AACR 2015: New PARP Inhibitor Combination Shows Early Promise for a Wide Range of Cancer Patients

“A combination of two molecularly targeted drugs, olaparib (Lynparza) and the investigational agent AZD5363, was safe and yielded responses in patients with a variety of cancer types, including breast, ovarian, and prostate cancers, regardless of BRCA1/2-mutation status, according to data from the ComPAKT phase I clinical trial presented at the AACR Annual Meeting 2015, held April 18 to 22 in Philadelphia (Abstract CT323).

“ ‘In this clinical trial, we evaluated for the first time whether it is possible to safely combine the investigational AKT inhibitor AZD5363 with olaparib, a PARP [poly ADP-ribose polymerase] inhibitor recently approved by the U.S. Food and Drug Administration for treating advanced ovarian cancer associated with defective BRCA genes,’ said Timothy Yap, MD, PhD, National Institute for Health Research Biomedical Research Centre Clinician-Scientist and Consultant Medical Oncologist at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust.

“ ‘Here, we are reporting results from the dose-escalation portion of the trial, which showed that it was indeed possible to combine these drugs safely,’ continued Dr. Yap. ‘We also observed that several different cancer types responded to the combination, including cancers without BRCA1/2 mutations. These early results are very exciting because preclinical data had suggested that the olaparib and AZD5363 combination had the potential to be effective in a much wider population of patients than just those harboring germline BRCA1/2 mutations.’ “


Targeted Therapy Combo Shows Benefit in Breast and Ovarian Cancer

“Combination treatment with the poly(ADP-ribose) polymerase (PARP) inhibitor olaparib plus the phosphatidylinositol 3-kinase (PI3K) inhibitor BKM120 resulted in clinical activity in women with triple-negative breast cancer and those with high-grade serous ovarian cancer.

“Patients that had BRCA-mutant and BRCA wild-type tumors responded to the treatment.

“The results of this phase I trial were presented at a press briefing at the American Association for Cancer Research (AACR) Annual Meeting, held April 18 to 22 in Philadelphia.”


Combination of a Dual mTOR Inhibitor and Fulvestrant Tested in ER+ Metastatic Breast Cancer

“The dual mTOR inhibitor AZD2014, when combined with the hormonal therapy fulvestrant (Faslodex), was found to be safe in patients with advanced estrogen receptor–positive breast cancer, and some of them experienced clinical benefit from the drug combination, according to phase I clinical trial data presented at the AACR Annual Meeting 2015, April 18 to 22 in Philadelphia (Abstract CT233).

“ ‘Patients with estrogen receptor–positive breast cancer respond to hormonal therapy, but over time, some eventually develop resistance to treatment. Their tumors become dependent on a cell-signaling pathway called the mTOR pathway for survival,’ said Manish R. Patel, MD, Associate Director of Drug Development for Sarah Cannon Research Institute and Director of Drug Development at the Florida Cancer Specialists and Research Institute.

“ ‘We are testing whether combining the hormonal therapy fulvestrant with the dual mTOR inhibitor AZD2014 can help overcome this resistance. AZD2014 is a new anticancer therapy and represents a potential improvement compared with other drugs that have similar mechanisms of action,’ Dr. Patel added.

“ ‘In this trial, we tested two dosing schedules of AZD2014: continuous dosing, in which the drug is given every day, and intermittent dosing, in which the drug is given only 2 days of each week,’ Dr. Patel explained. ‘We compared the side-effect profiles of the two dosing schedules. The response of individual patients to treatment was also monitored.’ “


Adding a Dual mTOR Inhibitor to Chemotherapy May Benefit Some Ovarian and Lung Cancer Patients

“Combining the investigational mTOR inhibitor AZD2014 with the chemotherapy paclitaxel showed better outcome than when the drugs were tested individually in preclinical studies of cancer models, and a phase I clinical trial of this combination in patients with advanced ovarian cancer and non-small cell lung cancer (NSCLC) showed clinical benefit in some, according to data presented here at the AACR Annual Meeting 2015, April 18-22.

“ ‘Many patients with ovarian cancer accumulate a lot of fluid in their abdomen, which is drained prior to chemotherapy. In an earlier study, we isolated cancer cells from the drained fluid from some patients and found that those whose cancer cells had elevated levels of a protein called pS6K developed resistance to chemotherapy,’ said Udai Banerji, MD, PhD, a reader in Molecular Cancer Pharmacology at The Institute of Cancer Research in London and The Royal Marsden NHS Foundation Trust, also in London, United Kingdom.

“ ‘AZD2014 is a dual mTOR inhibitor that can reverse the effects of pS6K. We first conducted preclinical studies to test whether combining AZD2014 with paclitaxel might help overcome resistance to treatment, and then initiated a phase I clinical trial to test this combination in patients with heavily pretreated ovarian cancer and NSCLC,’ Banerji explained.”


New Antibody-Drug Conjugate Shows Early Promise for Patients with Metastatic HER2-Positive Breast Cancer

“An investigational antibody-drug conjugate called MM-302 was safe, tolerable, and showed signs of clinical activity in heavily pretreated patients with metastatic, HER2-positive breast cancer, according to data from a phase I clinical trial presented here at the AACR Annual Meeting 2015, April 18-22.

“MM-302 is an antibody-drug conjugate composed of a HER2-targeted antibody linked to the cytotoxic chemotherapy liposomal doxorubicin. The HER2 antibody delivers the liposomal doxorubicin to HER2-positive breast cancer cells.

