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. 2025 Apr 1;10(4):104533. doi: 10.1016/j.esmoop.2025.104533

Benefit from maintenance with PARP inhibitor in newly diagnosed ovarian cancer according to BRCA1/2 mutation type and site: a multicenter real-world study

C Marchetti 1,2,†,∗, A Fagotti 1,2, R Fruscio 3, C Cassani 4,5, L Incorvaia 6, MT Perri 1, CM Sassu 1,†, CA Camnasio 4,5, E Giudice 1, A Minucci 7, M Seca 3, E Arbustini 4,5, L Vertechy 1, M De Bonis 7, SM Boccia 1, D Giannarelli 8, V Salutari 1, M Distefano 1, MG Ferrandina 1,2, C Nero 1, L Musacchio 1, A Russo 6, G Scambia 1,2, D Lorusso 9,10
PMCID: PMC11999263  PMID: 40174507

Abstract

Background

Knowledge about the association between the BRCA1/2 mutation type and location and response to poly (ADP-ribose) polymerase inhibitors (PARPis) as single agent in ovarian cancer is limited. This study aimed to investigate the effectiveness of PARPi based on functional domains (FD) [RING, BRCT, DNA-binding (BD), RAD51-BD] and types (frameshift, missense, nonsense, splicing) of BRCA1/2 gene mutations in ovarian cancer.

Materials and methods

This multicenter real-world study retrospectively enrolled BRCA1/2-mutated ovarian cancer patients receiving olaparib maintenance between January 2010 and December 2022. Data were compared with historical series of patients who did not receive olaparib and analyzed based on the FD involved in BRCA1/2 mutations. Progression-free survival was calculated from the date of the last platinum-based treatment until recurrence or last follow-up.

Results

After a median follow-up of 46 months (range 32-60 months), 140 patients who underwent olaparib maintenance were compared with 128 who did not. PARPi showed efficacy in the overall population. The no-exon 11 patients benefitted more from olaparib than exon 11 patients [hazard ratio (HR) 0.48, 95% confidence interval (CI) 0.25-0.93]. In the BRCA1 group, patients with mutations in RING and BRCT domains had significant benefits from PARPi (HR 0.08, 95% CI 0.01-0.75; HR 0.10, 95% CI 0.02-0.38, respectively). Among BRCA2-mutated patients, RAD51-BD mutations were associated with higher response to olaparib (HR 0.23, 95% CI 0.10-0.52). According to the mutation type, the major effect of PARPi was in the missense group (HR 0.04, 95% CI 0.01-0.31). No patients with p.(Ala1708Glu) in the BRCT domain (BRCA1) receiving PARPi experienced recurring disease in the study period.

Conclusions

BRCA1/2-mutated patients benefit from olaparib, but with variations according to the mutation type and FDs. BRCA1-mutated patients in the RING or BRCT and BRCA2-mutated in the RAD51-BD have the greatest benefit. Patients with missense mutations, especially those with p.(Ala1708Glu), have the most significant advantage from maintenance with PARPi.

Key words: ovarian cancer, BRCA mutation, PARP inhibitors, mutation type, mutation site

Highlights

  • •

    Olaparib showed to have higher efficacy in ovarian cancer patients with BRCA mutation out of the exon 11.

  • •

    In BRCA1-mutated patients, involvement of RING and BRCT domains was associated with significant benefits from olaparib.

  • •

    In BRCA2-mutated patients, those with a mutation in the RAD51-binding domain mostly benefitted from olaparib maintenance.

  • •

    Patients with a missense BRCA1/2 mutation had better survival during treatment with olaparib.

  • •

    Patients with p.(Ala1708Glu) in the BRCT domain of the BRCA1 gene had the best prognosis.

