Long-Term OS Data Guide Use of PARP Inhibitors in Ovarian Cancer

Preventing relapse of advanced ovarian cancer with PARP inhibitors is now an established strategy. As data from pivotal clinical trials have evolved, the stratification of patients by homologous recombination deficiency (HRD) and BRCA mutation status has offered further detail into what outcomes can be expected with PARP inhibitors, as was discussed in an in-person Case-Based Roundtable event in Jacksonville, Florida. The event’s moderator, Martin A. Martino, MD, medical director of gynecologic oncology at Ascension St. Vincent’s, reviewed the 3 trials and focused in particular on factors that are linked to patient outcomes, including HRD status and residual disease.

Targeted Oncology: What led to the use of PARP inhibitor maintenance in advanced ovarian cancer?

Martin A. Martino, MD: The phase 3 SOLO-1 study [NCT01844986] came out in the New England Journal of Medicine in 2018 and Kathleen Moore, MD, was the principal investigator on this. To review the criteria, [it enrolled] patients with stage III high grade or stage IV [ovarian cancer] who had BRCA mutations. They were cytoreduced, had a complete or partial response, and were randomly assigned on a 2:1 basis to olaparib [Lynparza] or placebo. Study treatment was continued to progression of disease, and they went on for 2 years of treatment. This was game-changing back in the day when this came out. I remember back then saying, when do you actually stop these patients after 2 years? Do we go to 3 years? We have the same [question] with pembrolizumab [Keytruda] now in some of our patients, which is a good thing.

The majority had germline [BRCA mutations]: 391 patients had a germline [mutation]. The primary end point was progression-free survival [PFS] by RECIST 1.1 and secondary end points were overall survival [OS], quality of life, and other factors.¹

Looking at 7-year data coming out of 2022, [OS had] a P value that was highly significant.² There was a 45% risk reduction from the olaparib arm vs the placebo arm, which is pretty impressive to see. Looking at the 7-year survival, 67% of patients out there [were alive with olaparib vs 46.5% with placebo].

They break this down to the percent of patients free from first subsequent therapy or second subsequent therapy. Clearly, if the patient’s on olaparib, they get their treatment and they’re done, which is one of the things that most patients are seeing compared with placebo in this arm.

How was olaparib studied in patients who received bevacizumab (Avastin)?

PAOLA-1 [NCT02477644] was the olaparib plus bevacizumab study. This study was for patients with newly diagnosed ovarian cancer of stage III or stage IV with no progressive disease when they’re done with chemotherapy. BRCA [or HRD status] initially was not required for eligibility. PFS was the primary end point and there was a 2:1 randomization as well. They had [prior] surgery either upfront or interval in the debulking, they received carboplatin plus paclitaxel, and they received at least 3 cycles of bevacizumab. The question here was to continue the bevacizumab alone or add olaparib at 100 mg twice a day for 2 years, and randomize that, stratified by BRCA and treatment outcomes.

[For post hoc exploratory OS analysis, patients with] lower risk in their criteria were those with upfront surgery and no residual disease, [whereas] higher risk was those with residual disease. Obviously, we try and get everything out we can see, [but] it’s not going to be easy or even feasible. Even though some gynecologic oncologists may say they got everything they could see, it’s not always that way.

The median OS for olaparib plus bevacizumab vs bevacizumab as a group [was 56.5 vs 51.6 months (HR, 0.92; 95% CI, 0.76-1.12; P = .4118]; the confidence interval crosses 1.00.³ Then you start to break it out to BRCA mutations, HRD mutations, or HRD negative, [which only showed significant benefit in the BRCA-mutated group]. So this not what we’re going to be doing for HRD-negative patients. That’s a good takeaway. But again, it’s important to test and understand. Even though in the study it was not significant, we still learned something from what was there when they looked at the 5-year OS by lower and higher risk [HRD-positive]. They wound up seeing improvements for both groups. There was a 0.7 HR for OS for higher-risk, and an HR of 0.31 in the lower-risk group. There’s some signal coming out for an OS now that we’re capturing in these risk groups.

What data support the use of niraparib (Zejula) in this setting?

