Dr Crane on the Ongoing Investigation of PARP Inhibitor Combinations in Ovarian Cancer 

Erin Crane, MD, MPH, associate professor, Division of Gynecologic Oncology, Atrium Health Levine Cancer Institute, discusses the evolving role of PARP inhibition in ovarian cancer, as well as ongoing trials investigating combining PARP inhibitors in combination with other investigational drugs agents, notably in the first-line setting.. These trials hold promise for elucidating potential synergistic effects and efficacy in this context.

Research in ovarian cancer is focused on develop a synergistic effect when combining PARP inhibitors with other agents, Crane begins. For example, the phase 3 PAOLA-1 trial showed a significant progression-free survival benefit with the addition of olaparib (Lynparza) to bevacizumab (Avastin) as first-line maintenance therapy, she details. This benefit was notable in patients with homologous recombination deficient (HRD) tumors, including those without 

There is also an unmet need for more tailored therapeutic strategies to treat patients with HRD-negative tumors, Crane continues.

Crane highlights the clinical challengeatients posed by homologous recombinationproficient (HRP) tumors, which typically exhibit earlier platinum resistance and have poorer prognoses compared with patients displaying HRD-positiveto HRD-positive tumors, Craneexplains. Accordingly, addressing therapeutic strategies tailored to this patient cohort remains imperative.

Trials investigating maintenance therapies and investigational drugs targeting HRD-negativeP tumors are underway, Crane says, aiming to enhance treatment options and outcomes for this subgroup. Crane underscores the necessity of such endeavors toThese research efforts are necessary to improve prolong survival outcomes and improve the clinical trajectory of patients with HRD-negative disease, thereby prolonging survival and augmenting overall prognoses within this subgroup.

Regarding the long-term efficacy of PARP inhibitors have demonstrated long-term efficacy, Crane emphasizes, adding that the their sustained benefits observed with these agents are, consistent with prior expectations. Notably, the enduring efficacy observed underscores the therapeutic significance of PARP inhibitors in the clinical landscape. The accrued dataData accrued over the past 5five years substantiate indicates the substantial impact of PARP inhibitors on the treatment paradigm in ovarian cancer, surpassing supplanting previous therapeutic modalities as a standard of care, she states.

Early testing for germline and somatic mutations to can improve the identificationy candidates for PARP maintenance therapy, is advocated by Crane adds. This personalized approach facilitates the timely initiation of appropriate therapies, optimizing patient outcomes and treatment efficacy. This emphasis on genetic testing also underscores the evolving paradigm of precision medicine in ovarian cancer, Crane states.

Crane underscores the continuing research landscape surroundingPARP inhibitors and their combination with investigational agents.

Overall, these efforts are directed towards refining treatment strategies for patients with HRD-negativeP tumors and , alongside exploring avenues to maximize the therapeutic benefits of PARP inhibitors in the upfront setting, Crane concludes. The pivotal role of genetic testing in treatment decision-making is underscored, highlighting the evolving landscape of precision oncology.

Videos

Erin K. Crane, MD, MPH, discusses the impact of the phase 3 PRIMA trial on second-line maintenance approaches in ovarian cancer.

Dr Crane on the PRIMA Trial of Niraparib Maintenance Therapy in Ovarian Cancer

Erin K. Crane, MD, MPH, associate professor, Division of Gynecologic Oncology, Atrium Health Levine Cancer Institute, discusses the impact of the phase 3 PRIMA trial (NCT02655016) evaluating second-line maintenance approaches in ovarian cancer.

The randomized phase 3 trial investigated the efficacy of niraparib (Zejula) as a maintenance treatment for all-comer patients with stage III/IV ovarian cancer who had undergone upfront maintenance treatment following frontline platinum-based chemotherapy, Crane begins. Patients were randomly assigned to receive either niraparib or placebo, irrespective of their 

 mutation status or homologous recombination deficiency (HRD) status, though they were stratified accordingly, she details.

