Adavosertib alone, in combination with olaparib effective in ovarian cancer subset
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Adavosertib alone and in combination with olaparib demonstrated efficacy among women with poly(ADP-ribose) polymerase (PARP) inhibitor-resistant ovarian cancer, according to study results presented during the virtual ASCO Annual Meeting.
Grade 3 to grade 4 treatment-associated adverse events were common among both groups but usually manageable with supportive care, dose interruptions and/or dose reductions, researchers noted.
“PARP inhibitors broadly entered the ovarian cancer clinical domain following the publication of the seminal phase 1 study by Fong and colleagues in 2009 in The New England Journal of Medicine. Subsequent refinement of both biomarkers and target patient population have dramatically altered not only the cache of active ovarian cancer agents but also the treatment paradigm — affecting both the recurrent and primary disease settings,” Robert L. Coleman, MD, FACOG, FACS, oncologist with Texas Oncology, told Healio. “Currently, PARP inhibitors are approved as single agents for all patients responding to induction chemotherapy as well as in combination with bevacizumab [Avastin, Genentech] in patients whose tumors are homologous recombination deficient as determined by a validated test. Given the prolific expansion of these agents in treatment, it was anticipated that a significant number of women would have prior exposure to PARP inhibitors at some point in their treatment journey, prompting several questions as to further utility. Initial work clearly demonstrated that if homologous recombination-deficient tumors developed proficiency through somatic alteration, PARP inhibitors were not clinically active. However, other agents involved in DNA damage response might provide a ‘work around’ under these induced conditions.”
The use of PARP inhibition is increasing in ovarian cancer and most of these patients will receive a PARP inhibitor at some point during their cancer therapy, whether that be in the front-line setting, as second-line maintenance or as a treatment strategy in recurrence, Shannon N. Westin, MD, MPH, FACOG, oncologist in the department of gynecologic oncology and reproductive medicine in the division of surgery at The University of Texas MD Anderson Cancer Center, said during her presentation
“With the increased use of PARP inhibitors, we are seeing increased incidence of resistance to PARP inhibitors, and this can occur through multiple mechanisms, such as restoration of homologous recombination activity, either directly through BRCA reversion mutations or indirectly through increased oncogenic signaling, among others," she said. "We also have preclinical data to indicate that the Wee1 inhibitor adavosertib [AZD1775, AstraZeneca] has the potential to synergize with PARP inhibitors, which is what led to the current study.”
The randomized, noncomparative, phase 2 EFFORT study assessed the objective response rate of adavosertib alone and in combination with olaparib (Lynparza; AstraZeneca, Merck) among 80 women (median age, 60 years; 78% white) with recurrent ovarian cancer who experienced documented progression after PARP inhibitor therapy. The women received a median four (range, 1-11) lines of prior therapies; 48% had germline or somatic BRCA mutations, 64% had platinum-resistant disease and 98% had high-grade serous histology.
“We also explored the overall safety and tolerability and response duration of these agents, as well as the disease control rate, PFS and OS, and we assessed treatment efficacy based upon BRCA status,” Westin said.
Researchers assigned the women, all of whom had measurable disease and adequate end organ function, to 21-day cycles of either 300 mg oral adavosertib daily on days 1 to 5 and 8 to 12 (n = 39) or 150 mg oral adavosertib twice daily on days 1 to 3 and days 8 to 10 plus 200 mg oral olaparib twice daily on days 1 to 21 (n = 41). Thirty-five women were evaluable in each group.
Results showed an ORR of 23% (95% CI, 12-38) and median duration of response of 5.5 months (95% CI, 2.8-not reached) in the adavosertib-alone group, and an ORR of 29% (95% CI, 16-44) and median response duration of 6.4 months (95% CI, 2.8-14.6) in the adavosertib-olaparib group.
The combination group had a higher clinical benefit rate (89%; 95% CI, 76-96 vs. 63%; 95% CI, 48-76) and longer median PFS (6.8 months; 90% CI, 4.3-8.3 vs. 5.5 months; 90% CI, 3.9-6.9) than the monotherapy group.
Among women with BRCA mutations, researchers observed an ORR of 20% with adavosertib monotherapy (n = 15) vs. 19% with the combination (n = 16), a median duration of response of 5.6 months vs. 6.4 months and a clinical benefit rate of 67% vs. 81%.
“In the BRCA wild-type group, we saw an interesting signal,” Westin said. “Response rates were higher in this group of patients, although we were not powered to look at this analysis.”
Patients with BRCA wild-type disease had an ORR of 31% with adavosertib alone (n = 16) vs. 39% with the combination (n = 18), a median duration of response of 4.1 months vs. 8.7 months and a clinical benefit rate of 69% vs. 94%. (95% CI, 2.8-not reached).
“The median clinical duration of benefit was quite high in the combination group, at 8.4 months,” Westin said.
Rates of adverse events appeared high among both groups; however, patients still achieved great clinical benefit, Westin added.
The majority (97%) of women in the adavosertib monotherapy group experienced at least one treatment-related adverse event, with treatment discontinuation by two patients (5%), dose reductions for 21 patients (54%) and dose interruptions for 28 patients (72%). Common grade 3 adverse events included neutropenia (8%), diarrhea (8%) and thrombocytopenia (3%).
All women in the combination group experienced at least one treatment-related adverse event, with treatment discontinuation by four patients (10%), dose reductions for 23 patients (56%) and dose interruptions for 35 patients (85%). Common grade 3 adverse events included diarrhea (12%), anemia (10%) and thrombocytopenia (10%).
“Toxicity of the combination was notably higher requiring more dose modifications and dose delays. However, the objective response rates were notable in this setting and provide strong momentum for further development,” Coleman said.
Overall, adavosertib alone and in combination with olaparib demonstrated efficacy for patients with PARP inhibitor-resistant ovarian cancer irrespective of BRCA status, although researchers are starting to see a trend among patients with wild-type BRCA, according to Westin.
“The one thing that is missing is that most of these patients did not have homologous recombination deficiency testing as part of their clinical strategy,” she added. “We are now performing this testing on the tissues that we obtained to understand how homologous recombination deficiency might factor into response to therapy.”
Westin said additional data indicate sequential administration of PARP inhibitors may aggregate toxicity and still retain efficacy.
“We are eagerly awaiting results from an analysis by Yap and colleagues looking at sequential administration of adavosertib in combination with olaparib to determine if this is safer and effective,” Westin said.
References:
- Fong PC, et al. N Eng J Med. 2009;doi:10.1056/NEJMoa0900212.
- Westin SN, et al. Abstract 5505. Presented at: Presented at: ASCO Annual Meeting (virtual meeting); June 4-8, 2021.
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Westin SN, et al. Abstract 5505. Presented at: Presented at: ASCO Annual Meeting (virtual meeting); June 4-8, 2021.
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