Introduction

Ovarian cancer is the second most common cause of gynecologic cancer death in women worldwide.1 Over 50%-60% of ovarian malignancies are categorized as high-grade serous ovarian cancer (HGSOC).2,3 About 50% of cases have a genetic mutation in DNA repair proteins. In particular, the most common mutations were detected in BReast CAncer genes (BRCA) 1 and 2, covering ∼20%-25% of all HGSOC.4, 5, 6 These two genes play a fundamental role in the repair processes of double-stranded DNA damage by homologous recombination. The mutations in these genes can affect different sites, impacting their functions differently.7,8 Notably, BRCA1 contains several important functional domains (FDs) that interact with various proteins. The Really Interesting Gene RING-finger domain (RING) binds to BRCA1 Associated RING Domain 1 (BARD1). The DNA-binding domain (DNA-BD) contributes to the DNA-repair-related functions mediated through the BRCA1-associated surveillance complex (BASC). The BRCA1 C-Terminal (BRCT) domains bind to many proteins, including RNA polymerase II.9

The central region of BRCA2 contains a RAD51-binding domain (RAD51-BD). At the C terminus of BRCA2, a prominent DNA-binding domain (DNA-BD) is present.10 Because of the interaction of BRCA1, BRCA2, and all these proteins, the reparation of DNA damage is possible. Furthermore, in the BRCA1 and BRCA2 genes, a large central area called exon 11 is recognized. Data showed inconsistencies regarding the impact of exon 11 involvement on prognosis and response to treatments.11, 12, 13

The most commonly used databases (Breast Cancer Information Core BIC nomenclature, BRCA Exchange, and ClinVar)14, 15, 16 consider several types of mutation, including missense, nonsense, frameshift, and splicing, that alter the protein with different effects on structure and functions.17, 18, 19, 20 Currently, we have limited knowledge about the association between the type and location of BRCA1/2 mutations, the prognosis, and the response to treatment, particularly to poly (ADP-ribose) polymerase inhibitors (PARPi) when used as a single agent in HGSOC. Clinical data from the PAOLA-1 study indicate that patients with mutations in the DNA-BD of BRCA1 are more responsive to the combination of olaparib and bevacizumab, while those with mutations in the DNA-BD of BRCA2 have better outcomes, regardless of the administered maintenance.13

The aim of this study was to investigate the effectiveness of the PARPi olaparib and survival outcomes based on the FDs of BRCA1/2 gene mutation. The impact of different mutation types (frameshift, nonsense, missense, and splicing) on survival and the involvement of exon 11 was also evaluated.

Materials and methods

In this multicenter real-world study, data were collected from a cohort of patients diagnosed with ovarian cancer who were treated between January 2010 and December 2022 in four Italian academic centers: Fondazione Policlinico Agostino Gemelli in Rome, Policlinico San Matteo in Pavia, University of Milan-Bicocca and University of Palermo (ESMO-GROW Flowchart, Supplementary Figure S1, available at https://doi.org/10.1016/j.esmoop.2025.104533).

Patients with newly diagnosed advanced HGSOC and high-grade endometrioid cancer with a definitely pathogenetic germline and/or somatic mutation in BRCA genes [class 5 Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) and the International Agency for Cancer Research (IARC)21] were enrolled, irrespective of surgical treatment (primary debulking surgery and interval cytoreductive surgery). Other histotypes, BRCA status unknown (neither germline nor somatic), or a variant of uncertain significance (VUS) in the BRCA1/2 gene (class 3) excluded patients from the analysis. Data of follow-up should be available.

According to maintenance treatment received after standard carboplatin–paclitaxel, patients were matched 1 : 1 in two cohorts: those who received olaparib maintenance and those who did not (a historical series of patients with similar clinical characteristics who did not undergo maintenance per clinical practice due to comorbidities, lack of indication or drug availability, clinician discretion, or patient preference). Information regarding patients’ characteristics, clinical data, disease presentation at diagnosis, medical and surgical treatment received, and survival outcomes was recorded in an anonymous database protected by a password.

The collection of detailed genetic data in the BRCA mutation variant was supervised and reviewed by specialized genomic experts (A.M, M.D.B). All patients signed the informed consent for their data to be collected for scientific purposes. The study was approved by the ethics committee. Mutations were reported on LRG_292t1 and LRG_293t1 on Human Genome hg19. For BRCA1, the following FDs were considered: RING domain involving amino acids (aa) 8-96; DNA-BD aa 452-1092; and BRCT aa 1646-1736 and 1760-1855.22,23 The following functional domains of BRCA2 were considered: RAD51-BD covering aa 900-2000 and DNA-BD aa 2459-3190.10 Exon 11 encompasses aa 225-1366 and aa 638-2281 in BRCA1 and BRCA2 genes, respectively.24 Regardless of the FD, analysis according to the type of BRCA1/2 gene mutation (frameshift, missense, nonsense, and splicing) was carried out.

