The EFFORT needed to overcome PARP resistance in ovarian cancer

Adavosertib with or without olaparib demonstrated clinical activity with a manageable toxicity profile in patients with PARPi-resistant ovarian cancer, regardless of BRCA status. Medicom’s journalist speaks with Dr. Shannon Neville Westin (Dept. Gynecologic Oncology and Reproductive Medicine, the University of Texas, MD Anderson Center) about the new phase 2 study, which was presented at the American Society of Clinical Oncology (ASCO) Annual Meeting, held virtually 4-10 June, 2021 [1].

The phase 2 EFFORT study (EFFicacy Of adavosertib in parp ResisTance: A randomized two-arm non-comparative phase 2 study of adavosertib with or without olaparib in women with PARP-resistant ovarian cancer; Clinical trial information: NCT03579316) examines the efficacy of adavosertib, with or without olaparib, in overcoming PARP resistance in women with ovarian cancer, and how BRCA mutation status might impact the response to therapy in this trial.

Pharmacological inhibitors of the enzyme poly ADP ribose polymerase (PARPi), induce irreparable DNA damage, leading to cell death, yet resistance to PARPi remains a clinical challenge. In a complementary pathway, the Wee1 kinase phosphorylates and inhibits cyclin-dependent kinases 1 and 2 and is involved in regulation of the intra-S and G2/M cell cycle checkpoint arrest for premitotic DNA repair. Inhibiting Wee1 activity with adavosertib can enhance cell death in PARPi-resistance either alone and in combination with olaparib in preclinical models. EFFORT examines benefit of this approach in ovarian cancer patients with progressive disease taking a PARPi.

All patients enrolled (n=80) either received adavosertib (300mg on days 1-5 and 8-12 of a 21-day cycle; n=39), or adavosertib in combination with olaparib (adavosertib 150mg twice daily on days 1-3 and 8-10; olaparib 200mg twice daily on days 1-21 per 21-day cycle; n=41). The median age was 60 years (range 36-76), most had platinum-resistant disease (64%), the median of prior therapies was 4 (range 1-11), and 48% had germline or somatic BRCA mutations. The primary endpoint was objective response (ORR) per RECIST 1.1 and was assessed every 2 cycles.

The initial efficacy results were positive. The ORR was 23% (90% CI 12-38) in the adavosertib monotherapy arm, and 29% (90% CI 16-44). The duration of response was 5.5 months (95% CI 12-38) for adavosertib alone, and 6.4 months (95% CI 2.8-14.6) in the adavosertib + olaparib arm. Clinical benefit (defined as proportion of pts with objective response or stable disease) was determined in 63% patients taking adavosertinib alone, and in 89% of those taking the combination regimen. The median progression-free survival was 5.5 months in the monotherapy arm, and 6.9 months with the combination treatment.

Although deemed manageable with supportive care, most patients in both monotherapy as well as combination arms required at least one dose interruption (72% vs 88%, respectively), required dose reduction (51% vs 71%), and 10% in the combination arm did not restart due to toxicity. The most commonly reported toxicities from adavosertib monotherapy were neutropenia (13%), thrombocytopenia (10%), and diarrhea (8%).  The combination arm had more toxicities, most commonly thrombocytopenia (20%), neutropenia (15%), diarrhea (12%), fatigue (12%), and anemia (10%).

Medicom interviewed Dr. Westin, about the implications of these data.

What is the unmet need that you are trying to address here in the patient population?

“We are seeing a large number of patients with ovarian cancer will be treated with PARP inhibitors, and that can happen really at any time now along their treatment continuum. Anywhere from frontline maintenance, to treatment of recurrence, more and more patients are developing resistance to PARP inhibitors. And so this is a huge unmet need where we need to be able to overcome this resistance, so patients can continue to get great outcomes.”

What was the rationale behind adding a Wee1 inhibitor in the EFFORT?

