Shannon Westin, MD, MPH, discusses the key takeaways from the EFFORT trial, future research directions with adavosertib, and the characteristics of PARP inhibitor resistance in patients with ovarian cancer.
The Wee1 inhibitor adavosertib, either alone or in combination with the PARP inhibitor olaparib (Lynparza), demonstrated promising efficacy in patients with PARP inhibitor–resistant ovarian cancer, according to Shannon Westin, MD, MPH, who added that additional efforts are underway to make the approach more tolerable in this population.
Results from the phase 2 EFFORT trial (NCT03579316), which were presented during the 2021 ASCO Annual Meeting, showed that adavosertib monotherapy induced an overall response rate (ORR) of 23% (95% CI, 12%-38%) and a clinical benefit rate (CBR) of 63% (95% CI, 48%-76%). When the agent was paired with olaparib, it resulted in an ORR of 29% (95% CI, 14%-44%) and a CBR of 89% (95% CI, 76%-96%). Notably, the benefits achieved with these approaches were observed, irrespective of BRCA mutational status.
However, although toxicities reported with these agents, such as diarrhea, neutropenia, and thrombocytopenia, were determined to be manageable with supportive treatment, dose reductions and interruptions may be necessary for certain patients.
“[Although these data are] very exciting, we want to ensure that we [make this approach] as tolerable as possible [for our patients],” Westin said. “To this end, we have an ongoing study that is examining the sequential dosing of adavosertib and olaparib to see whether…[it will result in] less toxicity and make it easier for our patients to tolerate.”
In an interview with OncLive®,Westin, an associate professor in the Department of Gynecologic Oncology and Reproductive Medicine, Division of Surgery, at The University of Texas MD Anderson Cancer Center, discussed the key takeaways from the EFFORT trial, future research direction with adavosertib, and the characteristics of PARP inhibitor resistance in patients with ovarian cancer.
Westin: Now that PARP inhibitors are accepted in almost every piece of the ovarian cancer journey—up-front maintenance, second-line maintenance, and even treatment—we are seeing more and more people [receiving treatment with] PARP inhibitors. With that, we are also seeing more resistance to [these agents]. There are several different mechanisms of PARP resistance, and one area we are still struggling with is how to know what patient has which mechanism of resistance, and what [is needed] to target that. Right now, we are trying to tackle common mechanisms of resistance, or common pathways that may be involved [in this process].
One pathway that we have seen is involved is the cell cycle. Specifically, when we treat patients with PARP [inhibitors], we can see upregulation of different cell-cycle regulators, indicating that the tumor is becoming dependent on them. As such, in the EFFORT study, we [set out to] target a specific regulator of the cell cycle, Wee1, and the drug that does that is adavosertib. What is interesting about this study is that, not only did we explore adavosertib on its own, but we also combined it with [another] PARP [inhibitor] to see whether that would help to overcome PARP resistance in this population.
Some early phase 1 and 2 data demonstrate that adavosertib appears to have activity. What we were not sure about, however, [what] the best potential population [is to receive this drug]. Several ongoing studies are looking for predictors of response to adavosertib and utilizing molecular factors [to figure this out]. However, we thought it might be worthwhile to explore [the agent] specifically in a PARP-resistant population.
Furthermore, [we know that] Wee1 acts along the cell cycle. p53 is involved in that same cell cycle, and high-grade serous ovarian cancer has a high proportion of these mutations. When [those mutations occur], the cell becomes extremely dependent on the G2-M [DNA damage] checkpoint, which is what Wee1 regulates. As such, [with Wee inhibition,] we are hitting the cancer cell in a couple of different ways. We are tackling this potential mechanism of PARP resistance, and we are tackling a potential area of injury to the cell already with that p53 mutation. We were hoping that a 2-hit [strategy] would lead to better outcomes for our patients.
The study was [comprised of] 2 parallel arms. [Although this] was a randomized study, the arms were not comparative. [Patients] either [received] adavosertib alone, or adavosertib plus the PARP inhibitor olaparib.
This was an open study [in the sense that] patients could have any recurrent ovarian, fallopian tube, or peritoneal cancer. We did not restrict [enrollment] based on histology or BRCA status. Patients [were also able to] have [received] unlimited prior therapies. The only real [eligibility] requirement was that they must have had progressive disease on a single-agent PARP inhibitor, and they could not have come off of that agent because of toxicity; it needed to be [because of] progressive disease. That PARP inhibitor could have been given for maintenance or for treatment; no selection was based on that.
