Homologous recombination deficiency in newly diagnosed advanced ovarian cancer across nine Middle East countries: prevalence, real-world testing pathways, and treatment implications

Abstract

Background

With current evidence of homologous recombination deficiency (HRD) emerging as a predictive and prognostic biomarker in high-grade serous/endometrioid ovarian cancers (HGSOC/HGEOC), the HALO study (NCT04991051) evaluated the prevalence of the HRD in patients with HGSOC/HGEOC, primary peritoneal cancer (PPC), and fallopian tube cancer (FTC) across Asia, Middle East and Africa (MEA), and Russia.

Methodology

The MEA subset of this cross-sectional, non-interventional study enrolled patients with newly diagnosed stage III/IV (International Federation of Gynaecology and Obstetrics [FIGO] classification) HGSOC/HGEOC, PPC, FTC during May 2021-Jan 2022 with formalin-fixed paraffin-embedded tumour block(s) collected within 120 days of enrolment. Primary endpoints included prevalence of HRD, genomic instability (GI) excluding tumour BRCA mutations (tBRCAm), and tBRCAm. Logistic regression model predicted the risk factors associated with HRD positivity and tBRCAm.

Results

Of 195 patients (median [range] age, 58.2 [24.0-89.0] years), 88.7% had primary ovarian tumour. The HRD status was analysed in 180 patients; 52.2% (94/180) were HRD positive – 23.9% (43/180) had high GI scores excluding tBRCA1/2m, and 28.3% (51/180) had tBRCAm. More than two-thirds (71.3%) of patients underwent debulking surgery, 45,1% received neoadjuvant and 50.8% received adjuvant therapy. No patients received PARPi therapy. In univariate analysis, nulliparity was associated with lower odds of HRD positivity (odds ratio [OR]: 0.27, p=0.003). Family history (OR: 0.39, p=0.02) and nulliparous women (OR: 0.19, p=0.03) were associated with lower odds of high GI score. Higher odds of tBRCAm were observed in ex-smokers (OR: 6.77, p=0.02), family history (OR: 3.11, p=0.0009), and surgically resected tissue (OR: 2.00, p=0.04); lower odds in patients with FIGO stage IV (OR: 0.26, p=0.004). In multivariate analysis, h/o genetic-related cancer (OR: 3.75, p=0.002), h/o contraceptive use (OR: 5.19, p=0.009) was associated with higher odds of tBRCA1m whereas FIGO stage IV disease (OR: 0.24, p=0.006) had lower odds of tBRCAm.

Conclusion

In the Middle East subset of HALO study, a substantial proportion of patients were HRD positive and had tBRCA1/2m, supporting the clinical relevance of these biomarkers for guiding novel targeted therapies. The study provides real-world evidence of HRD and tBRCA prevalence, informing future research and policy development in precision oncology for the region.

Trial registration

Number-NCT04991051 (Date of Approval-September 2020).

Supplementary Information

The online version contains supplementary material available at 10.1186/s12885-025-15537-3.

Introduction

Ovarian cancer (OC) is a leading cause of gynaecological cancer-related deaths worldwide, with 206,956 fatalities reported in 2022 [1–3]. In the MEA region, 5,930 deaths were recorded with 0.51% cumulative risk in 2022 [4]. High-grade serous ovarian carcinoma (HGSOC) is the frequent histologic type (~ 70%) of OC while primary peritoneal cancer (PPC), and fallopian tube cancer (FTC) account for less than 30% of OCs [5]. The standard treatment regimen for advanced OC includes cytoreductive surgery and platinum-based chemotherapies; bevacizumab is added as a maintenance therapy to increase progression-free survival (PFS) in the high-risk groups. However, recurrence occurs in 70% to 75% of patients with OC, with a 23% 5-year survival rate [6].

The genetic instabilities or BReast CAncer gene 1 (BRCA1) and BRCA2 mutations associated with HGSOCs are important in regulating the homologous recombination repair (HRR) pathway. Genetic alterations in the HRR pathway lead to deoxyribonucleic acid (DNA) double-stranded breaks resulting in homologous recombination deficiency (HRD) [7]. The HRD occurs due to germline and somatic mutations and epigenetic alterations of the genes associated with the HRR pathway [8]. These aberrations can cause genomic instability in the cells in the form of gene scars [7].

