At the recent American Association of Cancer Research (AACR) meeting, one of the most encouraging sets of presentations pertained to PARP inhibitors. What’s emerging is that this new class of drugs, once considered of limited benefit and primarily for cancer patients with BRCA mutations, offers a wide range of anti-tumor activity.
In December 2014, the FDA approved the first medication of this type, olaparib (brand name: Lynparza,
Based on new data from several early-phase trials reported at the 2015 annual AACR meeting in Philadelphia, it appears that Lynparza alone can shrink or stabilize various cancers, particularly but not exclusively in patients with inherited BRCA variants. When combined with other treatment – either old-fashioned chemo or novel targeted therapy – the effects (and potential toxicity) of PARP inhibition may be extended to other tumor types, and be more powerful.
Perhaps most intriguingly, several of the new reports reveal that Lynparza has activity in some cancer patients who lack inherited BRCA variants, but whose malignant cells have acquired mutations in BRCA-1, BRCA-2 or other genes encoding DNA repair proteins. Taken together, these findings support that some – and possibly many – human cancers harbor actionable BRCA mutations (among other defects) that would not be picked up on routine genetic testing of non-malignant cells.
The FDA’s approval of olaparib was crucial, says Dr. Ursula Matulonis. She’s a medical oncologist who directs the Gynecologic Oncology program at the Susan F. Smith Center for Women’s Cancers at the
"There has been significant activity with these drugs as single agents which has mainly in BRCA-deficient patients. However there are some patients who don’t harbor BRCA mutation, in whom these drugs can be active as well,” she observed.
A few years ago, Matulonis’s clinical research program gained support through a Stand Up To Cancer (SU2C) “dream team.” The team focuses on PI3-kinase (PI3K), an enzyme that’s over-active in some malignancies and can specifically be targeted with investigational drugs. The SU2C group shared results of pre-clinical studies suggesting a synergistic effect, and decided to try combining PI3K inhibitors with PARP inhibitors in patients with refractory, high-grade tumors.
At the AACR meeting, Matulonis presented findings from a Phase I trial designed to evaluate the tolerability and toxicity of drugs in women with advanced triple negative breast cancer or high-grade, refractory ovarian cancer. The study first examined how patients fared upon receiving olaparib and either of two PI3K inhibitors, BKM120 (Buparlisib,
The results presented pertained to 70 women (24 with breast cancer; mean age 47.5 years; the post-escalation cohort included some with other subtypes, such as progressive, estrogen receptor-positive disease) and 46 women with ovarian cancer (mean age 60 years) assigned to receive olaparib with BKM120 in the initial dose-escalation phase or later in the trial, once the maximum tolerated doses had been established.
“Overall, about half of the patients had stable disease in both groups,” Matulonis said, referring to women with refractory breast and ovarian tumors. “Somehow by combining the drugs, we’re making the cancer cell more prone to PARP inhibition,” she stated.
Matulonis emphasized that BKM120 can enter a patient’s central nervous system by crossing the blood-brain barrier. For this reason, this PI3K inhibitor carries a risk of psychological and neurological effects. One patient on the study had depression requiring hospitalization, she said. From olaparib, the observed toxicity was mostly blood-related. In this study, 25 percent of the patients who received both olaparib and BKM120 developed anemia, which was generally mild; lowering of the white blood cells and platelets was noted in 10 to 13 percent. Some of the patients experienced low-grade nausea and vomiting. The gastrointestinal effects were usually transient, Matulonis said. Other toxicity observed in the study participants included hyperglycemia (high blood sugar) and abnormalities in liver function. (Abstract #8972)
Dr. Matulonis reports that she’s received direct support from AstraZeneca,
In a phase I trial from the Women’s Malignancies Branch of the NCI, 59 women with progressive cancers (ovarian, triple-negative breast, uterine and endometrial) tried various dose-finding, toxicity-testing combinations of oral olaparib capsules and intravenous carboplatin. Only about half of the participants had inherited (germline) BRCA mutations. The most common problems reported were low blood counts. One preliminary result, noted by Dr. Victoria Chiou, is that among the women with ovarian cancer and inherited BRCA changes the overall responsiveness to olaparib approximately doubled when it was given with carboplatin, from 30 percent to 60 percent. (Abstract #1458)
One study that generated a lot of attention at the meeting is the phase II TOPARP trial of men with prostate cancer, presented by Dr. Joaquin Mateo of London’s Institute of Cancer Research. For this analysis, investigators used next-generation sequencing (NGS) to test for mutations, either germline (inherited) or somatic (acquired, in the tumor cells) among 50 men with advanced prostate tumors. Overall, nearly 33 percent of the men with otherwise progressive, castration-resistant cancer responded to olaparib.
