PARP x PARP1 x PARP2

Pictured: Gloved hands amid a collage of cancer treatments/Taylor Tieden for BioSpace Parsing key trends from 7,200 abstracts on cancer-related research can be challenging—take it from someone who’s spent the past week trying to do it! But pretty quickly, a few key themes became apparent at the American Association for Cancer Research’s annual meeting. First and foremost, the programs presented are tackling difficult cancers with a high unmet need and a dire prognosis. Some of the presentations last weekend involved drug candidates targeting pancreatic cancer, for example. In 2023, the five-year survival rate for pancreatic cancer was just 12%, according to the American Cancer Society. Two presentations—one on Bristol Myers Squibb’s blockbuster immunotherapy Opdivo, the other on a messenger RNA vaccine in development by BioNTech and Genentech—showed promising signals. Opdivo’s trial, the first reported of a PD1 inhibitor in neoadjuvant pancreatic cancer, indicated that the drug may improve outcomes, while BioNTech and Genentech’s vaccine continued to show potential in a particularly difficult-to-treat form of the disease. This announcement also dovetailed with another prominent theme at AACR: the resurgence of cancer vaccines, which are also making inroads in advanced liver cancer, head and neck cancer, non-small cell lung cancer and glioblastoma. Glioblastoma is a particularly aggressive form of brain cancer that carries a 5-year survival rate of just 10%; patients typically survive between 15 and 18 months after being diagnosed. A Phase I study of Diakonos Oncology’s dendritic cell vaccine showed “substantially increased survival” in glioblastoma patients; 88% of patients remained alive a year after treatment, compared to a historical 53% of those on standard regimens. Other platforms and approaches also appear to be breaking through against difficult-to-treat cancers, though many of the results presented at AACR are still early stage. As anticipated, antibody-drug conjugates (ADCs) were a focus, with Vincerx Pharma presenting Phase I data in metastatic tumors and Merck and Kelun-Biotech reporting a potential survival benefit from their TROP2-directed ADC in gastric cancer. Several other modalities were also on display at AACR. Phase I data from Menlo Park, Calif.–based Synthekine, for example, showed that its α/β biased interleukin-2 (IL-2) partial agonist, STK-012, has thus far avoided the toxicities associated with IL-2 therapies while also demonstrating a “favorable” efficacy pro advanced solid tumors. And TILT Biotherapeutics reported that TILT-123, an oncolytic adenovirus armed with tumor necrosis factor alpha and IL-2, “demonstrated signs of efficacy” when combined with Merck’s Keytruda in a Phase I trial in patients with platinum-resistant and refractory ovarian cancer. Another therapy that drew attention at the meeting was AstraZeneca’s next-generation poly-ADP ribose polymerase 1 (PARP1) selective inhibitor, which experts are hopeful can negate some of the toxicities caused by drugs that inhibit both PARP1 and PARP2. Timothy Yap, vice president and head of clinical development in the Therapeutics Discovery Division at The University of Texas MD Anderson Cancer Center, noted in his presentation of the positive Phase I/II trial data that there is a “great opportunity” to combine a selective PARP1 inhibitor with other therapies. This was a point also made by David Weinstock, vice president of discovery oncology at Merck, who in March told BioSpace that we are moving toward a future “where we have enough medications that each work individually and have minimal side effects so that we can create even larger combinations, which offer the most benefit to people.” As a science journalist, it’s easy to get bogged down in the data, the results and biggest trends (ADCs for all!) and forget the human face of cancer. As a human being, it’s easy to get depressed by improvements that might seem incremental, but an additional six months can mean another birthday, another anniversary or the birth of another grandchild. Elevation Oncology CSO David Dornan told me that solid cancers “are almost equally as hard and different in their own right.” But progress is being made. In 2023, the five-year survival rate for pancreatic cancer increased by one percentage point from the previous year, marking the second year in a row survival has increased. Overall, the cancer death rate in the U.S. has declined by 33% since 1991. I, for one, am looking forward to reading about the next advances at the American Society of Clinical Oncology’s annual meeting in June. Heather McKenzie is a senior editor at BioSpace. You can reach her at heather.mckenzie@biospace.com. Also follow her on LinkedIn.

