PARP inhibitors take big step toward changing practice

With four FDA-approved agents and several potentially practicing-changing studies presented at medical conferences this year, the role of poly(ADP-ribose) polymerase, or PARP, inhibitors is becoming more clearly defined.

Trial results presented at ASCO Annual Meeting in June showed a PFS benefit with a PARP inhibitor for certain patients with notoriously hard-to-treat pancreatic cancer.

Also, results of three randomized phase 3 studies presented at European Society for Medical Oncology Congress last month showed the efficacy of certain PARP inhibitors for ovarian, fallopian tube and primary peritoneal cancers. Two studies, simultaneously published in The New England Journal of Medicine, will likely change the standard of care for first-line ovarian cancer treatment.

Source: Juliana Thomas for Memorial Sloan Kettering Cancer Center.

“To have two studies simultaneously published in The New England Journal of Medicine for the treatment of ovarian cancer is impressive,” Roisin E. O’Cearbhaill, MD, research director of gynecologic medical oncology at Memorial Sloan Kettering Cancer Center, told HemOnc Today. “It will definitely be practice changing if these agents get FDA approval in the upfront setting, as this would increase opportunities for more of our patients to receive a PARP inhibitor as part of the initial therapy.

“Incorporation of PARP inhibitors in the initial management may represent the biggest step forward in the treatment of advanced ovarian cancer that we have seen in quite some time,” she added.

Despite this step, research into the potential uses of these drugs has merely scratched the surface, researchers say, and it is still unknown whether these treatments will extend survival.

Some patients also are beginning to develop resistance to the drugs, which could counteract PFS gains.

HemOnc Today spoke with medical oncologists and researchers about the recent advances and groundbreaking studies on the use of PARP inhibitors, the continued limitations of these agents, and long-term outcomes that may be achievable with these drugs.

Combating BRCA mutations

The link between BRCA1 and BRCA2 mutations and risk for breast, ovarian, fallopian tube and pancreatic cancer has been widely established.

The mutations lead to the inability to repair DNA double-strand breaks.

Tumors that occur in this environment depend on the PARP enzyme to repair DNA. PARP inhibitors work by blocking the enzymatic activity of PARP and trapping PARP at the sites of DNA damage. Thus, inhibition of PARP in cancers with a BRCA1 or BRCA2 mutation results in the accumulation of DNA damage that cannot be repaired, leading to tumor cell death.

“[PARP inhibitors] are lethal for cancer cells that have inactive BRCA1 or BRCA2 genes, whereas the regular cells have at least one functioning copy of the affected BRCA gene,” O’Cearbhaill said. “These drugs block certain pathways that allow cells to repair mistakes that can occur in genes during cell replication, and so are extra harsh on the cancer cells because those cells already have a defect in the DNA repair pathway that involves the BRCA gene. Ideally, this leads to cell death, a concept known as synthetic lethality.”

Three PARP inhibitors are approved for ovarian, fallopian tube or primary peritoneal cancer. Olaparib (Lynparza, AstraZeneca) was the first to be approved as a fourth or greater line of treatment for women with a deleterious germline BRCA1 or BRCA2 mutation. Rucaparib (Rubraca, Clovis Oncology) is indicated for tumors with germline and somatic BRCA1/BRCA2 mutations in the third or greater line of treatment. Niraparib (Zejula; GlaxoSmithKline, Tesaro) received approval for women, regardless of BRCA status, with recurrent ovarian cancer that had responded to further platinum-based therapy; olaparib and rucaparib subsequently received similar approvals in that setting.

Last month, the FDA expanded the approval of niraparib to include women with advanced ovarian, fallopian tube or primary peritoneal cancer that is positive for homologous recombination deficiency (HRD), another marker of DNA damage.

Olaparib also is approved for patients with metastatic HER2-negative breast cancer and a germline BRCA1/BRCA2 mutation, as is talazoparib (Talzenna, Pfizer).

Results of the EMBRACA trial showed talazoparib significantly extended PFS compared with chemotherapy among patients with advanced breast cancer and a germline BRCA mutation.