The last trial is PRIMA [NCT02655016]. These were patients with ovarian cancer who received 1 first-line platinum-based chemotherapy, had a complete or partial response with that, and then they had their testing and the same randomization, 2:1 to niraparib. They did the stratifications as well. I remember when niraparib came out and the thought was that there may be a significance, but with 3-year, 4-year, and 5-year OS, the curves are crossing and not seeing much significant difference.⁵ When they looked at HRD vs HRP [homologous recombination proficient], in the HRP arm, there was a little bit of a separation, but still, you get a 5-year OS at 29% vs 27%. And of course, in the HRD arm, we did not see any difference at all on that. Looking at BRCA status as well as HRD mutant status vs HRD and BRCA wild type, [there was also no OS difference].

Back when niraparib first came out, [it appeared that] you didn’t need to test BRCA status, because there was a little bit of a survival improvement that may have been identified, but now as the data have matured, that’s kind of gone away.

What are your takeaways of PARP inhibitor maintenance for the HRD-positive population?

…There was a significant benefit in the HRD population and the [BRCA]-mutated population in some of these studies; it really changed our management. We never used to do these. When I was a fellow, we didn’t have them. That was in 2005, and they were just working on this. It was cool to see a decade later when these started to come out we could give it a patient and see that even with ascites, the CA-125 starts trickling down in that setting, and at least there’s something [to use]. Now we see with immunotherapy and some other drugs where [patients with serious complications] have no more issues for a short time, 6 months, 12 months; it’s neat to be able to see.

What was the latest update on the use of PARP inhibitors based on the long-term data?

At the FDA’s request, the indication for niraparib was limited to maintenance treatment for adult patients with advanced ovarian cancer with HRD, including BRCA [mutation]. That used to be all comers. Now they limited it to HRD. Following final analysis of PRIMA with survival, the FDA said that the benefit-risk profile for non–HRD positive patients is no longer favorable. There had been a little signal there, but now they looked at it and said [it] no longer [shows this], so do not initiate new treatments with niraparib as maintenance, and discuss this information with patients who are on niraparib, just so they’re aware, because they may still be on it sometimes.

DISCLOSURES: There were no known relevant disclosures.

REFERENCES:

1. Moore K, Colombo N, Scambia G, et al. Maintenance olaparib in patients with newly diagnosed advanced ovarian cancer. N Engl J Med. 2018;379(26):2495-2505. doi:10.1056/NEJMoa1810858

2. DiSilvestro P, Banerjee S, Colombo N, et al. Overall survival with maintenance olaparib at a 7-year follow-up in patients with newly diagnosed advanced ovarian cancer and a BRCA mutation: The SOLO1/GOG 3004 trial. J Clin Oncol. 2023;41(3):609-617. doi:10.1200/JCO.22.01549

3. Ray-Coquard I, Leary A, Pignata S, et al. Olaparib plus bevacizumab first-line maintenance in ovarian cancer: final overall survival results from the PAOLA-1/ENGOT-ov25 trial. Ann Oncol. 2023;34(8):681-692. doi:10.1016/j.annonc.2023.05.005

4. Lorusso D, Mouret-Reynier MA, Harter P, et al. Updated progression-free survival and final overall survival with maintenance olaparib plus bevacizumab according to clinical risk in patients with newly diagnosed advanced ovarian cancer in the phase III PAOLA-1/ENGOT-ov25 trial. Int J Gynecol Cancer. 2024;34(4):550-558. Published 2024 Apr 1. doi:10.1136/ijgc-2023-004995

5. Monk BJ, Barretina-Ginesta MP, Pothuri B, et al. Niraparib first-line maintenance therapy in patients with newly diagnosed advanced ovarian cancer: final overall survival results from the PRIMA/ENGOT-OV26/GOG-3012 trial. Ann Oncol. 2024;35(11):981-992. doi:10.1016/j.annonc.2024.08.2241

6. Zejula. Prescribing information. GlaxoSmithKline, 2025. Accessed October 9, 2025. https://www.accessdata.fda.gov/drugsatfda_docs/label/2025/214876s003s004lbl.pdf