The primary endpoint was to assess the extent of the benefit from olaparib maintenance in terms of progression-free survival (PFS), based on the functional domain involved in mutations in the BRCA1 and BRCA2 genes. Secondary endpoint was the assessment of the PFS according to the type of BRCA1/2 mutation and the involvement of exon 11.

Statistical analysis

The data were summarized using descriptive statistical measures. In-depth, qualitative data were expressed as absolute and percentage frequency. Quantitative data distribution was assessed by the Shapiro–Wilk test, and then variables were described either as mean and standard deviation or median and interquartile range, as appropriate. Between-group differences were evaluated, as for qualitative data, by the chi-square test. For quantitative variables, either one-way ANOVA or Student’s t-test and the Mann–Whitney U test or Kruskal–Wallis test were applied, as appropriate. PFS was defined as the time interval between the last administration of platinum (first chemotherapy line) and the date of subsequent progression or last follow-up.

To evaluate the correlation between the BRCA mutation site, the type of mutation, and PFS, Kaplan–Meier survival analysis was computed. Notably, the log-rank test was used to assess the prognostic value of the BRCA mutation site and type on clinical outcomes. To reduce bias in survival estimation due to different follow-up durations in the two groups, PFS data were recorded up to a maximum of 60 months.

Estimated hazard ratios (HRs) and their two-sided 95% confidence intervals (CIs) were calculated using the Cox proportional hazards model. According to the results obtained in the PAOLA-1 study,13 a sample size of at least 200 patients would allow the detection of an HR of ≥0.50 with a power of 80% at a significance level of 1%, taking into account multiple testing. A P value <0.05 was considered statistically significant. All analyses were carried out using Statistical Package for Social Science (version 17.0, SPSS Inc., Chicago, I).

Results

A total of 140 BRCA-mutated patients who underwent olaparib as first-line maintenance were compared with 128 BRCA-mutated patients who did not receive PARPi in the same setting. The clinical and demographic characteristics according to the maintenance arm are summarized in Table 1. With the only exception of family history of cancer, the two groups were homogeneous regarding clinical characteristics, up-front treatment, and the response to platinum-based chemotherapy.

Table 1.

Characteristics and treatment of patients in the overall population, and according to PARPi maintenance