Patients demonstrated median PFS of 8.6 months (95% CI, 7.2-9.3) with talazoparib compared with 5.6 months (95% CI, 4.2-6.7) with chemotherapy (HR = 0.54; 95% CI, 0.41-0.71), leading to FDA approval.

Results of another phase 2 study — presented at ASCO Annual Meeting last year — showed that more than half of a small cohort of women with early-stage, BRCA-positive breast cancer who received talazoparib once daily before surgery exhibited no evidence of disease at the time of surgery. The study appeared to be the first to show a single targeted therapy induced pathologic complete response among women with BRCA-positive breast cancer.

“PARP inhibitors tested in patients with metastatic breast cancer have very consistent results when it comes to quality of life,” study author Jennifer K. Litton, MD, associate professor of breast medical oncology at The University of Texas MD Anderson Cancer Center, told HemOnc Today. “We are seeing a class effect, and quality of life is something that is very important to our patients and influences which drugs we pick.”

Changes in practice for ovarian cancer

The presence of BRCA mutations in ovarian cancer is about 15% to 20% for germline mutations and 5% for somatic mutations.

For newly-diagnosed advanced ovarian cancer, the goal of treatment is to delay progression and maintain quality of life with the intent of achieving complete remission or cure.

The three studies presented at ESMO — PAOLA-1, PRIMA and VELIA — evaluated the role of PARP inhibitors in the upfront setting, with stratification by BRCA status.

PAOLA-1 is the first phase 3 trial to evaluate maintenance therapy with a PARP inhibitor in combination with bevacizumab (Avastin, Genentech), regardless of BRCA status, following response to first-line chemotherapy for advanced ovarian cancer.

Isabelle L. Ray-Coquard, MD, PhD, medical oncologist in the medical oncology department and Institute for Clinical Science at Centre Leon Berard in France and professor of medical oncology at University Claude Bernard Lyon I, and colleagues evaluated data on 806 women with stage III or stage IV high-grade serous or endometrioid ovarian, fallopian tube or primary peritoneal cancer who were in clinical complete or partial response after receiving standard platinum-based chemotherapy in combination with bevacizumab. Researchers randomly assigned women 2:1 to maintenance bevacizumab with olaparib (n = 537) or bevacizumab alone (n = 269).

PFS in the intent-to-treat population served as the study’s primary endpoint.

Results showed significantly longer median PFS in the olaparib group (22.1 months vs. 16.6 months; HR = 0.59; 95% CI, 0.49-0.72).

Researchers observed a PFS benefit with olaparib maintenance regardless of whether women had BRCA-mutated tumors (median PFS, 37.2 months vs. 21.7 months; HR = 0.31; 95% CI, 0.2-0.47) or not (18.9 months vs. 16 months; HR = 0.71; 95% CI, 0.58-0.88).

The benefit appeared particularly notable among women with BRCA-mutated tumors positive for HRD. These women achieved median PFS of 37.2 months with olaparib compared with 17.7 months in the control group (HR = 0.33; 95% CI, 0.25-0.45). Women with HRD-positive status without BRCA mutations also benefited (median PFS, 28.1 months vs. 16.6 months), whereas the addition of olaparib did not confer benefit to women with HRD-negative or unknown status (16.9 months vs. 16 months).

The results support use of this regimen as a standard of care in this setting regardless of BRCA mutation status, Ray-Coquard told HemOnc Today.

“It also confirms the importance of bevacizumab in the treatment of patients with ovarian cancer in the first-line setting,” she said. “It is interesting to note that PFS in the combination arm is longer than what was seen in the SOLO-1 trial, which is probably due to the use of bevacizumab.”

Results of that trial, presented at ESMO last year, showed first-line maintenance olaparib yielded an almost 70% reduction in risk for progression or death at 3 years compared with placebo among patients with a germline or somatic BRCA mutation.

“The positive results from the PAOLA-1 trial demonstrate a potential benefit of adding olaparib for patients receiving bevacizumab maintenance as part of their initial therapy for advanced ovarian cancer,” O’Cearbhaill said. “This follows the impressive results from the SOLO-1 trial that led to the approval of olaparib in women with BRCA gene mutations, and PAOLA-1 may have the potential to change the standard of care in first-line maintenance for a broader subgroup of women with advanced ovarian cancer.”