Poly (ADP-ribose) polymerase (PARP) inhibitors are efficient as single agents for maintenance therapy in patients with HRR mutations [8]. The PARPi exhibit synthetic lethality by impairing the repair of single-stranded DNA breaks resulting in cell death. The PAOLA-1 trial (2019) demonstrated improved efficacy of the bevacizumab and olaparib combination as maintenance therapy in platinum-responsive high-grade OC with BRCA1/2 mutations and/or HRD [9]. The SOLO1 trial showed clinically improved overall survival (OS) with maintenance olaparib in patients with advanced OC and BRCA mutations [10]. In the VELIA trial, significant improvement in PFS was reported for the veliparib arm compared to the chemotherapy arm in overall cohort along with BRCA-mutated cohort as well as HRD positive cohort [11]. The PRIMA trial showed numerically higher PFS in the niraparib arm compared to the control arm in patients with advanced HGSOC or high-grade endometrioid OC (HGEOC), PPC, or FTC with BRCA mutations irrespective of HRD status [12]. Similarly, rucaparib as first-line maintenance monotherapy demonstrated improved PFS in patients including those without BRCA1/2 mutations or other evidence of HRD (ANTHENA trial) [13].

The Food and Drug Administration (FDA) approved olaparib for the treatment of patients with deleterious or suspected deleterious germline or somatic BRCA-mutated advanced OC who had complete or partial response to first-line platinum-based chemotherapy [14]. The National Comprehensive Cancer Network Guidelines^® (version 1, 2025) recommend olaparib, and niraparib for BRCA-mutated advanced OC, while rucaparib is recommended for advanced OC irrespective of BRCA status, bevacizumab and olaparib for BRCA-mutated and HRD advanced OC and niraparib plus bevacizumab for patients intolerable to olaparib [15].

Nearly 20% to 55% of the women with serous or endometrioid OCs are reported to have HRD [6, 16]. Compared to Western populations, Asian populations, particularly those from Japan and China, may exhibit higher rates of HRD, ranging from 60% to 74% [17, 18]. Real-world access to genomic testing and targeted therapies remains uneven across the Middle East, especially in Egypt, Turkey, Iraq, Jordan, Qatar, Oman, Saudi Arabia, Kuwait, and the UAE [19]. While the prevalence of BRCA1/2 mutations in OC ranges from 17% to 30.7% in the Middle East region [20–23], , up to 50% of HGSOC exhibit HRD, which is associated with improved response to platinum-based chemotherapy and PARPi [24]. A recent study from the MEA region reported HRD positivity in 24% of OC cases and also highlighted a paucity of regional data, likely driven by low testing rates and inconsistent referral practices [20]. There is a significant disparity in the healthcare system across Middle East countries; high-income countries like the United Arab Emirates have better access to advanced healthcare technologies, including genetic testing for HRD, whereas low-income countries such as Yemen face limitations in healthcare resources [25, 26]. Regulatory framework in the Middle East region may impede the approval and availability of novel therapies, such as PARPi with delays in access often arising due to inconsistencies in regulatory policies across these countries [25]. Given the significant impact of HRD profiling on treatment decisions, the HALO, a real-world study, was conducted to investigate the prevalence of HRD, high genomic instability score (GIS) without tumour BRCA mutation (tBRCAm), and tBRCAm along with associated risk factors in women with advanced HGSOC or HGEOC, PPC, or FTC across Asia, Middle East, and Russia. We present the real-world data from the Middle East subset.

Methods

Study design

The Middle East cohort (part of the HALO study) was a multicentre, observational, cross-sectional, non-interventional study that included nine countries (Egypt [n = 53], Turkey [n = 59], Iraq [n = 45], Jordan [n = 15], Qatar [n = 10], Oman [n = 4], The Kingdom of Saudi Arabia [n = 4], Kuwait [n = 3], and the United Arab Emirates [n = 2]) across the Middle East between May 2021 and January 2022. The study protocol (NCT04991051) was approved by the institutional review boards/independent ethics committees prior to patient enrolment. The study was conducted per the Declaration of Helsinki, Good Clinical Practices, the International Council for Harmonisation, and the applicable regulations on non-interventional and observational studies. This manuscript is reported as per the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) checklist [27].

Study population and data collection

The Middle East cohort consecutively enrolled adults aged ≥ 18 years with histologically confirmed, newly diagnosed stage III or IV (per Federation of Gynaecology and Obstetrics [FIGO] classification, 2014) [28] HGSOC or HGEOC, PPC, or FTC. Patients with available medical records pertaining to the diagnosis, histopathology reports, and formalin-fixed paraffin-embedded (FFPE) tumour tissue blocks collected within 120 days were included. Patients with clear cell, mucinous, undifferentiated carcinoma or malignant Brenner’s tumour, severe acute or chronic medical or psychiatric conditions were excluded. Before data collection, all patients (or next of kin/legal representatives) provided written informed consent. Retrospective data collected from patient’s medical records were transcribed into an electronic data capture system. It included socio-demographics (age, body mass index, smoking history, family history), clinical characteristics (FIGO stage, Eastern Cooperative Oncology Group performance status [ECOG PS]), reproductive history (age at menarche, parity, contraceptive usage [oral or injectable], h/o postmenopausal hormone replacement therapy), histopathological type (serous, endometrioid, and other epithelial non-mucinous), and treatment patterns. To determine the HRD status, the FFPE tissue blocks were tested at reference accredited laboratories using next-generation sequencing-based validated tests at accredited reference laboratories identified in each country. The testing methods with interpretation of the test results are detailed in Supplementary Table 1.