Overall population PARPi No PARPi P valuea
Total n (%) 268 (100) 140 (100) 128 (100)
Age at diagnosis
 Mean (SD) 54.26 (10.06) 54.69 (9.7) 53.79 (10.4) 0.46
 Median (IQR) 53.5 (47-61) 54 (48-61) 52.5 (47-61) 0.90
BRCA genen (%)
 BRCA1 167 (62.3) 86 (61.4) 81 (63.3) 0.75
 BRCA2 101 (37.7) 54 (38.6) 47 (36.7)
Functional domainn (%)
 BRCA1 RING 13 (4.9) 8 (5.7) 5 (3.9) 0.24
 BRCA1 DNA-BD 25 (9.3) 8 (5.7) 17 (13.3)
 BRCA1 BRCT 29 (10.8) 19 (13.6) 10 (7.8)
 BRCA1 other 100 (37.3) 51 (36.4) 49 (38.3)
 BRCA2 RAD51-BD 51 (19) 28 (20) 23 (18)
 BRCA2 DNA-BD 16 (6) 10 (7.1) 6 (4.7)
 BRCA2 other 34 (12.7) 16 (11.4) 18 (14.1)
Mutation typen (%)
 Frameshift 151 (56.3) 72 (51.4) 79 (61.7) 0.38
 Missense 32 (11.9) 18 (12.9) 14 (10.9)
 Nonsense 74 (27.6) 43 (30.7) 31 (24.2)
 Splicing 11 (4.1) 7 (5) 4 (3.1)
EXON 11n (%)
 No 125 (46.6) 68 (48.6) 57 (44.5) 0.50
 Yes 143 (53.4) 72 (51.4) 71 (55.5)
FIGO stagen (%)
 III 227 (84.7) 116 (82.9) 111 (86.7) 0.38
 IV 41 (15.3) 24 (17.1) 17 (13.3)
Histologyn (%)
 Serous 265 (98.9) 138 (98.6) 127 (99.2) 0.53
 Endometrioid 3 (1.1) 2 (1.4) 1 (0.8)
Family historyn (%)
 No 89 (33.2) 34 (24.3) 55 (43) <0.001
 Yes 167 (62.3) 102 (72.9) 65 (50.8)
 Missing 12 (4.5) 4 (2.8) 8 (6.2)
Performance statusn (%)
 0 230 (85.8) 119 (85) 111 (86.7) 0.65
 1 34 (12.7) 19 (13.6) 15 (11.7)
 Missing 4 (1.5) 2 (1.4) 2 (1.6)
Surgeryn (%)
 PCS 175 (65.3) 89 (63.6) 86 (67.2) 0.44
 NACT + ICS 92 (34.3) 51 (36.4) 41 (32)
 No surgery 1 (0.4) 0 1 (0.8)
Residual tumor at surgeryn (%)
 No RT 216 (80.6) 122 (87.1) 94 (73.4) 0.13
 RT present 39 (14.6) 17 (12.1) 22 (17.2)
 Missing 12 (4.5) 1 (0.7) 11 (8.6)
 No surgery 1 (0.4) 0 1 (0.8)
Type of chemotherapyn (%)
 Platinum + paclitaxel 261 (97.4) 138 (98.6) 123 (96.1) 0.48
 Platinum alone 1 (0.4) 0 1 (0.8)
 Other platinum doublet 5 (1.9) 2 (1.4) 3 (2.3)
 Missing 1 (0.4) 0 1 (0.8)
Best responsen (%)
 CR 218 (81.3) 111 (79.3) 107 (83.6) 0.20
 PR 44 (16.4) 27 (19.3) 17 (13.3)
 Missing 6 (2.2) 2 (1.4) 4 (3.1)
Recurrencen (%)
 No 120 (44.8) 100 (71.4) 20 (15.6) <0.001
 Yes 148 (55.2) 40 (28.6) 108 (84.4)
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CR, complete response; DNA-BD DNA-binding; FIGO, International Federation of Gynecology and Obstetrics; ICS, interval cytoreductive surgery; IQR, interquartile range; NACT, neoadjuvant chemotherapy; PARPi, poly (ADP-ribose) polymerase inhibitors; PCS, primary cytoreductive surgery; PR, partial response; RAD51-BD, RAD51-binding; RT, residual tumor, SD, standard deviation.

a

Only in patients with available data.

Most patients were diagnosed with International Federation of Gynecology and Obstetrics (FIGO) stage III ovarian cancer with serous histotype. More than 60% of patients underwent primary cytoreductive surgery without residual tumor. Almost all patients received neoadjuvant and/or adjuvant therapy with carboplatin and paclitaxel with complete/partial response after treatment.

Among the enrolled population, 62.3% harbored mutation in BRCA1 (n = 167) and 37.7% in BRCA2 (n = 101). Without statistical difference according to olaparib administration, BRCT was the most frequently mutated FD in the BRCA1 gene (17.4%, n = 29/167), followed by DNA-BD (15%, n = 25/167) and RING domain (7.8%, n = 13⁄167). For BRCA2, more than half of the mutations were located in the RAD51-BD (50.5%, n = 51⁄101), followed by DNA-BD (15.8%, n 16⁄101). A significant portion of the mutations were detected outside these FDs of BRCA1 and BRCA2, comprising 59.9% (n = 100/167) and 33.7% (n = 34/101) of the mutations, respectively. The most frequent type of mutation was frameshift (56.3%), followed by nonsense (27.6%), without statistical difference between patients who received PARPi and patients who did not. Slightly more than 50% of the mutations occurred in exon 11.

After a median follow-up of 46 months (range 32-60 months), better survival was observed in patients who received olaparib after first-line treatment. Relapse was observed in 84.4% of patients without olaparib maintenance (n = 108) compared with 28.6% in the PARPi group (n = 40). The benefit from maintenance with PARPi was observed in the overall population (HR 0.25, 95% CI 0.17-0.36) and in both the genes (BRCA1, HR 0.29, 95% CI 0.18-0.45; BRCA2, HR 0.20, 95% CI 0.10-0.38; Table 2).