It’s also important to note that, unlike the other two ESMO studies, PAOLA-1 is the only one with an active control arm, Robert L. Coleman, MD, professor of gynecologic oncology and reproductive medicine at The University of Texas MD Anderson Cancer Center, told HemOnc Today.

“All others use placebo, and this is important because patients entering into these maintenance trials may actually have measurable persistent disease after chemotherapy and wind up getting randomized to placebo,” he said.

The other two headline studies presented at ESMO provided the first glimpse into how these drugs could benefit newly diagnosed patients.

Specifically, results of the phase 3 PRIMA study showed niraparib significantly extended PFS among women with newly diagnosed advanced ovarian cancer regardless of BRCA mutation status, although, as expected, the benefit appeared most pronounced among those with the mutation.

Antonio Gonzalez-Martin, MD, co-director of the department of medical oncology at Clinica Universidad de Navarra in Spain, and colleagues randomly assigned 487 women to niraparib and 246 to placebo. About half of the women in each treatment group had HRD-positive tumors, and 30% harbored BRCA mutations.

Results showed niraparib significantly extended median PFS, the study’s primary endpoint, among HRD-positive women (21.9 months vs. 10.4 months; HR = 0.43; 95% CI, 0.31-0.59) and in the overall study population (13.8 months vs. 8.2 months; HR = 0.62; 95% CI, 0.5-0.75).

“If granted FDA approval, we will have another option for patients in the upfront setting,” O’Cearbhaill said. “In the PRIMA study, researchers included patients without BRCA mutations, so we now have evidence of the benefits of using PARP inhibitors in a broader population of patients with newly diagnosed high-grade ovarian cancer.”

It is important to note that the patient population targeted for enrollment in the PRIMA study included women with high-risk disease, which is why the placebo arm is the poorest performing of all the studies, Coleman said.

A third study — the randomized phase 3 VELIA/GOG-3005 trial — demonstrated the addition of veliparib (ABT-888, AbbVie) to front-line chemotherapy followed by maintenance with veliparib monotherapy significantly prolonged PFS among women with newly diagnosed, high-grade serous ovarian carcinoma. Researchers observed this benefit in the entire cohort regardless of BRCA mutation or HRD status.

The analysis included 1,140 women, 26% of whom harbored BRCA mutations and 55% of whom had HRD. Investigators randomly assigned patients 1:1:1 to one of three regimens: chemotherapy plus placebo followed by placebo maintenance (control group; n = 375); chemotherapy plus veliparib followed by placebo maintenance (veliparib combination-only group; n = 383); or chemotherapy plus veliparib followed by veliparib maintenance (veliparib-throughout group; n = 382). The difference in investigator-assessed PFS between the veliparib-throughout group and control group served as the primary endpoint.

Overall, women in the veliparib-throughout group achieved significantly longer median PFS than women in the control group in the intent-to-treat population (23.5 months vs. 17.3 months; HR = 0.68; 95% CI, 0.56-0.83), with pronounced benefits observed among women with BRCA mutations (34.7 months vs. 22 months; HR = 0.44; 95% CI, 0.28-0.68) and HRD-positive disease (median, 31.9 months vs. 20.5 months; HR = 0.57; 95% CI, 0.43-0.76).

These data support veliparib administration during chemotherapy and continuation as maintenance as a new standard of care for women with newly diagnosed ovarian cancer, Coleman, who served as the lead study author, told HemOnc Today.

“PARP inhibitors are broadly approved in the recurrent setting and as primary maintenance. Now we have a new crop of patients who have had a PARP inhibitor earlier,” he said. “We are already starting to deal with the issue of how we interpret the ‘old’ studies, given the fact none of those patients had a PARP inhibitor before. We’ll have to start stratifying for prior exposure.”

Previously, PARP inhibitor-chemotherapy combinations have resulted in excessive hematologic toxicity requiring substantial dose reductions, but veliparib has demonstrated safety when combined with cytotoxic agents, Coleman said.