“One of the mechanisms of resistance to PARP inhibition can occur through the cell cycle and essentially in tumors that have P53 mutations, which is arguably almost every high-grade ovarian cancer. The cancer cells become very dependent on the checkpoint that is regulated by Wee1. The rationale is, if you can block Wee1, and they already are completely dependent on that checkpoint to be able to fix their DNA damage, you can kill the cell. The proof of concept was clearly convincing in preclinical studies of synthetic lethality. It is a kind of a neat way to hit the cell in two places and hopefully kill the cells.

The cancer cells go into mitotic catastrophe because they cannot fix that damage. The cells  need that the cell cycle checkpoint to stop the cell when it is going awry, give it the time to fix its problems. But if those cell cycle checkpoints are not there, the cell just spirals out of control.”

EFFORT

“In EFFORT, the patients were heavily pre-treated, with a median of 4 lines of prior therapy, although some had as many as 11 lines. So this was a population of women that had documented resistance to PARP inhibitors. Probably the majority of those women had benefit from a PARP inhibitor initially, but later progressed, although there were a proportion of women who had immediate progression while on a PARPi.

Please note that this is not a comparative trial. We looked at the Wee1 inhibitor adavosertib on its own and we looked at adavosertib plus the olaparib on its own, and looked at signals. We were also very interested in looking for things that predicted who might respond from the Wee1 inhibitor alone versus who might benefit from the combination. Those are the type of goals that we had with the trial.”

BRCA status matter?

‘’It was a low-hanging fruit to look at the response based on BRCA mutation. Surprisingly, we are starting to see an interesting signal, in fact. Namely, in the patients whose tumours harbor BRCA mutation, either a somatic mutations in the tumor or in their germline DNA, the objective response rates were lower.

The ORR in BRCA-mutant tumors for adavosertib alone was 20%, and in adavosertib with olaparib it was 19%, compared with the 23% and 29% ORRs in the overall cohort, respectively. Now, it is important to note that the clinical benefits still remained very high. For adavosertib alone, a 67% clinical benefit was seen, and 81% of the adavosertib/olaparib arm. Although these patients are clearly getting benefit, we just did not see as the objective response in that population that was quite as high in the population as a whole.

Conversely, that suggests that when we saw higher response rates in the entire group, it was being driven by the patients with wild-type BRCA. When we performed that subanalysis, we saw 31% response rate in adavosertib alone with a 69% clinical benefit. In the combination arm, those numbers climbed to 39% response rate with a 94% clinical benefit. Our preliminary conclusion is that almost every patient with a BRCA wild-type tumor got clinical benefit. This is a signal we are very excited about.”

What are the next steps?

“One thing we have not talked about that I would be remiss if I did not mention is the side effect profile. Adverse events are common on this regimen, on both regimens. 100% of patients had some kind of adverse event, 10% had to discontinue due to toxicity. It is important to note though, that these difficulties can be mitigated and you will see even with patients that required multiple dose holds or multiple dose reductions, we could still keep them on therapy for over 400 or 500 days. We really need to build a strategy to actively manage patients’ side effects.

Accordingly, there are a couple of things that are kind of ongoing right now to move this forward. One is there is an ongoing trial that is looking at sequential dosing of the 2 drugs, instead of giving both at the same time. We do have preclinical data to indicate that that is just as efficacious and has lot less toxicity. We are eagerly anticipating that trial to read out soon. I think that if sequential treatment improves the toxicity profile, that may be a way to move this combination forward in ovarian cancer. I think  the other main thing point we need to address is doing the bigger study to really tease out who needs the Wee1 inhibitor alone, and who benefits from the combination approach, so we can figure out the best treatment for the right patients. Other factors we hope to still tease out are things like platinum-sensitivity versus platinum-resistance, whether there were other intervening therapies, and how long patients were on their prior PARP inhibitor. It has really been exciting!”

 

1. Westin SN. EFFORT: EFFicacy Of adavosertib in parp ResisTance: A randomized two-arm non-comparative phase II study of adavosertib with or without olaparib in women with PARP-resistant ovarian cancer. J Clin Oncol. 2021;39(suppl 15):5505. 10.1200/JCO.2021.39.15_suppl.5505

 

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Posted on 6 August 202117 May 2024