Table 2.

PARPi benefit in the overall population, according to the gene involved, the site, and the type of mutation (hazard ratio)

Hazard ratio (95% CI) P value
Overall population 0.25 (0.17-0.36) <0.001
BRCA gene
 BRCA1 0.29 (0.18-0.45) <0.001
 BRCA2 0.20 (0.10-0.38) <0.001
Mutation site
 BRCA1 RING 0.08 (0.01-0.75) 0.02
 BRCA1 DNA-BD 0.75 (0.23-2.43) 0.64
 BRCA1 BRCT 0.10 (0.02-0.38) 0.001
 BRCA1 other 0.35 (0.20-0.61) <0.001
 BRCA2 RAD51-BD 0.23 (0.10-0.52) <0.001
 BRCA2 DNA-BD 0.24 (0.04-1.34) 0.10
 BRCA2 other 0.15 (0.04-0.54) 0.003
Mutation type
 Frameshift 0.21 (0.13-0.35) <0.001
 Missense 0.04 (0.01-0.31) 0.002
 Nonsense 0.43 (0.22-0.82) 0.01
 Splicing 1.03 (0.18-5.69) 0.96
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CI, confidence interval; DNA-BD, DNA-binding; PARPi, poly (ADP-ribose) polymerase inhibitors; RAD51-BD, RAD51-binding.

Patients with or without mutations located in exon 11 of both genes derived benefit from PARPi (exon 11, HR 0.38, 95% CI 0.24-0.61; no-exon 11, HR 0.14, 95% CI 0.08-0.26; Supplementary Table S1, available at https://doi.org/10.1016/j.esmoop.2025.104533). The no-exon 11 patients tended to benefit more from receiving olaparib than exon 11 patients (HR 0.48, 95% CI 0.25-0.93). The magnitude of the benefit was particularly evident in BRCA2 no-exon 11 patients (HR 0.10, 95% CI 0.02-0.47); Supplementary Table S1, available at https://doi.org/10.1016/j.esmoop.2025.104533).

Differences in outcomes were found when comparing groups according to the involved FD and the type of mutations. Notably, among patients with BRCA1 involvement, those with mutation located in the RING and BRCT domains showed a significant benefit from olaparib maintenance [RING 24-month PFS: 65.6% versus 0%, median PFS (mPFS): not reached (NR) versus 11 months, HR 0.08, 95% CI 0.01-0.75 and BRCT 24-month PFS: 94.4% versus 30%, mPFS: NR versus 13 months, HR 0.10, 95% CI 0.02-0.38, respectively] (Tables 2 and 3, Figure 1A). For BRCA2-mutated patients, among cases with mutation in FDs, those with mutations in the RAD51-BD had the most relevant advantage from PARPi (24-month PFS: 81% versus 43.5%, mPFS: NR versus 20 months, HR 0.23, 95% CI 0.10-0.52; Tables 2 and 3, Figure 1B).

Table 3.

PARPi benefit in the overall population, according to the gene involved, the site, and the type of mutation (24-month PFS and median PFS)

PARPi
24-month PFS (%)		 No PARPi
24-month PFS (%)		 PARPi median PFS, months (95% CI) No PARPi median PFS, months (95% CI) P value
Overall population 81.8 42.1 NR 19.0 (14.6-23.4) <0.001
Mutation site
 BRCA1 RING 65.6 0 NR 11.0 (8.8-13.1) 0.006
 BRCA1 DNA-BD 100 58.8 31.0 (29.9-32.1) 33.0 (7.4-58.5) 0.63
 BRCA1 BRCT 94.4 30 NR 13.0 (9.9-16.1) 0.001
 BRCA1 other 75 44.8 NR 20.0 (13.2-26.8) <0.001
 BRCA2 RAD51-BD 81 43.5 NR 20.0 (7.5-32.5) <0.001
 BRCA2 DNA-BD 77.8 66.7 NR 28.0 (0.56-55.4) 0.08
 BRCA2 other 87.5 27.8 NR 16.0 (11.8-20.2) <0.001
Mutation type
 Frameshift 85.8 36.6 NR 17.0 (12.9-21.0) <0.001
 Missense 92.3 35.7 NR 17.0 (11.5-22.5) <0.001
 Nonsense 74.5 58.1 NR 29.0 (17.0-41.0) 0.007
 Splicing 57.1 50 30.0 (6.9-53.1) 14.0 (0-48.6) 0.96
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CI, confidence interval; DNA-BD, DNA-binding; NR, not reached; PARPi, poly (ADP-ribose) polymerase inhibitors; PFS, progression-free survival; RAD51-BD, RAD51-binding.