Study endpoints

The primary endpoint was the prevalence of HRD (deleterious or suspected deleterious mutations in BRCA1/2 genes and/or GIS-positive status). The secondary endpoints included region-specific prevalence of HRD, high GIS without tBRCA1/2 mutations, and tBRCA1/2 mutations. Exploratory endpoints included associations of HRD status and tBRCA1/2 mutations with clinicodemographic factors.

Statistical analyses

Detailed sample size estimation along with precision assumptions are reported in HALO global manuscript. All analyses were performed using SAS^® 9.4 software (SAS Institute Inc. Cary, NC, USA) on the full analysis set comprising all the patients who fulfilled the eligibility criteria. Descriptive statistics were used to summarise socio-demographics, HRD testing results, and treatment patterns. For categorical variables, frequencies and percentages were reported with 95% confidence intervals (CIs). Mean, standard deviation, minimum, and maximum values were used to describe continuous variables. Factors associated with HRD positive status, tBRCA1/2 mutations, and high GIS without tBRCA1/2m (post-hoc analysis) were identified through logistic regression analysis. A p-value of less than 0.05 was considered statistically significant.

Results

Baseline characteristics

Of the 214 screened patients in the Middle East, 195 were included in the final analysis; 19 patients failed the eligibility criteria. The distribution of patients is presented in Fig. 1. The median age (range) of patients was 58.0 (24.0–89.0) years; majority were non-smokers (92.3%, n = 180) and more than one-third (35.9%, n = 70) had a family history of cancer. Most patients were multiparous (79.3%, n = 146) and had attained menopause (78.2%, n = 151). No patients received hormone replacement therapy. The primary tumour location was ovaries in most of the patients (88.7%, n = 173) with 71.8% (n = 140) having FIGO stage III disease and 87.1% (n = 170) with ECOG PS of ≤ 1. Hypertension (35.3%, n = 69) and diabetes mellitus (22.0%, n = 43) were the frequently reported comorbidities (Table 1).

Fig. 1.

Patient disposition. FAS population: The subjects who completed the studies and did not violate inclusion criteria i.e., the subjects who had the following tumour types: “Ovarian high-grade serous (FIGO stage III-IV only)”, “High-grade endometrioid cancer”, “Primary peritoneal”, and “Fallopian tube cancer” FAS test population: Subjects who were included in FAS population and had HRD tumour laboratory test. FAS: full analysis set; FIGO: Federation of Gynaecology and Obstetrics; HRD: homologous recombination deficiency; N: number of patients. Note: HALO is an acronym used for this study adopted from the title “A Cross-sectional, Non-interventional, Multicentre Study to Determine the Prevalence of Homologous Recombination Deficiency Among Women With NewLy Diagnosed, High-grade, Serous or Endometrioid Ovarian, Primary Peritoneal, and/or Fallopian Tube Cancer”

Table 1.

Baseline demographic and clinical characteristics

Parameters		Middle East Subset
Demographics
Age (years), median (range)		58.0 (24.0–89.0)
Age categories (years) (N = 195), n (%)	< 65	135 (69.2)
	≥ 65	60 (30.8)
Clinical characteristics
Comorbidities (N = 192)a n (%)	Hypertension	69 (35.9)
	Diabetes mellitus	43 (22.4)
	Obesity	11 (5.7)
	Asthma or COPD	10 (5.2)
Smoking history (N = 195), n (%)	Current smoker/Ex-smoker	15 (7.7)
	Never smoker	180 (92.3)
Family cancer history (N = 195), n (%)	Yes	70 (35.9)
	Genetic relatedb	24 (12.3)
	Non-genetic relatedb	46 (23.6)
	No	125 (64.1)
ECOG performance score (N = 195), n (%)	≤ 1	170 (87.2)
	≥ 2	25 (12.8)
FIGO stage (N = 195), n (%)	Stage III	140 (71.8)
	Stage IV	55 (28.2)
Primary tumour location and histopathologic type (N = 195), n (%)	Ovary	173 (88.7)
	HGSOC only	154 (79.0)
	HGSOC and others	12 (6.2)
	HGEOC	7 (3.6)
	Peritoneum	17 (8.7)
	Fallopian tube	5 (2.6)
Reproductive characteristics
Age at menarche (years) (N = 193), n (%)	< 13	50 (25.9)
	13 to 15	133 (68.9)
	> 15	10 (5.2)
Onset of menopause (N = 193), n (%)	Yes	151 (78.2)
	No	42 (21.8)
Age at menopause (years) (N = 151), n (%)	< 45	12 (7.9)
	45 to 49	62 (41.1)
	50 to 52	52 (34.4)
	> 53	25 (16.6)
Parity (N = 190), n (%)	Multiparous	152 (80.0)
	Primiparous	8 (4.2)
	Nulliparous	30 (15.8)
History of ICs or OCs (N = 193), n (%)	Yes	14 (7.3)
	No	179 (92.7)

