Table 2.

Clinical trials utilizing biomarker stratification analysis.

Trial Name	Short Description	Experiment Arms/Cohorts	Biomarker Stratification
KEYNOTE-158	Phase II, two arm, open-label trial investigating pembrolizumab and evaluating predictive biomarkers in subjects with advanced solid tumors	Arm 1: Pembrolizumab 200 mg Arm 2: Participants failed at least one line of therapy and have TMB high.	TMB high
NCT03428802 [133]	Phase II, single-arm, open-label trial studying the use of pembrolizumab in patients with metastatic, recurrent, or locally advanced solid tumors and genomic instability	Arm 1: Pembrolizumab and lab biomarker analysis	Response rate will be stratified by mutation type (POLE and POLD1 versus BRCA1/2) Patient/clinical outcomes will be stratified by PD-L1 expression and presence of PD-1/PDL-1 polymorphisms and presence of immunoregulatory gene mutations (via deep sequencing) Response will be stratified by presence of immunogenic neoantigens (via exome sequencing) and expression of checkpoint genes, immune-regulatory modules, or non-coding RNAs including repetitive RNAs and retroelements (via RNA sequencing)
DUO-O [134]	Phase III, randomized, double-blind, placebo-controlled, multicenter trial studying the use of durvalumab with chemotherapy and bevacizumab followed by maintenance durvalumab, bevacizumab, and olaparib in advanced ovarian cancer	Arm 1: Platinum-based chemotherapy with bevacizumab and durvalumab placebo followed by maintenance bevacizumab, durvalumab placebo, and olaparib placebo Arm 2: Platinum-based chemotherapy with bevacizumab and durvalumab followed by maintenance bevacizumab, durvalumab, and olaparib placebo Arm 3: Platinum-based chemotherapy with bevacizumab and durvalumab followed by maintenance bevacizumab, durvalumab, and olaparib tBRCAm Cohort: Platinum-based chemotherapy with bevacizumab and durvalumab followed by maintenance bevacizumab, durvalumab, and olaparib (bevacizumab is optional)	Somatic BRCA mutation status
V3-OVA [135]	Phase II, single-arm, open-label trial studying the use of vaccine V3-OVA in ovarian cancer	Arm 1: V3-OVA vaccine (containing ovarian cancer antigens)	Secondary outcomes will assess the effect on level of serum tumor markers compared to baseline (including CA-125)
AdORN [136]	Phase I/II, single-arm, open-label trial studying the use of atezolizumab with neoadjuvant chemotherapy in interval cytoreductive surgery in patients with newly diagnosed advanced-stage epithelial ovarian cancer	Arm 1: Atezolizumab, carboplatin, and paclitaxel (and optional bevacizumab)	PFS will be stratified based on the expression of PD-L1, tumor-infiltrating lymphocytes, immune checkpoint receptors, and cytokines and gene expression profiles Each of those subsets will be further stratified by BRCA mutation status and tumor mutation profile
OLAPem [137]	Phase II, single-arm, open-label trial studying the use of olaparib monotherapy and olaparib and pembrolizumab combination therapy in ovarian cancer	Arm 1, Cohort 1: Olaparib before surgery Arm 1, Cohort 2: Olaparib and pembrolizumab before surgery	Therapeutic effect will be stratified by biomarkers (germline mutations), change in tumor-infiltrating lymphocytes, and tumor mutation burden
NCT02983799 [138]	Phase II, non-randomized, open-label trial studying the use of olaparib in patients with platinum-sensitive, relapsed, high-grade serous or high-grade endometrioid epithelial ovarian, fallopian tube, or primary peritoneal cancer that have different HRD tumor status and have received at least 1 prior line of chemotherapy	Arm 1: Germline BRCAm given olaparib Arm 2: Somatic BRCAm and germline BRCAwt given olaparib Arm 3: myChoice® HRD positive and BRCAwt given olaparib Arm 4: myChoice® HRD negative and BRCAwt given olaparib	Experimental arms stratified by HRD and BRCA mutation status Objective response rate will be stratified by HRD status as per HRRm gene panel assessment in BRCAwt cohorts 3 and 4
BOLD [139]	Phase II, single-arm, open label trial studying the use of bevacizumab, olaparib, and durvalumab in patients with relapsed advanced epithelial ovarian cancer	Arm 1: Bevacizumab, olaparib, and durvalumab combination	Response to treatment (evaluated by immune-related response criteria) will be stratified by tumor mutation burden, homologous repair status, and tumor immune infiltrate and immune check point status (PD-1/PDL-1 driven versus other immune check points involved).
AMBITION [140,141]	Phase II, randomized, multicenter, open label trial for HRD+ patients and a biomarker-driven multiple-arm phase II trial for HRD- patients studying the use of various combination therapies in the treatment of platinum-sensitive recurrent ovarian cancer	Arm 1: Olaparib plus cediranib Arm 2: Durvalumab plus olaparib Arm 3: Durvalumab plus chemotherapy (paclitaxel, topotecan, or pegylated liposomal doxorubicin) Arm 4: Durvalumab plus tremelimumab and chemotherapy (paclitaxel, topotecan, or pegylated liposomal doxorubicin) Arm 5: Durvalumab plus tremelimumab and paclitaxel	Patients HRD and PD-L1 status and presence of biomarkers will be evaluated and used to allocate treatment arms HRD+ patients will be randomly allocated to Arm 1 or 2 HRD- patients will be allocated to Arm 3 or 4 based on PD-L1 expression (allocation to Arm 3 if high PD-L1 expression and to Arm 4 if low PD-L expression)

These ongoing phase I/II/III trials have shown evidence of increased response in ovarian cancer patients treated with immunotherapy, often in combination with other therapies. Additional studies investigating biomarkers correlated with increased and decreased response are critical. There is great therapeutic potential in the use of immunotherapy in ovarian cancer, and there appears to be patients that do respond; however, more research needs to be done before we can understand its full potential.