Biomarkers may predict olaparib efficacy in advanced prostate cancer

prostate cancer

Genomic defects in DNA repair genes may predict response to olaparib in patients with metastatic castration-resistant prostate cancer (mCRPC), a study presented at the American Association for Cancer Research (AACR) 2015 Annual Meeting has shown.

Among 49 patients with mCRPC who received olaparib in the phase II TOPARP-A study, 16 responded, giving an overall response rate of 32.7 percent. [AACR 2015, abstract CT322]

“Patients with homozygous deletions and/or putatively deleterious mutations in DNA repair genes were more likely to respond to olaparib,” reported Dr. Joaquin Mateo of the Institute for Cancer Research and Royal Marsden NHS Foundation Trust, London, UK. “The majority of these genomic defects occurred in BRCA2 and ATM, but biallelic loss of other relevant genes, including members of the Fanconi Anaemia complementation group and CHEK2, were also found.”

Of 15 patients with these genomic defects, 13 (86.7 percent) responded to olaparib, including all seven patients with BRCA2 loss and four of five patients with ATM truncating mutations.

“The specificity of the biomarker suite was 94 percent,” said Mateo. “Our findings offer a possibility for the very first molecular treatment stratification of advanced prostate cancer.”

“Olaparib showed durable anti-tumour activity in our heavily-pretreated population of mCRPC patients,” he added. “All study patients had received prior docetaxel therapy, 96 percent had received prior abiraterone, and 58 percent had received prior cabazitaxel. Of the 16 patients who responded to olaparib, 11 and four had been on olaparib therapy for >6 and >12 months, respectively.”

New two-drug combination shows activity in ovarian cancer.

A novel pairing of two cancer drug types showed promising activity and had manageable toxicities, according to a first-of-its-kind clinical trial led by scientists at Dana-Farber Cancer Institute

The combination of a PARP inhibitor and an anti-angiogenesis drug, tested for the first time in advanced ovarian and triple-negative breast cancers, achieved a 61 percent clinical benefit rate in the ovarian cancer patients, said the researchers, led by Joyce Liu, MD, MPH, and Ursula Matulonis, MD, of Dana-Farber. The drug combination was less active in the small number of advanced breast cancer patients.

The report was posted online by the European Journal of Cancer.

“This study shows that the combination of a PARP inhibitor and an angiogenesis inhibitor is feasible with toxicities, and had definite clinical activity in ovarian cancer patients,” said Liu, a gynecological oncologist with the Susan F. Smith Center for Women’s Cancers at Dana-Farber/Brigham and Women’s Cancer Center.

Clinical benefit rate” refers to the percentage of patients with advanced cancer that have experienced a complete response (cancer no longer visible on imaging), a partial response (the burden of cancer has decreased by at least 30 percent), or whose disease has remained stable for at least six months.

One of the ovarian cancer patients had a complete response and seven had partial responses – a 44 percent response rate – and three additional patients had stable disease for at least 24 weeks. The drugs didn’t achieve clinical responses in the breast cancer patients, though two patients had stable disease for 24 weeks or more.

“The trial began in April 2010, and some patients have done very well, with a few still on treatment after over two years on trial,” Liu said. The study was designed to evaluate the toxicity profile of various doses of the drug, and to look for signs of clinical activity, but overall survival wasn’t measured.

The patients experienced significant toxicities, including fatigue, high blood pressure, and diarrhea; Liu said these symptoms were controlled with medications and reducing doses when necessary. “The side effects were very representative of what you’d expect to see with either of the drugs alone,” she added.

The Phase 1 trial included 20 patients with ovarian cancer and eight with triple-negative breast cancer, meaning the tumors lack receptors for estrogen, progesterone, and HER2/neu. Patients took the two drugs daily in pill form: Olaparib, a PARP inhibitor, and cediranib, an angiogenesis inhibitor. PARP inhibitors block the activity of a repair protein in cancer cells, causing them to self-destruct. Cediranib blocks a protein, VEGF, that enables tumors to grow new blood vessels to feed their rapid growth. Angiogenesis inhibitors are designed to prevent new vessels from developing.

PARP inhibitors also have some anti-angiogenic effects, suggesting that the two types of drugs might have synergistic effects in cancer. The current trial was the first designed to test this idea specifically in breast and ovarian cancers. The next stage of this two-part trial is a Phase 2 study that will examine whether the two-drug combination is better than olaparib alone in recurrent ovarian cancer.

“We do need to ask if this combination is superior to a PARP inhibitor alone, and we are hoping to determine this in our ongoing Phase 2 trial,” said Liu.