Percentage was calculated considering the number of patients available per category

COPD Chronic obstructive pulmonary disease, ECOG Eastern Cooperative Oncology Group, FIGO Federation of Gynaecology and Obstetrics, HGEOC High-grade endometrioid ovarian cancer, HGSOC High-grade serous ovarian cancer, IC Injectable contraceptive, OC Oral contraceptive

“N” represents the total number of patients in “full analysis set”

“n” represents the total number of patients in each row category

^aComorbidities including coronary/ischaemic heart disease, atrial fibrillation, bleeding disorders, chronic kidney disease, heart failure, osteoporosis, stroke, and cerebrovascular events observed in < 5% of patients are not presented

^bGenetically related cancers include ovarian, breast, prostate, and pancreatic cancers; Non-genetic-related cancers include bile duct cancer, bladder cancer, brain cancer, colorectal cancer, gastric cancer, head and neck cancer, hepatic cancer, lung cancer, melanoma, penile cancer, renal cancer, skin cancer, testicular cancer, cervical cancer, duodenal cancer, endometrial cancer, uterus cancer, vulva cancer, stomach cancer, other, unknown

Prevalence of HRD, high GIS without tBRCA, and tBRCA mutations

Of the 180 patients analysed for HRD status (15 patients were excluded due to unavailability of HRD test results), 52.2% (n = 94) were HRD positive, which included high GIS excluding tBRCA1/2 mutations in 23.9% (n = 43), tBRCA1 mutations observed in 16.1% (n = 29), tBRCA2 mutations in 8.3% (n = 15), and tBRCA1/2 mutations in 3.9% (n = 7) patients. Out of the 94 HRD positive patients, 45.7% (43/94) had high GIS without tBRCA mutations and 54.2% (51/94) had tBRCA mutations. The HRD status was unknown for one patient (Fig. 2).

Fig. 2.

Prevalence of HRD, high GIS without tBRCAm, and tBRCAm (N=180). HRD prevalence in patient is calculated by using the number of patients whose status information has been reported. Positive HRD status was based on high GIS without tBRCAm (VUS and likely non-pathogenic, no mutation detected, non-deleterious) or tBRCAm (pathogenic and likely pathogenic, deleterious and likely deleterious). The tumours are HRD status negative if the genomic instability is negative and tBRCAm is negative (VUS and likely non-pathogenic, no mutation detected, non-deleterious). GIS, genomic instability score; HRD, homologous recombination deficiency; tBRCAm, tumour BRCA mutation; VUS, Variants of uncertain significance

HRD testing was performed predominantly using commercial kits in 59.4% (n = 107) patients: laboratory-developed tests in 38.3% (n = 69) and Myriad MyChoice^® in 1.1% (n = 2) patients. AmoyDx^® (34.4%, n = 62) and HRD-Info (23.9%, n = 43) were the frequently used commercial kits. For most patients, oncologists (73.3%, n = 132) had advised HRD testing, and the tissue sample was obtained through biopsy (55.6%, n = 100) (Supplementary Table 2).

Treatment patterns

Most patients (71.3%; n = 139) underwent surgery; of which 74.8% (n = 104) and 26.6% (n = 37) patients underwent primary and interval debulking, respectively. Per available data, complete resection of the tumour was reported in 43.1% (n = 53/123) and microscopic residual tumour was reported in 39.0% (n = 48/123) of patients. Neoadjuvant chemotherapy was received by N = 88 patients, including carboplatin in 100% (n = 88) and paclitaxel in 89.7% (n = 79) of patients. Adjuvant chemotherapy was received by 50.8% (N = 99) patients, paclitaxel by 90.9%, (n = 90) and carboplatin by 82.8%, (n = 82). Bevacizumab was administered in 5.7% (n = 5) and 14.1% (n = 14) patients in neoadjuvant and adjuvant settings, respectively (Supplementary Table 3). PARPi maintenance therapy was not reported in MEA cohort.

Regression analysis

A significant association was found between nulliparity and HRD positivity (odds ratio [OR]: 0.27, 95% CI: 0.11–0.65, p = 0.003) in the univariate analysis. None of the factors influenced the occurrence of HRD positivity in the multivariate analysis (Fig. 3; Supplementary Table 4).

