Early Success With Olaparib Plus Selumetinib Leads to Further Exploration in RAS-mutated Gynecologic Cancers

Shannon N. Westin, MD, MPH, FACOG

The degree of clinical benefit observed with olaparib (Lynparza) plus selumetinib (Koselugo) in patients with RAS-mutated endometrial and ovarian cancers has inspired further efforts to determine whether the PARP/MEK inhibitor combination has superior antitumor activity to that achieved with single agents alone, according to Shannon N. Westin, MD, MPH, FACOG.¹

Previously reported data from the dose-escalation portion of the phase 1b SOLAR trial (NCT05554328) showed that when olaparib was given at 300 mg and selumetinib was administered at 75 mg, the doublet was well tolerated in patients with RAS-mutated solid tumors.² The regimen also had preliminary antitumor activity in this patient population.

Atthe 2023 Society of Gynecologic Oncology (SGO) Annual Meeting on Women’s Cancer,results from the dose-expansion portion of the trial indicated that the combination had a clinical benefit rate (CBR) of 69% and a partial response (PR) rate of 32% in patients with RAS-aberrant ovarian cancer (n = 19).1 In those with RAS-aberrant endometrial cancer (n = 17), the CBR and PR rates were 59% and 35%, respectively. No new safety signals were observed.

These findings supported the launch of the phase 2 ComboMATCH trial (NCT05554328), which will further evaluate olaparib plus selumetinib or selumetinib alone in patients with RAS-mutant, recurrent or persistent ovarian and endometrial cancers 3 The study is currently enrolling.

“[Although] it’s still early, this [trial] is certainly one of the successes where preclinical data led to an important clinical outcome [for] our patients,” said Westin, who is the director of the Early Drug Development and Phase I Trials Department, and a professor in the Department of Gynecologic Oncology and Reproductive Medicine of the Division of Surgery, at The University of Texas MD Anderson Cancer Center, in Houston, Texas. “I’m hopeful that our colleagues will open the ComboMATCH study and put patients on this [regimen…This effort] will help us determine the contribution of [each] component, [and hopefully confirm our] expectation that the combination is better than the single agents. [We hope that] the trial will answer [these] questions a little more fully and get these drugs to our patients.”

In an interview with OncLive®, Westin shared preclinical data that provided the impetus for the SOLAR trial of olaparib and selumetinib in patients with RAS-mutated gynecologic cancers, shared key findings from the dose-escalation and -expansion portions of the research, and shared next steps with the combination.

OncLive®: Could you provide some background on the phase 1b dose-expansion trial of olaparib and selumetinib?What inspired this research?

Westin: RAS mutations and aberrations are common across multiple solid tumors, but especially in gynecologic cancers. When we look at endometrial cancer, we see upwards of 30% of patients with RAS abnormalities. In ovarian cancer, specifically low-grade serous ovarian cancer, [the incidence] can be up to 50% or 60%. [This indicates that] it’s a worthwhile target [for exploration]. However, [attempts to] target [these abnormalities] with single agents have not been that great. It has been OK, but there is always room for improvement.

We [conducted] a [previous] study that was looking at PARP inhibitors in combination with a PI3K inhibitor in ovarian and endometrial cancer. We found the most interesting thing: the presence of a RAS mutation or abnormality was associated with resistance to that combination. We were intrigued, and [wanted to know whether] we could overcome resistance by using a combination. We then did some in vitro and in vivo work, which confirmed that RAS seemed to drive PARP resistance, and that the combination of the two [agents, olaparib and selumetinib,] was synergistic over either one alone. That made us excited to [investigate the regimen] in a clinical trial.

What data from the dose-escalation portion of this trial have been previously reported?

The drugs we were using were selumetinib and olaparib. Selumetinib is a MEK inhibitor, and olaparib is a PARP inhibitor. We were able to combine them safely at the highest dose level, which was the maximum tolerated dose of each drug. The good news is [that] we saw no dose-limiting toxicities. We did see toxicities, but they were as expected for both drugs. [Adverse effects (AEs) included] fatigue, rash, and bone marrow abnormalities, but they were all low grade. Only a small proportion [of patients had] high-grade toxicities, and they were all [easily] mitigated [using] normal strategies. In addition, we saw a hint of activity [with the combination] in that early [portion of the] trial. [The regimen elicited] about a 17% response rate, with responders seen in lung cancer and ovarian cancer. That was exciting as we moved forward into the next phase.

What efficacy findings from the dose-expansion were presented at the 2023 SGO Annual Meeting?

[In the phase 1b dose-expansion], we looked at 4 different expansion groups: RAS-mutant endometrial cancer, RAS-mutant ovarian cancer, RAS-mutant solid tumors, and patients with ovarian cancer who had resistance to a PARP inhibitor. RAS-mutant [cancers] included several abnormalities in the pathway, [such as] KRAS, NRAS, HRAS, and BRAF. In each cohort, we saw varying degrees of efficacy with the [regimen].

