FIRST Trial: No Safety Interaction Between Dostarlimab and Niraparib

Initiated in 2018, the global, randomized, double-blind phase 3 FIRST/ENGOT-OV44 trial (NCT03602859) set out to investigate whether the addition of the PD-1 inhibitor dostarlimab-gxly (Jemperli) to platinum-based chemotherapy, followed by maintenance with the PARP inhibitor niraparib (Zejula), could improve progression-free survival (PFS) in patients with newly diagnosed stage III to IV advanced nonmucinous epithelial ovarian cancer.¹ Here, 1162 patients were randomly assigned 1:2 to receive either paclitaxel/carboplatin chemotherapy plus dostarlimab with or without bevacizumab (Avastin), or the same regimen replacing dostarlimab with placebo. The maintenance regimen consisted of niraparib plus dostarlimab or placebo, with or without bevacizumab.

Efficacy results of this trial, shared at the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting and concurrently published in Annals of Oncology, revealed that while there was a statistically significant improvement in median PFS in the treatment arm (20.6 months; 95% CI, 19.2-22.8) compared with the placebo arm (19.2 months; 95% CI, 16.6-21.0) (HR, 0.85; 95% CI, 0.73-0.99; P =.0351), the clinical benefit was modest.²

Recently, at the European Society of Medical Oncology (ESMO) Congress 2025, investigators presented a poster that explored whether adding dostarlimab affected niraparib tolerability, exposure, or dose modification in the FIRST trial, which could have attenuated the efficacy results.³

In an interview with Targeted Oncology®, Kathleen N. Moore, MD, MS, professor of gynecologic oncology at the University of Oklahoma College of Medicine, associate director of clinical research at Stephenson Cancer Center, and study investigator, discussed the rationale that drove this analysis and the conclusions drawn from the results.

Targeted Oncology: Could you provide a brief background on the FIRST study?

Kathleen N. Moore, MD, MS: The FIRST study, as a reminder, was a very large phase 3 clinical trial that evaluated the addition of the immune checkpoint inhibitor [ICI] dostarlimab to chemotherapy and to follow in combination with the PARP inhibitor niraparib, with or without bevacizumab. It started off as a 3-arm study. One of the arms did not have niraparib maintenance, and as PARP inhibitors became approved for standard of care, that arm was discontinued. This was a 2-arm study that evaluated paclitaxel/carboplatin, with or without bevacizumab, investigator’s choice. The experiment was adding dostarlimab, and then both arms received niraparib maintenance, 1 with and 1 without dostarlimab.

This was a true study, really trying to demonstrate the relative contribution of dostarlimab with all patients receiving what we would consider, or considered at the time, to be the standard-of-care maintenance therapy, which is a PARP inhibitor, niraparib, and bevacizumab, per the physician’s discretion. [It] helped us sort out whether dostarlimab made a difference, and statistically it did. There was an improvement in [PFS], but it was really a clinically not-relevant improvement. The study, I think we would say, was statistically positive, and I'm incredibly proud of it. We're going to learn a tremendous amount from it, but clinically, it did not change practice, and we do not recommend the addition of dostarlimab.

What was the rationale that prompted this analysis presented at ESMO?

This poster was done to look at whether there was a negative impact of adding dostarlimab to the expected benefit of the PARP inhibitor. The reason that is a question is that there was another clinical trial called ATHENA-COMBO [NCT03522246],⁴ which was a different design, a switch maintenance. In this [FIRST] study, patients were enrolled from the beginning of chemotherapy. ATHENA-COMBO enrolled patients at the end of chemotherapy in response—so it's a slightly different patient population—and randomized them to the PARP inhibitor rucaparib [Rubraca], with or without the immune checkpoint inhibitor nivolumab [Opdivo]. It's similar in that it was head-to-head with PARP inhibitor maintenance and trying to sort out the relative contribution of the addition of nivolumab, and that study showed a detriment in [PFS] for the combination arm. There were and still are a lot of questions as to why that happens, because you wouldn't have expected that, but one of the hypotheses is that there was some sort of safety interaction that led to a sizable number of patients discontinuing both therapies in that maintenance arm. Medicines don't work if you don't use them. And so, if a number of patients discontinued the PARP inhibitor—which we think is the effective drug because of toxicities related to the nivolumab—could that have confounded that whole clinical trial based on some sort of safety interaction? That remains to be further elucidated. We don't know that definitively, but that's sort of the hypothesis.

We went back and looked at FIRST, which admittedly did not show the magnitude of benefit of the combination that we hoped for when we designed the studies, and said, was the same sort of interaction at play here? Did we see more dose modifications of the PARP or discontinuations of the PARP in the combination arm, that maybe could explain the attenuated efficacy benefit, or the lack of efficacy benefit that the study showed? That's what drove this analysis.

What was the conclusion and main takeaway of this analysis?

We did not see that the addition of dostarlimab had any significant impact on the tolerability of niraparib, and that was measured by the duration of niraparib exposure. We didn't see patients discontinuing the niraparib more commonly in the combination arm than we did in the single-agent arm, and we didn't see more treatment-emergent adverse events leading to niraparib dose reductions, interruptions, or discontinuations in that arm. We didn't see any evidence of whatever happened with ATHENA-COMBO in this clinical trial, and that, I think, is the take-home from this poster: It may be that the experiment just wasn't successful. It's not because patients stopped the PARP. That's, I think, somewhat reassuring, that it wasn't a safety issue, and it really is that the dostarlimab just didn't help.

REFERENCES:

1. A comparison of platinum-based therapy with TSR-042 and niraparib versus standard of care (SOC) platinum-based therapy as first-line treatment of stage III or IV nonmucinous epithelial ovarian cancer (FIRST). ClinicalTrials.gov. Updated March 13, 2025. Accessed October 28, 2025. https://www.clinicaltrials.gov/study/NCT03602859

2. Hardy-Bessard AC, Pujade-Lauraine E, Moore RG, et al. Dostarlimab and niraparib in primary advanced ovarian cancer. Ann Oncol. May 30, 2025. doi:10.1016/j.annonc.2025.05.009

3. Moore, KN. FIRST/ENGOT-OV44 trial: does the addition of dostarlimab impact niraparib tolerability, exposure, or dose modification?. Poster presented at: ESMO Congress 2025; October 17-21, 2025; Berlin, Germany.

4. Monk BJ, Oaknin A, O'Malley DM, et al. LBA30 ATHENA-COMBO, a phase III, randomized trial comparing rucaparib (RUCA) + nivolumab (NIVO) combination therapy vs RUCA monotherapy as maintenance treatment in patients (pts) with newly diagnosed ovarian cancer (OC). Ann Oncol. 2024;35:S1223-S1224. doi:10.1016/j.annonc.2024.08.2269