Kristen R. Ibanez

Combination Therapy Approach to Overcome the Resistance to PI3K Pathway Inhibitors in Gynecological Cancers

The PI3K signaling pathway plays an essential role in cancer cell proliferation and survival. PI3K pathway inhibitors are now FDA-approved as a single agent treatment or in combination for solid tumors such as renal cell carcinoma or breast cancer. However, despite the high prevalence of PI3K pathway alterations in gynecological cancers and promising preclinical activity in endometrial and ovarian cancer models, PI3K pathway inhibitors showed limited clinical activity in gynecological cancers. In this review, we provide an overview on resistance mechanisms against PI3K pathway inhibitors that limit their use in gynecological malignancies, including genetic alterations that reactivate the PI3K pathway such as PIK3CA mutations and PTEN loss, compensatory signaling pathway activation, and feedback loops causing the reactivation of the PI3K signaling pathway. We also discuss the successes and limitations of recent clinical trials aiming to address such resistance mechanisms through combination therapies.

The CHK1 inhibitor prexasertib in BRCA wild-type platinum-resistant recurrent high-grade serous ovarian carcinoma: a phase 2 trial

Abstract The multi-cohort phase 2 trial NCT02203513 was designed to evaluate the clinical activity of the CHK1 inhibitor (CHK1i) prexasertib in patients with breast or ovarian cancer. Here we report the activity of CHK1i in platinum-resistant high-grade serous ovarian carcinoma (HGSOC) with measurable and biopsiable disease (cohort 5), or without biopsiable disease (cohort 6). The primary endpoint was objective response rate (ORR). Secondary outcomes were safety and progression-free survival (PFS). 49 heavily pretreated patients were enrolled (24 in cohort 5, 25 in cohort 6). Among the 39 RECISTv1.1-evaluable patients, ORR was 33.3% in cohort 5 and 28.6% in cohort 6. Primary endpoint was not evaluable due to early stop of the trial. The median PFS was 4 months in cohort 5 and 6 months in cohort 6. Toxicity was manageable. Translational research was an exploratory endpoint. Potential biomarkers were investigated using pre-treatment fresh biopsies and serial blood samples. Transcriptomic analysis revealed high levels of DNA replication-related genes (POLA1, POLE, GINS3) associated with lack of clinical benefit [defined post-hoc as PFS < 6 months]. Subsequent preclinical experiments demonstrated significant cytotoxicity of POLA1 silencing in combination with CHK1i in platinum-resistant HGSOC cell line models. Therefore, POLA1 expression may be predictive for CHK1i resistance, and the concurrent POLA1 inhibition may improve the efficacy of CHK1i monotherapy in this hard-to-treat population, deserving further investigation.

Impact of Global Enrollment on Race, Ethnicity, and Age Representation in Pivotal Gynecologic Cancer Trials Leading to US Food and Drug Administration Drug Approvals

PURPOSE To evaluate the impact of international enrollment in landmark gynecologic cancer (Gyn-Ca) trials that supported the US Food and Drug Administration (FDA) drug approvals. METHODS We examined the FDA drug approval database for approved Gyn-Ca agents between January 2014 and June 2024. We then extracted clinical trial identifiers supporting these approvals using FDA safety labels. Expected enrollment was calculated using gynecologic disease site incidence data from the US Cancer Statistics Program and compared with actual trial enrollment reported on ClinicalTrials.gov. RESULTS From 2014 to 2024, 30 Gyn-Ca trials supporting 28 FDA approvals were conducted in US/international (86.7%), international-only (10%), and US-only sites (3.3%) and enrolled 15,294 patients, with 14,053 remaining (74.0% White, 4.1% Black, 12.7% Asian, 8.7% other) after screening for trials not reporting race. Black (–11.0%; P < .0001), Hispanic/Latino (–3.5%; P < .0001), and elderly (–12.6%; P < .0001) participants were under-represented, whereas Asians (+6.8%; P < .0001) were over-represented. Asian (18.3% v 3.5% in trials with or without East Asian sites; odds ratio [OR], 6.19 [95% CI, 5.29 to 7.25]; P < .0001) and Hispanic/Latino (18.6% v 4.6% in trials with or without South American sites; OR, 4.75 [95% CI, 4.00 to 5.63]; P < .0001) enrollment was higher in trials that included East Asian and South American sites, respectively. Black enrollment did not improve despite trials including recruitment in Africa (3.2% v 4.1% Black enrollment in trials with or without African sites; OR, 0.83 [95% CI, 0.38 to 1.83]; P = .53). CONCLUSION Black, Hispanic/Latino, and elderly patients were under-represented in pivotal Gyn-Ca trials, whereas Asian patients were over-represented, compared with expected enrollment proportions. Postmarketing studies on under-represented groups should be considered to assess drug efficacy and safety in these populations.