Approved PARP inhibitors include AstraZeneca and Merck & Co.’s Lynparza, pharmaand’s Rubraca and GSK’s Zejula. The University of Texas MD Anderson Cancer Center’s Timothy Yap, M.D., doesn’t know why AstraZeneca’s PARP inhibitor saruparib seems to be spurring responses in patients who have previously not had much luck with the drug class. “It is something that I've been scratching my head on ever since we presented the case, two years ago at this meeting. One could argue that we have a better drug here, that we're achieving much higher drug exposures in patients,” Yap said during a press conference at the American Association for Cancer Research annual meeting on Monday morning. He serves as a professor of investigational cancer therapeutics and vice president and head of clinical development in the cancer center's therapeutics discovery division. Approved PARP inhibitors include AstraZeneca and Merck & Co.’s Lynparza, pharmaand’s Rubraca and GSK’s Zejula. The first-in-human results for saruparib, presented by Yap from the phase 1/2a PETRA module trial, showed an objective response rate of 48.8% in the 31 evaluable patients at the target dose. Median progression-free survival was 9.1 months. Click here for more AACR 2024 coverage from the Fierce Biotech team.  The main goal of the study was safety and tolerability, with secondary goals providing an early look at efficacy. Patients in the part A dose escalation group had advanced, metastatic breast cancer and had previously tried at least three prior lines of therapy. Forty-five percent had prior treatment with a PARPi and/or chemotherapy. The part B dose expansion featured patients with HER2-negative disease who had not previously received a PARP inhibitor. Most had BRCA mutations, and there was no limit on the number of prior chemotherapy treatments. Yap explained that saruparib is highly selective for PARP1. The oral therapy has “superior” pharmacokinetic and pharmacodynamic properties and efficacy when compared with approved PARP inhibitors, according to the presentation. “The approved PARP inhibitors we know benefit patients. But these are all PARP1 and PARP2 inhibitors and in the patients that we've already been treating … we know that there are associated toxicities,” Yap said, noting gastrointestinal toxicities and fatigue as the main issues. “We also know that PARP1 inhibition alone is all you need to really shrink cancers and to benefit patients and lead to efficacy. And that really provides a whole rationale to really dial out the PARP2.” That’s why saruparib was developed. “What we have seen on trial, to summarize, is we really get bang for your buck," Yap said. Patients may also be able to stay on treatment longer at an optimal dose, meaning improved efficacy. The PETRA trial also showed durable responses with the 60-mg dose in a heavily pretreated population of patients. That’s the dose that will be taken forward, in line with the FDA’s Project Optimus, which asks drug developers to test a wider range of doses early on to determine the safest and most efficacious dose. Overall, the study had 141 patients who were evaluable for a safety analysis on the 60-mg dose. The safety data were consistent with the earlier 2022 data release, when fewer patients were in the trial with less follow-up time, according to Yap. In this group, 14.2% of patients had to reduce dosage, and 3.5% stopped altogether due to adverse events like anemia, neutropenia, thrombocytopenia, fatigue and asthenia. The trial did, however, show that the 140-mg dose was not tolerable. Four out of six patients in that cohort had dose interruptions or reductions. But up to 60 mg was tolerated, so this was chosen as the preferred go-forward dose.  Yap said the safety profile in the heavily pretreated population was in line with the approved PARP inhibitors. A phase 3 test is ongoing with the 60-mg dose in a test called EvoPAR-Prostate01. The therapy will be tested in combination strategies.

SAN DIEGO — AstraZeneca’s experimental PARP1 inhibitor helped shrink tumors in nearly half of people with breast cancers harboring certain DNA repair defects in an early-stage study. The drug, saruparib, is the most advanced candidate in a new class of compounds that takes aim at the DNA repair enzyme. While there are several PARP inhibitors already on the market, including AstraZeneca and Merck’s Lynparza and Pfizer’s Talzenna, they target two similar enzymes, PARP1 and PARP2, and cause side effects like nausea, anemia and low white blood cell counts. You’ll get access to free articles each month, plus you can customize what newsletters get delivered to your inbox each week, including breaking news.