As detailed by Dr. Mateo in his presentation, seven of the 50 men in this prostate cancer study had BRCA-2 mutations, and at least five of those seven with BRCA-2 abnormalities had demonstrable responses to the PARP inhibitor. But only three of the seven had inherited BRCA-2 changes. Rather, four of the seven men who responded to olaparib had acquired (somatic) BRCA-2 mutations detected by sequencing DNA of the tumor cells. Dr. Mateo also showed evidence for acquired mutations in the gene encoding ATM in at least four men in this trial who responded to olaparib. (Like PARP and the BRCA proteins, ATM is involved in DNA repair.) Other mutations noted, in a few cases among the 50 men enrolled, include changes in the FANCA, BRCA-1 and PALB-2 genes.
Dr. Mateo briefly discussed the concept of synthetic lethality, and how PARP inhibitors are thought to work. Mateo is a fellow of the Medical Research Council and the Movember Foundation. This research project is supported by Cancer Research UK, the Prostate Cancer Foundation, SU2C and AstraZeneca. As indicated by the AACR announcement about this work, the UK-based group collaborates with the SU2C prostate cancer dream team in the TOPARP study. (Abstract #8311)
In another plenary paper on olaparib, on combining it with an experimental AKT inhibitor in the dose-escalation phase of the ComPAKT trial, UK-based investigators observed significant responses in patients with and without BRCA mutations. Among the 20 patients evaluated, only 9 had inherited BRCA mutations. The malignancies included advanced ovarian, prostate, colorectal, cervical, pancreatic, uterine, bladder, mesothelioma and a GI stromal tumor. They received olaparib at a fixed dose, along with an investigational AKT inhibitor (AZD5363, AstraZeneca). Dr. Timothy Yap presented the work, which was supported by AstraZeneca and the Royal Marsden NHS Foundation Trust. A significant proportion of the patients on this trial experienced nausea and vomiting, feeling tired, diarrhea and anemia. Rash was a dose-limiting toxicity in some cases. The upshot is that the researchers found a well-tolerated and safe combination of the two drugs with significant clinical activity, Yap indicated. (Abstract #8529)
Dr. Mark Robson is a medical oncologist and clinical director of the Clinical Genetics Service at Memorial Sloan Kettering Cancer Center who was not directly involved with the studies outlined above, but has participated in other early and current studies of PARP inhibitors. He receives research support from AstraZeneca (for which he heads a relevant trial), BioMarin and
“In all of these trials of PARP inhibitors, the side effects need be monitored closely,” Robson said by phone. Because these kinds of drugs interfere with DNA repair, the possibility of causing serious bone marrow disorders like myelodysplasia (MDS) or leukemia must be taken seriously, he considered. “But so far the data on toxicity don’t extend beyond what you’d expect to see in a heavily-pretreated group of cancer patients,” he said. “It appears to be more of a theoretical concern.”
“These drugs were on life support” Robson said, reflecting on the time it took to get the first PARP inhibitor approved, and so many trials going. “It’s great that there’s so much interest now,” he said. “These drugs will definitely be useful for people who have cancer and known BRCA mutations, and also for some people with other genetic changes in the tumors.”
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