Fig. 3.

Forest plot of adjusted odds ratios for clinical and demographic factors associated with HRD Positivity. Forest plot showing adjusted odds ratios (aORs) and 95% confidence intervals (CIs) from multivariate logistic regression assessing associations between clinical and demographic factors and HRD (homologous recombination deficiency) positivity in ovarian cancer patients (N = 180). HRD positivity was defined by genomic instability score (GIS) and/or pathogenic tumour BRCA mutations (tBRCAm). Variables analysed include age, BMI, smoking, comorbidities (n = 47), family cancer history, ECOG status, reproductive history, FIGO stage, and tumour sample characteristics. No factors were statistically significant (p < 0.05). Abbreviations: aOR, adjusted odds ratio; BRCA, breast cancer gene; CI, confidence interval; ECOG, Eastern Cooperative Oncology Group; FIGO, Federation of Gynaecology and Obstetrics; GIS, genomic instability score; HRD, homologous recombination deficiency; LDT, laboratory-developed test; OR, odds ratio; tBRCAm, tumour BRCA mutation; VUS, variant of uncertain significance

In patients with high GIS without tBRCA mutations, family history of cancer (OR: 0.39, 95% CI: 0.17–0.87, p = 0.02) and nulliparity (OR: 0.19, 95% CI: 0.04–0.86, p = 0.03) were associated with lower odds of high GIS scores (Fig. 4; Supplementary Table 5). However, after adjusting for covariates in the multivariate analysis, none of these factors were associated with high GIS scores without tBRCA mutations.

Fig. 4.

Forest plot of adjusted odds ratios for factors associated with HRD positivity based on high GIS without tBRCAm. Forest plot showing adjusted odds ratios (aORs) and 95% confidence intervals (CIs) from multivariate logistic regression analysis of factors associated with HRD positivity defined by high genomic instability score (GIS) in the absence of tumour BRCA mutations (tBRCAm), among ovarian cancer patients (N = 43). Variables included age, comorbidities (n = 22), family cancer history, ECOG performance status, reproductive history, FIGO stage, and FFPE sample shipment. HRD positivity was based on GIS positivity without pathogenic or likely pathogenic tBRCAm. No variables were statistically significant (p < 0.05). Abbreviations: BRCA, breast cancer gene; CI, confidence interval; ECOG, Eastern Cooperative Oncology Group; FIGO, Federation of Gynaecology and Obstetrics; GIS, genomic instability score; HRD, homologous recombination deficiency; LDT, laboratory-developed test; OR, odds ratio; tBRCAm, tumour BRCA mutation; VUS, variant of uncertain significance

We found a significant association between tBRCA1/2 mutations and ex-smokers (OR: 6.77, 95% CI: 1.26–36.18, p = 0.02), family history of genetically related cancers (OR: 3.11, 95% CI: 1.58–6.09, p = 0.0009), and surgically resected tissue sample (OR: 2.00, 95% CI: 1.03–3.88, p = 0.04). FIGO stage IV disease (OR: 0.26, 95% CI: 0.10–0.66, p = 0.004) had significantly lower odds of tBRCA1/2 mutations in the univariate analysis. Family history of genetically related cancers had three times the risk of tBRCA mutations (aOR: 3.75, 95% CI: 1.58–8.87, p = 0.002) and history of contraceptive use (aOR: 5.19, 95% CI: 1.48–18.09, p = 0.009) had five times higher risk of tBRCA mutations, whereas patients with FIGO stage IV disease (aOR: 0.24, 95% CI: 0.08–0.66, p = 0.006) had lower odds of tBRCA mutations in multivariate analysis (Fig. 5; Supplementary Table 6).

Fig. 5.

Forest plot of adjusted odds ratios for clinicoemographic factors associated with HRD positivity (High-GIS, No-tBRCAm). Forest plot showing adjusted odds ratios (aORs) and 95% confidence intervals (CIs) from multivariate logistic regression assessing the association between clinical and demographic variables and HRD positivity defined by high genomic instability score (GIS) without pathogenic/likely pathogenic tumour BRCA mutations (tBRCAm) among ovarian cancer patients (N = 43). The multivariate analysis included 25 patients with various comorbidities. HRD positivity was assigned to patients with positive GIS regardless of tBRCAm status, excluding those with deleterious mutations. Significant associations were observed for: Genetically related family history of cancer (aOR = 3.75, 95% CI: 1.58–8.87). Use of injectable or oral contraceptives (aOR = 5.19, 95% CI: 1.48–18.09). FIGO Stage IV versus Stage III (aOR = 0.24, 95% CI: 0.08–0.66). Other factors such as age, ECOG performance status, comorbidities, and reproductive history were not statistically significant. Abbreviations: aOR, adjusted odds ratio; BRCA, breast cancer gene; CI, confidence interval; ECOG, Eastern Cooperative Oncology Group; FIGO, Federation of Gynaecology and Obstetrics; GIS, genomic instability score; HRD, homologous recombination deficiency; LDT, laboratory-developed test; tBRCAm, tumour BRCA mutation; VUS, variant of uncertain significance