” ‘The main purpose of our study was to establish whether MM-302, alone or in combination with trastuzumab, was safe and tolerable for patients with metastatic, HER2-positive breast cancer whose disease had progressed following numerous prior treatments,’ said Patricia LoRusso, DO, associate director of innovative medicine and professor of medicine (medical oncology) at Yale Cancer Center in New Haven, Connecticut, and professor of medicine in the Division of Oncology at Yale University. ‘We found that the drug was well tolerated when administered to these women.’ “


A New Drug for ER+ Breast Cancer Shows Promise in Early Trial

“The new investigational estrogen receptor (ER) degrader GDC-0810 was safe and tolerable in postmenopausal women with advanced ER-positive breast cancer, and a subset of the women, all of whom were previously treated with standard endocrine therapy, gained clinical benefit from the drug, according to data from a first-in-human phase I/IIa clinical trial presented here at the AACR Annual Meeting 2015, April 18-22.

” ‘Most breast cancers diagnosed in the United States are ER-positive, and their growth is fueled by the hormone estrogen,’ said Maura N. Dickler, MD, associate member of the Breast Medicine Service at Memorial Sloan Kettering Cancer Center and Weill Medical College of Cornell University in New York. ‘Resistance to currently available therapies targeting estrogen and the estrogen receptor causes morbidity and mortality for women with metastatic ER-positive breast cancer and new therapies that have activity against tumors resistant to currently available treatments are urgently needed.

” ‘The phase I dose-escalation portion of the study enrolled heavily pretreated patients, and the observed antitumor activity is promising for GDC-0810, which is demonstrating clinical benefit in these patients who have developed resistance to other endocrine therapies for ER-positive breast cancer patients,’ continued Dickler. ‘The phase IIa dose-expansion portion of the study is ongoing. It is evaluating GDC-0810 efficacy in more defined patient subpopulations and will provide more information about how effective this estrogen receptor degrader is.’ “


Trial Shows Benefit of 'BRCA-Targeting' Drug in Prostate Cancer

“Men with prostate cancer benefit from treatment with the pioneering drug olaparib – the first cancer drug to target inherited mutations – according to the results of a major trial presented today (Tuesday).

“Olaparib was licensed in December for women with ovarian cancer and inherited BRCA mutations, but the new research suggests it could also benefit men with genomic faults within their tumours.

“Researchers told the American Association of Cancer Research (AACR) conference in Philadelphia that up to 30 per cent of men with advanced prostate cancer had tumours with defects in repairing DNA – and these responded particularly well to olaparib.

“The men most likely to benefit could be identified by genetic testing to look for mutations in genes responsible for DNA repair – including the BRCA genes and the gene ATM.”


Investigational Personalized Cellular Therapy Tolerated Well by Patients with Advanced Mesothelioma, Ovarian and Pancreatic Cancers

“Genetically modified versions of patients’ own immune cells successfully traveled to tumors they were designed to attack in an early-stage trial for mesothelioma and pancreatic and ovarian cancers at the Perelman School of Medicine at the University of Pennsylvania. The data adds to a growing body of research showing the promise of CAR T cell technology. The interim results will be presented at the American Association for Cancer Research (AACR) Annual Meeting 2015, April 18-22.

” ‘The goal of this phase I trial was to study the safety and feasibility of CART-meso cells in patients with mesothelin-expressing tumors,’ says Janos L. Tanyi, MD, PhD, an assistant professor of Gynecologic Oncology. ‘We found no major adverse events associated with the treatment, which suggests that the patients tolerated it very well. But importantly, the T cells successfully targeted the patients’ tumor sites and survived in the blood stream for up to 28 days.’

“Tanyi will present data on five patients (two with ovarian cancer, two with epithelial mesothelioma, and one with pancreatic cancer) who received the new investigational therapy. All patients who received the therapy had cancers which had stopped responding to conventional treatments.”


Combining Chk1 Inhibition with Standard Dose Gemcitabine May Be Safe and Effective

“Adding the investigational agent GDC-0425, which blocks the function of a protein called checkpoint kinase 1 (Chk1), to standard doses of the chemotherapy drug gemcitabine, was safe and yielded responses in patients with a variety of cancer types, including triple-negative breast cancer, melanoma, and cancer of unknown primary, according to data from a phase I clinical trial presented at the AACR Annual Meeting 2015, held April 18-22.

” ‘Gemcitabine is a chemotherapy agent that works by damaging the DNA of cancer cells while they are dividing to form more cancer cells,’ said Jeffrey R. Infante, MD, director of the drug development program at Sarah Cannon Research Institute in Nashville, Tennessee. ‘Sometimes cancer cells pause during the process of cell division and the cell has time to repair the DNA damage caused by gemcitabine, making the drug less effective. Chk1 is a protein kinase that can trigger this pause, and the idea underpinning our trial was that blocking Chk1 with GDC-0425 might prevent cancer cells from having time to repair gemcitabine-damaged DNA.

” ‘We were excited to find that we could safely combine GDC-0425 with the standard 1000 milligram per m2 dose of gemcitabine because we had been concerned that this combination might not be tolerable,’ continued Infante. ‘We are also encouraged to see responses in patients with a variety of cancer types. The results have given us a good platform for moving forward with Chk1 inhibitor/gemcitabine combination therapy for further study.’ “