The most exciting data [was seen] in RAS-mutant ovarian and endometrial [cancers]. The [PR] rate for RAS-mutant ovarian cancer was 32% in the [total] group. When we [looked at] the group with low-grade serous ovarian cancer, [the PR rate] was 44%. We were really excited about those numbers because [they] seem to be above what we would expect with MEK [inhibitors] alone, although you must [be] cautious not to [make a] cross-trial comparison. In endometrial [cancer,] we also saw a high [PR rate] of 35%. Importantly, about 60% of those patients actually [experienced] clinical benefit. The duration of response [for both endometrial and ovarian] was impressive, with patients staying on [treatment] for over a year. That’s exciting because we don’t [typically] see activity like that in these 2 malignancies.

In our all-solid tumor and PARP-resistant cohorts, [the data] were a little less exciting. Activity was still seen [with the regimen], but it wasn’t as profound as what we saw in the other 2 groups. We did see an 8% [PR rate] for patients with all solid tumors. Interestingly, both responders [had] lung cancer. When we looked at the lung cancer group, [42%] of [patients derived] some clinical benefit. Perhaps something there [could be] of interest [for future investigation]. Conversely, in the PARP-resistant group, [there was a] 17% [PR rate]; this is not at all what we were expecting based on our preclinical data. Seventeen percent is about what we would expect with chemotherapy, but [this] was not as impressive as those other 2 cohorts.

Were any new safety signals observed with the regimen?

We had safety data [from] about 88 patients who participated in the expansion [study]. We saw a similar proportion of patients [experience] the same issues [that] we saw in the dose-escalation [phase]. Again, we saw fatigue, rash, diarrhea, abdominal pain, and bone marrow issues. We did specifically look at some severe AEs that can be seen with MEK inhibition or with PARP inhibition. [However, we] saw low rates of creatinine phosphokinase elevation, edema, and cardiac issues like decreased ejection fraction. Only one patient developed myelodysplastic syndrome during the trial. Those were important safety [findings] to note.

What next steps are planned for this research?

I’m really excited because often we present these kinds of data and say [that] we need to verify [them] in a [future] clinical trial, but we have a [confirmatory] clinical trial that is [already] open and enrolling. [It is] the [EAY191-N4 Arm I] of the National Cancer Institute’s ComboMATCH study. This arm [is comprised of] 2 cohorts: a RAS-mutant endometrial cohort and a RAS-mutant ovarian cohort. Both have a single-agent MEK [inhibitor] arm, or a PARP and MEK [inhibitor] arm, and patients are randomized between the 2.

[Additionally,] we’ve done quite a bit of translational work [in this study to] obtain baseline and on-treatment biopsies in the expansion phase. We’ll be doing a deep dive [on] genomics, RNA [expression], and protein [expression] to understand the changes that are occurring in those tumors, and if any of those changes are potentially associated with response or resistance to therapy.

What other research were you most excited to see presented at the meeting?

I’d be remiss if I didn’t say I was [excited about] the data presented on the [phase 3] Ruby [NCT03981796] and GY018 [NCT03914612] studies. These studies are on [the addition] of immune checkpoint inhibitors to chemotherapy in recurrent or advanced endometrial cancer. [I am] hoping to see a big change in the standard of care with those regimens.

I was [also] excited about my own work in the [early phase 1] NOW study [NCT03943173], where we looked at olaparib in a neoadjuvant setting for patients with newly diagnosed advanced stage ovarian cancer. [We] saw that you could utilize 2 cycles of olaparib rather than chemotherapy and get the majority of patients right to surgery. Patients were excited about it, and some of the clinicians [at SGO] were excited about it, too.

Disclosure: Dr Westin reports serving in a consultory or advisory role for AstraZeneca, Bayer, Caris, Clovis Oncology, Eisai, EQRX, GSK, ImmunoGen, Lilly, Merck, Mersana, NGM Bio, Nuvectis, Roche/Genentech, Seagen, Vincerx, Zentalis; she received research funding from AstraZeneca, AvengeBio, Bayer, Clovis Oncology, GSK, Mereo, Novartis, Roche/Genentech, Zentalis.

References

1. Kurnit KC, Meric-Bernstam D, Hess K, et al. Abstract CT020: Phase I dose escalation of olaparib (PARP inhibitor) and selumetinib (MEK Inhibitor) combination in solid tumors with RAS pathway alterations. Cancer Res. 2019;79(suppl 13):CT020. doi:10.1158/1538-7445.AM2019-CT020
2. Westin SN, Kurnit KC, Fellman B, et al. SOLAR: Phase Ib dose expansion of selumetinib (MEK Inhibitor) and OLAparib (PARP Inhibitor) combination in solid tumors with RAS pathway alterations and in PARP inhibitor-resistant ovarian cancer. Presented at: 2023 Annual Meeting on Women’s Cancer; March 25-28, 2023; Tampa, Florida. Abstract 218.