Discussion

To our knowledge, HALO is the first comprehensive real-world study of its kind in the Middle East region, with 92.3% (180 out of 195) of OC patients successfully tested for HRD and tBRCA mutations. The prevalence of HRD was determined to be 52.2%, which includes high GIS (excluding tBRCA1/2 mutations) at 23.9%, and tBRCA mutations at 28.3%.

The baseline clinical and demographic characteristics were comparable to the HALO global study [29] with a similar percentage of patients below 65 years (69.2% versus 70.0%), having FIGO stage III tumour (71.8% versus 74.8%) and ECOG of ≤ 1 (87.2% versus 92.8%). The Middle East subset had a numerically higher proportion of PPC compared with the overall global HALO study (8.7% versus 4.1%).

The HRD prevalence in the Middle East subset (52.2%) is comparable to the HALO global data (56.0%) [29]. The findings also align with global HRD prevalence rates reported in PARPi studies ranging from 45% to 51% [9, 30, 31]. A systematic review conducted in Arab countries reported that 1 in 5 patients with hereditary breast cancer and/or OC carried BRCA mutations [32]. Additionally, a single-centre, retrospective study from the United Arab Emirates reported HRD prevalence of 24.0% [6/25] in patients with OC [20]. In the current study, numerically lower proportion of patients with high GIS excluding tBRCA1/2 mutations (23.9% versus 30.8%) and higher proportion of tBRCA1/2 mutations (28.3% versus 25.2%) were reported compared with the HALO global study. Previous real-world studies from the Middle East region reported a varied prevalence of tBRCA1/2 mutations: 30.7% (cross-sectional study from Saudi Arabia), 17% (retrospective study from Gulf [Kuwait, Oman, and the United Arab Emirates]), 20.5% (cross-sectional study from the Middle East) among women with advanced epithelial OC [20, 21, 23].

The differences in the prevalence of HRD and tBRCA1/2 mutations in these regional studies may be due to variances in the sample sizes and genetic testing sample, inclusion criteria, and different diagnostic techniques employed in the studies. Ethnicity can also play a substantial role in hereditary OC through its associations with founder mutations. Identification of such distinct variants may aid in developing the panel for HRD or BRCA screening, improving genetic testing strategies, and risk assessments for patients. Azribi et al. [22] used next-generation sequencing (NGS) while a study by Siraj et al. [23] utilised the Sanger sequencing technique for genetic testing (BRCA mutations). The study by Syed et al. [20] used both blood and tissue samples for HRD testing, while studies by Siraj et al. [23] and Alhuqail et al. [21] used only blood samples for BRCA or HRD testing. Azribi et al. [22] used tissue samples for BRCA testing similar to our study. The present study primarily utilised NGS-based HRD testing platforms, with 59.4% of tests conducted using the AmoyDx^® commercial kit. Most pivotal PARPi trials have employed FDA-approved companion diagnostics such as Myriad MyChoice CDx and FoundationOne CDx. Notably, a study comparing AmoyDx^® to Myriad MyChoice CDx demonstrated high concordance rates (87.8%) with a significantly shorter turnaround time (7 days versus 18 days), supporting the real-world feasibility of AmoyDx^® in clinical settings [33].

More than two-thirds (71.3%) of the Middle East region patients underwent debulking surgery, which aligns with treatment guidelines [15]. Nearly half of them received neoadjuvant (45.1%) and adjuvant therapies (50.8%), mostly chemotherapies; bevacizumab was administered in 5 and 14 patients as neoadjuvant and adjuvant therapies, respectively, which concur with the international recommendations during the data collection period [15, 34]. Understanding the factors associated with HRD is essential for the timely initiation of PARPi therapy. In the Middle East region, olaparib is available in eight countries (Egypt, Jordan, Kuwait, Oman, Qatar, Saudi Arabia, Turkey, and the United Arab Emirates), niraparib is available in six countries (Egypt, Kuwait, Oman, Qatar, Turkey, and the United Arab Emirates), whereas rucaparib is not yet approved in any of them.