The primary end point [of the trial] was to look at the efficacy in both arms. Again, we were not comparing [the efficacy in these arms], we were just reporting the data for adavosertib alone and the combination.
Overall, yes; the population was very representative of our general patient population with ovarian cancer. We had many patients with high-grade serous [disease]. The median prior lines of therapy was 4, so this was a heavily pretreated group. The bulk of the patients had platinum-resistant disease, which is of course a worse population for outcomes. Most patients did have some benefit from their prior PARP inhibitor—either they had reduction of disease or stable disease, and were able to stay on it for a significant amount of time. This is a good population and is very reflective of the population we see that is developing PARP resistance.
We saw activity in both arms of the trial. With adavosertib alone, the ORR was 23% and the CBR, which included not just objective response, but also those who were able to achieve stable disease for more than 4 months, was 63%. Thus, this [approach] was very active [as a monotherapy]. The adavosertib/olaparib arm also demonstrated activity. Here, the ORR was 29% and the CBR was 89%. [Thus, these data showed that] most patients derived benefit from these regimens.
We were also interested to see whether the response [to treatment] could be predicted, whether it was associated with the presence of a BRCA mutation, or whether better activity [would be observed] in tumors that were BRCA wild-type. Interestingly, we found that patients who had BRCA mutations seemed [to have] lower levels of response; [the ORRs were] 20% in the adavosertib-alone arm and 19% in adavosertib/olaparib arm. The [CBRs in this subgroup] were similar to [those seen in the] group as a whole, at 67% with adavosertib alone and 81% with the combination.
Interestingly, however, for the BRCA wild-type subgroup, we saw higher levels of response, with [an ORR of] 31% in the adavosertib-alone arm and a [CBR of] 69%; with the combination, the ORR was 39% with a CBR of 94%. [Those are] exciting numbers, [although] we always have to be careful because the samples are getting smaller. Regardless, [we] definitely [saw] a hint that there is something going on here.
One thing we were missing, that we are obtaining now, is the homologous recombination deficiency [HRD] status of these patients. [This information will help us tease out whether] that clinical benefit in the wild-type group is driven by an HRD tumor, or whether it is in a truly wild-type tumor that we are seeing activity. [We are] very excited to generate those data so we can understand this a little bit more.
Adavosertib alone, and in combination with the PARP inhibitor, [has shown] impressive activity. There are a few things that we want to tease out. First, we want to [really understand] who is benefiting [from these approaches]. To this end, we are doing a deep [molecular] dive [into these data], and we are starting with the low hanging fruit of looking at HRD. Then, we want to expand that [exploration] to other potential markers of response and resistance to therapy. This effort is being made as we speak, and we are excited about where that [research] might lead us.
The other thing that is important to note, is that there are toxicities with these agents. As such, we really do need to explore different dosing strategies. Adavosertib alone is tolerable, although [we know that there] are several AEs [with this agent]. Ninety-seven percent [of patients on the trial experienced] a treatment-related AE, but only 5% required discontinuation because of toxicity. The AEs that we see very commonly with this drug [as a monotherapy] include nausea, vomiting, fatigue, diarrhea, and bone marrow issues. [These are] standard toxicities that can be mitigated but we need to prepare for.
The combination is a little trickier. Most patients are able to stay on the [regimen], but 56% of patients needed a dose reduction, 85% had to have a dose interruption, and 10% discontinued [treatment] due to AEs. Similar types of AEs [were reported with the doublet] in that [patients experienced] gastrointestinal, fatigue, and bone marrow issues.
[To make these approaches easier to receive, we are] figuring out whether sequential administration is better tolerated. After this, we will move forward to tease out who needs the single agent and who needs the combination.
Similar to what we have seen with other combination strategies, it is important to engage the patient, your pharmacist, and your nursing staff to ensure that everyone is aware of the potential AEs, as well as set expectations to make sure patients know. We may start on 1 dose, but there may be a need to hold, and to reduce as needed to make this tolerable. That would be the major thing. As far as where this is going, scientifically, this is very exciting. Clinically, we are seeing the benefit we need, but it is not quite ready for primetime. We need to do a little bit more study before it is going to be in the hands of clinicians in practice.