“The theme here is giving more patients access to PARP inhibitors earlier in their disease course,” O’Cearbhaill said. “The hope is that the survival data will reflect the impressive PFS results reported. Seeing more patients being cured would be amazing.”

Promising results In pancreatic cancer

PARP inhibitors also have shown some promise for pancreatic cancer, which has one of the worst 5-year survival rates among all cancers.

About 5% to 10% of cases occur among individuals with a family history of pancreatic cancer, and the most common genetic mutations involved in familial disease are BRCA1 and BRCA2.

At this year’s ASCO Annual Meeting, data from the phase 3 POLO trial showed maintenance therapy with olaparib significantly improved PFS among patients with metastatic pancreatic cancer and germline BRCA mutations.

The study served as the first phase 3 trial to validate biomarker-driven treatment for patients with pancreatic cancer.

“When I started in oncology 10 years ago, there was one drug for pancreatic cancer, and the disease was usually fatal within 6 to 8 months,” Michael J. Hall, MD, MS, chairman and associate professor in the department of clinical genetics at Fox Chase Cancer Center, and co-author of the POLO study, told HemOnc Today. “The results were actually even better than I expected.”

Hall and colleagues randomly assigned 154 patients to 300 mg twice-daily maintenance olaparib (n = 92) or placebo (n = 62). Two-thirds of patients harbored BRCA2 mutations, and the others had BRCA1 mutations.

Patients in the olaparib group demonstrated significantly longer PFS than patients assigned placebo (7.4 months vs. 3.8 months; HR = 0.53; 95% CI, 0.35-0.82). These results were consistent regardless of response to previous chemotherapy.

Given that most patients with this disease survive less than a year from diagnosis, these results with a single-agent oral therapy are clinically meaningful, Hall said.

“This is a disease that often has pain, cachexia, sarcopenia and weight loss associated with progressive disease, with an unending need for aggressive multiagent chemotherapy,” he said. “In pancreatic adenocarcinoma, it’s not just the length of survival or the length of stable disease that matters, it is what you have to do to get it. It is the quality of that time as much as the quantity that is important to patients.”

At 6 months, the percentage of progression-free patients in the olaparib arm appeared double that of the placebo arm (53% vs. 23%). This PFS benefit continued at 1 year (33.7% vs. 14.5%), 18 months (27.6% vs. 9.6%) and 2 years (22.1% vs. 9.6%).

The interim OS analysis showed an HR of 0.91 (95% CI, 0.56-1.46), with median OS of 18.9 months in the olaparib group and 18.1 months in the placebo group.

Researchers also evaluated time to second progression, which may be suggestive of durability of treatment benefit beyond progression. Results showed median PFS2 of 13.2 months in the olaparib group and 9.2 months in the placebo group (HR = 0.76; 95% CI, 0.46-1.23).

“Chemotherapy is always going to have a role in treating this cancer, but this trial offers us a new option for select patients,” Hall said. “Understanding that mechanism and the role of the immune system in these kinds of tumors is very important. There is a lot of science and research ahead of us.”

Continued limitations

Although these studies suggest PARP inhibitors are making headway in a variety of diseases, experts acknowledge that challenges remain in refining the role of these agents and continuing to improve outcomes.

Given that these studies primarily looked at PFS, the long-term gains remain unknown.

There are caveats with each of the three ESMO studies, Coleman said.

For example, the VELIA trial did not have a veliparib-only arm, so it’s unknown whether a PARP inhibitor needs to be given during chemotherapy. Also, the benefit seen overall appeared to be driven by the BRCA population, so the benefit for patients with wild-type BRCA is less clear.

“In PAOLA-1, there appears to be a benefit with the addition of olaparib, but among patients with a BRCA mutation, the benefit doesn’t appear to be enhanced by bevacizumab,” Coleman said. “Also, there appears to be no effect on PFS in the HRD-negative group, which again begs the question whether you need to give both agents with the extra toxicity.”