International guidelines now recommend HRD and BRCA1/2 testing for all patients diagnosed with advanced high-grade OC [15]. More than 50% of the tested cohort (94 out of 180 patients) were HRD positive, reflecting a high rate of molecular eligibility for PARPi therapy. However, PARPi maintenance therapy was not reported during the study period. A single-centre retrospective study by Syed et al., conducted during the same period as the current study, reported 66.6% of HRD positive patients received PARPi therapy and remaining progression-free [20]. In a multicentre study in Turkey (LynTurk), improved survival outcomes with a 1-year PFS rate of 88.4% and a 1-year OS rate of 92.3% were reported with olaparib early access program in patients with advanced OC, signifying the need for reimbursement strategies [35]. A study utilising a real-world clinico-genomic database across approximately 280 US cancer clinics reported 64% reduction in risk of progression in patients who received PARPi compared to those who did not receive maintenance therapy [36]. Similarly, a meta-analysis of randomized controlled trials indicated that HRD positive patients, including those with BRCA mutations, experienced a 60%-62% reduction in progression risk when treated with PARPi [37].

Studies have shown a substantial gap between biomarker-driven eligibility and treatment, highlighting potential systemic barriers including delayed reimbursement processes [38], limited access to genomic testing [39], fragmented incorporation of clinical guidelines [40], and constrained provider awareness [41]. Given the prevalence of HRD, our study highlights a substantial subset of patients with OC in the Middle East who could benefit from novel targeted therapies, emphasizing that understanding the HRD burden may aid in extending the benefits of these drugs to eligible patients in the region. Enhanced diagnostic infrastructure as well as comprehensive policy initiatives, expanded insurance coverage, and region-specific investments in precision oncology implementation are needed to improve survival outcomes in eligible patients with advanced OC by timely initiation of targeted therapies.

To our best knowledge, none of the studies presently determined the association of HRD with clinicodemographics factors. However, family history of ovarian or breast cancer, age over 60 years, early menarche, late menopause, and having fewer pregnancies or never being pregnant were associated with increased risk of OC [42–45]. We found history of genetically related cancer (p = 0.002), history of contraceptive use (p = 0.009), and FIGO disease stage IV (p = 0.006) to be significant risk factors for tBRCA mutations, which were not reported in the HALO global cohort. An observational study from the Saudi Arabia presented an association between family history and tBRCA1/2 variants [23]. In our study, family history of cancer (p = 0.02) and nulliparous women (p = 0.03) had a significant association with high GIS without tBRCA mutations. A real-world study from United States evaluating HRD cancer in patients with OC reported a significant association of high GIS with high-grade serous histology, grade 3 tumours, and patient age < 60 years (p < 0.001) [46]. The positive family history of genetic cancer underpins the importance of genetic counselling, early detection, implementation of cost-effective screening strategies, and involvement of multidisciplinary teams. The study highlights the need to prioritise the patients with these risk factors in regions with limited resources for HRD testing.

Limitations of this study include a small sample size and non-uniform distribution of patients in various Middle Eastern countries resulting in challenges to generalise the study results. Also, due to the cross-sectional study design, the study could not determine whether eligible patients received PARPi later in their treatment trajectory. Thus, longitudinal data on eventual PARPi exposure are lacking, which might have led to underestimation of real-world access among eligible patients. Our study did not consider the pathogenic sequence variants (PSVs) in BRCA1/BRCA2 mutations which are inevitably present in high-risk OC. Furthermore, evaluating germline and somatic BRCA1/BRCA2 PSVs can help better understand the PARP-sensitive tumours. Various commercial kits were utilised across different study sites which could have affected the HRD detection rates. Evaluation of the survival outcomes in patients with OC in our study would have provided further insights into treatment efficacy, disease progression patterns, and potential prognostic factors, thereby strengthening the clinical relevance of our findings.

Future direction and research

Albeit the limitations, the high prevalence of HRD in the Middle East region highlights the need to adopt international guidelines for universal multigene panel testing. HRD profiling can assist clinicians in implementing preventive strategies and making informed decisions, ultimately improving clinical outcomes through the use of PARPi. To maximize the use of these therapies, healthcare authorities must develop strategies to optimize health insurance schemes and financial assistance programs, ensuring patients can access and afford novel targeted therapies. Authorities in the Middle East should also provide cost-effective HRD screening to facilitate timely and well-informed treatment decisions with PARPi therapies for eligible patients. Extensive studies are needed to evaluate the survival outcomes and long-term effects of personalised treatment regimens with PARPi. Additional cost-effective studies on the PARPi along with establishing healthcare infrastructure to support HRD testing are warranted in the Middle East region.

Conclusion

In the Middle East subset of the HALO study, > 50% of the patients were HRD positive, and nearly one-third had tBRCA1/2m. The absence of data on PARPi uptake among eligible patients may reflect a gap between biomarker-defined eligibility and treatment access. These findings suggest the need for national and regional policies to harmonise diagnostic approaches and improve access to targeted therapies. By reporting real-world HRD and tBRCA prevalence, the study provides important evidence to support future research and policy development in precision oncology across the Middle East.

