Our findings indicate that anti-CTLA-4 immune checkpoint therapy warrants additional studies in order to develop treatment strategies that may improve survival of patients with metastatic prostate cancer.”

Moving forward, the authors plan to investigate this question in larger, multi-institutional studies to validate the findings of the current trial.

The research was supported in part by the immunotherapy platform and the Prostate Cancer Moon Shot^®, both part of MD Anderson’s Moon Shots Program. The research also was supported by: Bristol Myers Squibb, the Stand Up To Cancer-Cancer Research Institute Immunology Dream Team Translational Research Grant, the Prostate Cancer Foundation Young Investigator Award, and the National Cancer Institute (CA1633793, P30CA016672). Padmanee Sharma and James Allison are members of the Parker Institute for Cancer Immunotherapy at MD Anderson.

In addition to Subudhi and Sharma, MD Anderson researchers collaborating on the study include: Luis Vence, Ph.D., Hao Zhao, Ph.D., Jorge Blando, Ph.D., Shalini Yadav, Ph.D., and Qing Xiong, all of the immunotherapy platform; Alexandre Reuben, Ph.D., of Thoracic/Head & Neck Medical Oncology; Ana Aparicio, M.D., Paul Corn, M.D., Ph.D., and Christopher Logothetis, M.D., all of Genitourinary Medical Oncology; Brian Chapin, M.D., and Louis Pisters, M.D., both of Urology; Patricia Troncoso, M.D., of Pathology; Rebecca Tidwell, and Peter Thall, Ph.D., both of Biostatistics;

 Chang-Jiun Wu, Ph.D., Jianhua Zhang, Ph.D., and Andrew Futreal, Ph.D., all of Genomic Medicine; and Jim Allison, Ph.D., of Immnology and the immunotherapy platform. A full list of the authors’ disclosures can be found with the full paper here.