Lastly, the PRIMA trial may be limited by the fact that it uses placebo as a control arm and, although patients had high-risk disease, the “magnitude of benefit is significant but questionably meaningful,” he added. “The benefit appears to be in line with single-agent bevacizumab in a cross-trial look and driven by patients with HRD, like in VELIA.”

Further, it remains unknown how to manage patients who are resistant to or experience progression on a PARP inhibitor.

“Future studies will look at giving a different PARP inhibitor following progression, as well as novel combinations, such as with immunotherapy,” O’Cearbhaill said. “I imagine that we will need to give PARP inhibitors in combination with other drugs that target PARP inhibitor resistance pathways.”

Cost of the drugs also must be considered, and patients will need to be carefully selected based on who is most likely to benefit from them, she added.

Simply readministering a PARP inhibitor to a patient who did not respond or has progressed will not induce any clinical benefit, Coleman said.

“It would be extremely unlikely that a patient with progression on one of the available PARP inhibitors would respond to retreatment with another in this group of drugs, given the mechanism of action and the mechanism of resistance,” he said. “It is likely that retreatment in patients not progressing on PARP inhibitors will be a viable option — which is currently being explored — as might be the combination of a PARP inhibitor with another agent restoring an HRD-like state in the tumor.”

Efforts also must continue to improve outcomes among patients who already respond to this class of agents, Coelman added.

“Although this is a great class of drugs that has changed the standard of care, we can still do better for these patients,” he said. “The question is, how?” – by John DeRosier

Click here to read the , “Will the use of PARP inhibitors in advanced ovarian cancer with wild-type BRCA lead to improved OS rates?”

References:

Coleman RL, et al. N Engl J Med. 2019;doi:10.1056/NEJMoa1909707.

Golan T, et al. N Engl J Med. 2019;doi:10.1056/NEJMoa1903387.

González-Martín A, et al. N Engl J Med. 2019;doi:10.1056/NEJMoa1910962.

Litton JK, et al. N Engl J Med. 2018;doi:10.1056/NEJMoa1802905.

Litton JK. Abstract 508. Presented at: ASCO Annual Meeting; June 1-5, 2018; Chicago.

Moore K, et al. N Engl J Med. 2018;doi:10.1056/NEJMoa1810858.

Ray-Coquard IL, et al. Abstract LBA2_PR. Presented at: European Society for Medical Oncology Congress; Sept. 27-Oct. 1, 2019; Barcelona, Spain.

For more information:

Robert L. Coleman, MD, can be reached at rcoleman@mdanderson.org.

Michael J. Hall, MD, MS, can be reached at michael.hall@fccc.edu.

Jennifer K. Litton, MD, can be reached at jlitton@mdanderson.org.

Roisin E. O’Cearbhaill, MD, can be reached at ocearbhr@mskcc.org.

Isabelle L. Ray-Coquard, MD, PhD, can be reached at isabelle.raycoquard@lyon.unicancer.fr.

Disclosures: Coleman reports consultant/advisory roles with, research grants/funding from, or travel expenses from Abbott, AbbVie/Stemcentrx, Array BioPharma, AstraZeneca/MedImmune, Clovis Oncology, Esperance, Genentech/Roche, GamaMabs Pharma, Genmab, Gynecologic Oncology Group, Johnson & Johnson, Merck, National Comprehensive Cancer Network, Oncolytics, OncoMed, Research to Practice, Sotio, Tesaro and Vaniam Group. Hall reports research funding from AstraZeneca, Caris Life Sciences, Foundation Medicine and Myriad Genetics. Litton reports speakers bureau or consultant/advisory roles with and/or institutional research funding or travel expenses from AstraZeneca, Bristol-Myers Squibb, EMD Serono, Genentech, GlaxoSmithKline, Jounce Therapeutics, Med Learning Group, Medivation/Pfizer, Medscape, Novartis, Physicians’ Education Resource and UpToDate. O’Cearbhaill reports advisory roles with Clovis, GlaxoSmithKline and Tesaro; she also served on the steering committee of the PRIMA study. Ray-Coquard reports consultant roles with and/or honoraria, research funding or travel expenses from AstraZeneca, Clovis Oncology, Merck, Pfizer, Pharma Mar, Roche and Tesaro.