Findings from PRIMA supported the FDA's approval of the maintenance treatment for adult patients with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a complete or partial response to first-line platinum-based chemotherapy on April 29, 2020, Crane reports.

PARP maintenance therapy showed benefits across all subgroups, with the most substantial improvements in progression-free survival (PFS) observed in patients with 

-positive or HRD-positive tumors, Crane states. The median PFS in the homologous recombination deficient population was 21.9 months with niraparib compared with 10.4 months for those receiving placebo (HR, 0.43; 95% CI, 0.31-0.59; P < .0001). The median PFS in the overall population was 13.8 months with niraparib compared with 8.2 months for those receiving placebo (HR, 0.62; 95% CI, 0.50-0.76; P < 0.0001). Patients with homologous recombination-proficient tumors also experienced modest PFS improvements, Crane adds.

restricted niraparib’s second-line maintenance indication

 to patients with recurrent platinum-sensitive ovarian cancer harboring deleterious or suspected deleterious germline 

 mutations in 2022 based on updated data from the phase 3 ENGOT-OV16/NOVA trial (NCT01847274). The decision to use niraparib underscores the importance of personalized treatment approaches and discussions between clinicians and patients regarding the use of PARP maintenance therapy in specific patient populations, Crane concludes.

Erin K. Crane, MD, MPH, associate professor, Division of Gynecologic Oncology, Atrium Health Levine Cancer Institute, discusses findings from 3 trials demonstrating the benefits of PARP inhibitor maintenance in patients with ovarian cancer.

The phase 3 SOLO1 trial (NCT01844986) randomized patients with somatic or germline 

-mutated ovarian cancer who had completed chemotherapy to receive either olaparib (Lynparza) or placebo. Long-term findings from this trial continue to display the practice-changing benefits of olaparib in the 

-mutant population, Crane says. The 7-year overall survival rate in the olaparib arm was 67.0% vs 46.5% in the placebo arm.

The phase 3 PRIMA trial (NCT02655016) enrolled all-comers with ovarian cancer who had received frontline platinum-based chemotherapy, including those with 

 mutations, those with homologous recombination deficiency (HRD)–positive ovarian cancer, and those with homologous recombination–proficient tumors. These patients were randomly assigned 2:1 to receive niraparib (Zejula) or placebo. Data from the primary analysis of this trial showed that in all-comers, the median progression-free survival (PFS) was 13.8 months vs 8.2 months with niraparib and placebo, respectively. In the HRD-positive population, the median PFS was 21.9 months with niraparib vs 10.4 months with placebo. These findings led to the 2020 

 in adult patients with ovarian cancer who responded to frontline platinum-based chemotherapy, regardless of 

The phase 3 PAOLA-1 trial (NCT02477644) randomized patients with ovarian cancer to receive olaparib plus bevacizumab (Avastin) or bevacizumab alone as frontline maintenance therapy after completing chemotherapy, regardless of 

 mutation or HRD status. Treatment with the combination resulted in a median PFS of 22.1 months vs 16.6 months in those who received bevacizumab alone. The combination provided a notable benefit in patients with HRD-positive disease, including those with 

 mutations, with a median PFS of 37.2 months vs 17.7 months in the bevacizumab-alone arm. These findings supported the 2020 

FDA approval of olaparib plus bevacizumab

 in the frontline maintenance setting in patients with HRD-positive ovarian cancer.

As these 3 study populations differed slightly from one another, the indications for these 3 PARP maintenance regimens differ as well, Crane concludes.

Erin K. Crane, MD, MPH, discusses findings from 3 trials demonstrating the benefits of PARP inhibitor maintenance in patients with ovarian cancer.

Dr Crane on PARP Inhibitor Maintenance in Ovarian Cancer


Gina Mauro is your lead editorial contact for 

. She joined the company in 2015 and has held various positions on 

; she is also the on-air correspondent for 

. Prior to joining MJH Life Sciences, she worked at Gannett as a full-time reporter with the Asbury Park Press. Email: gmauro@onclive.com 

OncLive sits down with Nicholas J. Vogelzang, MD, and Erin K. Crane, MD, MPH to discuss the biggest abstracts in genitourinary cancers and gynecologic cancers, respectively, at the 2021 ASCO Annual Meeting.