Abbreviations

aOR

Adjusted odds ratio

CI

Confidence interval

COPD

Chronic obstructive pulmonary disease

ECOG

Eastern Cooperative Oncology Group

ESGO

European Society of Gynaecological Oncology

ESMO

European Society for Medical Oncology

ESP

European Society of Pathology

FDA

Food and Drug Administration

FIGO

International Federation of Gynaecology and Obstetrics

FTC

Fallopian tube cancer

GI

Genomic instability

HGEOC

High-grade endometrioid ovarian cancer

HGSOC

High-grade serous ovarian cancer

HRD

Homologous recombination deficiency

IC

Injectable contraceptive

LDT

Laboratory-developed test

MEA

Middle East and Africa

NCCN

National Comprehensive Cancer Network

NGS

Next-generation sequencing

OC

Oral contraceptive

OR

Odds ratio

OS

Overall survival

PARPi

Poly (adp-ribose) polymerase inhibitor

PFS

Progression-free survival

PPC

Primary peritoneal cancer

PS

Performance status

STROBE

Strengthening the reporting of observational studies in epidemiology

tBRCAm

Tumour BRCA mutation

VUS

Variant of uncertain significance

Authors’ contributions

Emad Shash, Mehemet Ali Vardar, Cagatay Taskiran, Salha Boujassoum, Jamila Riromar, Ahmed Aboutaleb, Farah Sadek, Eman Samy, and Waleed Bahaj made substantial contributions to the conception or design of the work and/or the acquisition, analysis, or interpretation of data; were involved in drafting the manuscript and/or critically revising it for important intellectual content; gave final approval of the version to be published; and agree to be accountable for all aspects of the work.

Funding

This study was supported by AstraZeneca and Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, who are co-developing olaparib.

Data availability

The datasets used and/or analysed during the current study are available from the author on reasonable request. Correspondence should be addressed Ahmed Aboutaleb at ahmed.aboutaleb@astrazeneca.com.

Declarations

Ethics approval and consent to participate

The study protocol (ClinicalTrials.gov: NCT04991051) and all study documents were reviewed and approved prior to enrolment by the following independent ethics committees/institutional review boards. Written informed consent was obtained from all participants (or next of kin/legal representatives) before any study procedures. The study was conducted in accordance with the Declaration of Helsinki, Good Clinical Practice, and applicable local regulations.

• Egypt:

◦ Research Ethics Committee for Human Subject Research, National Air Force Specialized Hospital, Cairo, Egypt

◦ Institutional Review Board, Faculty of Medicine, Alexandria University, Alexandria, Egypt

◦ Institutional Review Board, Faculty of Medicine, Assiut University, Assiut, Egypt

◦ Institutional Review Board, National Cancer Institute, Cairo University, Cairo, Egypt

◦ Institutional Review Board, Shifaa Al-Orman Hospital, Luxor, Egypt

• Iraq:

◦Ministry of Health and Environment – The National Centre for Training and Human Development, Baghdad, Iraq

• Jordan:

◦ King Hussein Cancer Center Institutional Review Board, Amman, Jordan

• Saudi Arabia:

◦ Research and Innovation, King Abdullah Medical City in the Holy Capital (KAMC-HC), Makkah, Saudi Arabia

◦ Institutional Review Board, International Medical Center, Jeddah, Saudi Arabia

• Turkey:

◦ Çukurova University Clinical Research Ethics Committee, Adana, Turkey

• United Arab Emirates:

◦ Scientific Research Ethics Committee, Department of Health – Abu Dhabi, Abu Dhabi, UAE

• Kuwait:

◦ Scientific Research and Ethics Committee, Ministry of Health, Kuwait

• Oman:

◦ Scientific Research Committee, Royal Hospital, Muscat, Oman

• Qatar:

◦ Hamad Medical Corporation Institutional Review Board, Doha, Qatar

Consent for publication

Not applicable.

Competing interests

Dr. Emad Shash served in advisory or consultancy roles for Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Clinart MENA, Genomics Genetics, GSK, Hikma, EVA Pharma, Janssen, Lilly, MSD, Mundipharma, Newbridge, Novartis, Pfizer, Pierre Fabre, and Roche. He received travel grants from Boehringer Ingelheim, Hikma, Janssen, Lilly, MSD, Mundipharma, Novartis, Pfizer, and Roche. He participated as an investigator in clinical trials sponsored by AstraZeneca, Boehringer Ingelheim, Novartis, Pfizer, and Roche. Dr Cagatay Taskiran, Dr. Jamila Riromar, Dr. Mehemet Ali Vardar, Dr. Salha Boujassoum, and Dr. Waleed Bahaj do not have any conflict of interest.Ahmed Aboutaleb, Eman Samy, and Farah Sadek are employees at AstraZeneca.