Ceralasertib/Olaparib Combo Elicits Promising Activity in PARP-Resistant Ovarian Cancer

Stephanie Lorene Wethington, MD, MSc

The combination of ceralasertib and olaparib (Lynparza) induced clinical activity and was well tolerated in patients with homologous recombination deficient (HRD), recurrent platinum-sensitive, PARP inhibitor–resistant ovarian cancer, according to findings from the phase 2 CAPRI trial (NCT03462342) that were presented during the 2021 ASCO Annual Meeting.¹

In the trial, patients received 300 mg of oral olaparib twice daily on days 1 through 28 plus 160 mg of oral ceralasertib daily on days 1 through 7. Among 13 evaluable patients, the objective response rate (ORR) was 46% (n = 6), and the progression-free survival was 7.5 months (95% CI, 4.7–not reached).

Among patients with germline BRCA mutations, somatic BRCA mutations, and HRD positivity, the ORRs were 69% (n = 9), 23% (n = 3), and 8% (n = 1), respectively.

Patients who had received a prior PARP inhibitor in the frontline maintenance, second-line maintenance, and treatment settings had ORRs of 8% (n = 1), 38% (n = 5), and 54% (n = 7), respectively.

Grade 3 or 4 adverse effects included anemia (7.7%; n = 1), thrombocytopenia (23.1%; n = 3), leukopenia (7.7%; n = 1), and neutropenia (7.7%; n = 1). Investigators reported 2 treatment interruptions because of thrombocytopenia and COVID-19 infection, and 4 dose reductions because of olaparib (n = 3) and ceralasertib (n = 1).

“In the recurrent setting, we really want to be sure that we are providing our patients with regimens that are well tolerated. In this small series, we saw excellent tolerance and a very intriguing response rate. This by no means is a definitive series, but [this] well-tolerated regimen with a favorable response rate is worthy of further investigation,” said lead study author, Stephanie Lorene Wethington, MD, MSc.

In an interview with OncLive, Wethington, director of The Susan L. Burgert MD Gynecologic Oncology Survivorship Program and an assistant professor of Gynecology and Obstetrics at Johns Hopkins Medicine, discussed the results of the study and importance of studying combination treatments in patients with PARP-resistant ovarian cancer.

OncLive: How has the emergence of HRD as a biomarker changed the paradigm in ovarian cancer?

Wethington: Over the past decade, there has been a complete transformation in how we think about ovarian cancer. Most remarkably, in 2021, there has been this focus and emphasis on HRD, and how that should or shouldn’t, in different moments, guide our therapeutic approaches. The idea of HRD as a key discriminator in the management of high-grade serous ovarian cancers has been one of the real revolutionary changes that we are currently experiencing and practicing within.

What are some of the opportunities for further research with HRD?

The first challenge we face is how we assess HRD. Which of the many different assays do we use? What sequence do we complete the testing in? How do we then interpret the test results and counsel our patients based on those results?

As treatment paradigms have shifted over time, we have a growing patient population that has received a PARP inhibitor in the past, and PARP inhibitors are those therapeutic approaches that really target HRD as their primary mechanism. Now we have many patients who have been treated with PARP inhibitors, and what do we do for them? What is the next best therapy? Can we reuse a PARP inhibitor? Can we only reuse PARP inhibitors after a certain amount of time?

Is there a particular test that we should use to see whether patients have retained PARP sensitivity, or whether they have become PARP resistant? All these questions are outstanding in the sense that we don’t yet have a data-driven answer to provide to our patients. Over the course of the next 5 years [at least], I’m sure we’ll get there.

What has been learned about PARP inhibitor resistance?

PARP inhibitor resistance is not a single entity. There are many mechanisms of PARP inhibitor resistance and [there are] increasing papers and publications on additional mechanisms [that arise] over time. The one that most people hear about, and we think about the most is reversion mutations. This is one that’s somewhat easier to assay for using available commercial tests.

Certainly, the idea of PARP inhibitor resistance as the clinical concept or the phenotype of someone no longer responding to a PARP inhibitor is what we mean when we talk about PARP inhibitor resistance. In the laboratory, we really mean those specific mechanisms. What Fiona Simpkins, MD, of the University of Pennsylvania, laboratory has elegantly demonstrated is that ATR inhibitors are one potential avenue to resensitize cells, mouse patient-derived xenograft models, and maybe even patients with high-grade serous ovarian cancers, to a PARP inhibitor and therefore introduce the option or possibility of another therapeutic approach––that therapeutic approach being a combination of a PARP inhibitor and an ATR inhibitor.

How did the phase 2 CAPRI trial aim to take Dr Simpkins’ work to the next stage of development?

The study that we presented at the 2021 ASCO Annual Meeting was a small 13 patient, single-arm study looking at the combination of ceralasertib and olaparib. Patients all had platinum- sensitive disease, and they had all received a prior PARP inhibitor. Patients could have received the PARP inhibitor in the up-front maintenance setting, in the platinum-sensitive recurrent setting, or in the treatment setting, but they all had to have received a benefit from the PARP inhibitor. We defined [benefit] differently for each of those categories, but each patient must have received a benefit from the PARP inhibitor and then experienced progression on treatment or in that short interval afterwards, so it’s this very specific detailed patient population. Most of the patients progressed while on the PARP inhibitor.

We studied in this patient population the combination of ceralasertib and PARP inhibitor, and in this way, we took Dr Simpkins’ laboratory data and translated it into a study in the clinical setting to establish the ORR and the tolerability of this regimen.

What did you find intriguing about the results?

The ORR was 46%; this consisted of 6 partial responses, and we found that it was a well-tolerated regimen. Although we did see a 31% rate of grade 3 or grade 4 toxicities and 4 dose reductions, no patient had to come off therapy because of toxicity. The 46% response rate is intriguing. We saw responses in patients who received a PARP inhibitor as part of maintenance, and we saw responses in patients who received a PARP inhibitor as part of their treatment. There doesn’t seem to be a distinction there. That 46% response rate [came from] a heterogeneous group of patients within our very narrowly defined population of patients who are platinum sensitive and received a prior PARP inhibitor and progressed with that prior PARP inhibitor.

We saw excellent tolerability with no patients having to come off therapy because of toxicity and a quite remarkable 46% ORR, which supports the preclinical data that Dr. Simpkins’ laboratory developed.

What are the key takeaways from this study?

We always must consider the tolerability of a regimen. When we start to combine therapies, for instance, a PARP inhibitor and an ATR inhibitor, the first thing we all worry about is the tolerability of that regimen.

The take-away message in this case is that the excellent tolerability and the excellent response rate [of the combination] lend themselves to the need for further research.

Are there any next steps planned for further research?

We are in the process of working to expand the trial and to set up a comparative trial. The intent is that we will continue to study this regimen, adding a greater number of patients and being able to better quantify the benefits and tolerability [of the regimen] and compare it with the standard of care.

Reference

1. Wethington SL, Shah PD, Martin LP, et al. Combination of PARP and ATR inhibitors (olaparib and ceralasertib) shows clinical activity in acquired PARP inhibitor-resistant recurrent ovarian cancer. J Clin Oncol. 2021;39(suppl 15):5516. doi:10.1200/JCO.2021.39.15_suppl.5516