Updates in Genitourinary, Gynecologic Cancers From ASCO 2021: Drs Nick Vogelzang and Erin Crane

Erin K. Crane, MD, MPH, a gynecologic oncologist at Levine Cancer Institute, of Atrium Health, discusses the benefit of maintenance PARP inhibitors in ovarian cancer.

The phase 3 SOLO-1 trial proved that maintenance PARP inhibitors should be the standard of care for patients with ovarian cancer who harbor somatic or genomic 

 mutations, according to Crane. Although overall survival data are not yet available for this trial, the most updated findings for progression-free survival was 56 months with olaparib (Lynparza) versus 13.9 months with placebo in this population, says Crane.

The role of maintenance therapy for patients with ovarian cancer is 2-fold: it helps to decrease the risk of disease recurrence and extend the duration of time before recurrence. Although OS data have not been finalized, the field is hopeful that maintenance therapy may be effective in preventing recurrence, says Crane. This patient population can have a good quality of life following treatment before they need to go on subsequent therapies; this approach possesses potential to extend the time to next treatment, Crane concludes.

Erin K. Crane, MD, MPH, discusses the benefit of maintenance PARP inhibitors in ovarian cancer.

Dr. Crane on the Benefit of Maintenance PARP Inhibitors in Ovarian Cancer

Erin K. Crane, MD, MPH, gynecologic oncologist, Levine Cancer Institute, Carolinas HealthCare System, discusses the toxicity profile of combination regimens for patients with ovarian cancer.

When you combine cytotoxic chemotherapy drugs there tends to be a higher toxicity profile, but physicians are learning more about this from ongoing trials, explains Crane. Physicians should be careful with bone marrow suppression and nausea, but there are medications that can decrease these adverse events and improve the patients' quality of life.

However, a remaining challenge in the field has been the underrepresentation of women, particularly minorities, in clinical trials, says Crane. That coupled with the fact that there has been decreased funding for trials in the past couple of years has affected the development of treatment. According to Crane, enrollment for clinical trials for patients with gynecologic malignancies has decreased by 90%. However, work is being done with pharmaceutical industries to open more trials. Getting women enrolled in trials, particularly minority patients who disproportionally are not enrolled, is an unmet need.

Dr. Crane on the Toxicity Profile of Combinations for Ovarian Cancer

Erin K. Crane, MD, MPH, gynecologic oncologist, Levine Cancer Institute, Carolinas HealthCare System, discusses combinations with PARP inhibitors in ovarian cancer.

There are at least 30 trials looking at combinations with PARP inhibitors. Crane says that one of the more interesting questions being asked of PARP inhibitors is their potential as a maintenance in the frontline setting in combination with chemotherapy. Additionally, investigators are looking to determine if PARP inhibitors can be used in the recurrent setting in combination with either targeted drugs or chemotherapy.

With the addition of cytotoxic chemotherapy, any side effect profile will increase, says Crane. Combinations of PARP inhibitors and chemotherapy can lead to toxicities, such as bone marrow suppression and nausea.

Dr. Crane on Combinations With PARP Inhibitors in Ovarian Cancer

Erin K. Crane, MD, MPH, gynecologic oncologist, Levine Cancer Institute, Carolinas HealthCare System, discusses the impact of PARP inhibitors for patients with ovarian cancer.

In December 2014, olaparib (Lynparza) was approved by the FDA for use in patients with germline 

 mutations who had 3 or more prior treatments. This has led to more PARP inhibitors being pushed through the pipeline, explains Crane, such as rucaparib (Rubraca), and niraparib (Zejula) for patients with recurrent disease.

Trials are being conducted in all-comers with platinum-sensitive disease, which may lead to further FDA approvals. Close to 1-year improvement in progression-free survival with a good quality of life has been seen with PARP inhibitors, says Crane.

Erin K. Crane, MD, MPH

Articles