Figure 1.

Figure 1

Figure 1

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Progression-free survival according to functional domain in the BRCA1-mutated population (A) and in the BRCA2-mutated population (B). DNA-BD, DNA-binding; PARPi, poly (ADP-ribose) polymerase inhibitors; RAD51-BD, RAD51-binding.

Regarding the type of mutation, the major effect of olaparib was obtained in missense mutation (24-month PFS: 92.3% versus 35.7%, mPFS: NR versus 17 months, HR 0.04, 95% CI 0.01-0.31; Tables 2 and 3, Figure 2). No significant benefit from PARPi was observed in patients with splicing mutation or in the BRCA1/2 DNA-BD groups (Tables 2 and 3, Figures 1 and 2).

Figure 2.

Figure 2

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Progression-free survival in the overall population according to the type of mutation. PARPi, poly (ADP-ribose) polymerase inhibitors.

Among the patients with missense mutations in our population, 28% (n = 9/32) presented with the mutation p.(Ala1708Glu), located in the BRCT domain (BRCA1). Eight received PARPi after first-line chemotherapy. None of these eight patients experienced recurrence during the study period (Supplementary Table S2, available at https://doi.org/10.1016/j.esmoop.2025.104533).

Discussion

In our multicenter retrospective study, we confirmed with compelling evidence that patients carrying BRCA1/2 mutations derive substantial benefit from olaparib maintenance. Nevertheless, differences in the magnitude of benefit were reported when analyzed according to the specific location and type of mutation. We observed that patients with BRCA1 mutations in the RING domain and BRCA2 mutations in the RAD51-BD had the greatest benefit from PARPi administration. No significant benefits were found in BRCA1/2 DNA-BD mutation groups. Additionally, it appears that patients with missense mutations, especially those with p.(Ala1708Glu), experience the most relevant benefits.

The introduction of PARPi marks a revolutionary advancement in the treatment of BRCA1/2-mutated HGSOC. Nevertheless, it has become increasingly evident that the efficacy of PARPi varies among patients according to several variables, including their genomic instability score.25 Thus, a pathogenic BRCA mutation does not always ensure a favorable response to PARPi and resistance can develop over time. Among several mechanisms of primary resistance to PARPi that have been proposed, some suggest that the different BRCA1/2 mutation types and locations may be associated with platinum and PARPi sensitivity, potentially influencing secondary reversion mutation occurrence.26, 27, 28, 29, 30 BRCA1 and BRCA2 are two large genes characterized by large central exon 11 and different FDs. In particular, BRCA1 includes three different FDs: the RING, the DNA-BD and the BRCT domain, all involved in DNA repair and the latter domain also in cell cycle control (through G2/M and S-phase checkpoints). The two FDs of BRCA2 are RAD51-BD and DNA-BD and are implicated in homologous recombination pathways. Based on these distinct but complementary functions, some authors have focused on the survival outcomes according to the gene involved and showed different chemotherapy and PARPi sensitivity in BRCA1 versus BRCA2-mutated patients.26,31,32

In preclinical studies, mutations of BRCA1 involving the exon 11 appear to be associated with less sensitivity to PARPi than those outside the exon 11.11 Additionally, it was observed that deletion in the DNA-BD of BRCA2 seemed to increase sensitivity to olaparib and cisplatin in engineered cell lines.33 In a recent analysis of the PAOLA-1 phase III clinical trial, researchers looked at the impact of the location of BRCA1/2 mutations on the sensitivity to PARPi and bevacizumab.13 A total of 233 of 806 randomly assigned patients were analyzed and it was found that those with BRCA1/2 mutations involving exon 11 derived greater benefit from olaparib plus bevacizumab compared with patients with mutations outside exon 11. Patients with mutations in the DNA-BD of BRCA1 also showed significant benefit from olaparib plus bevacizumab.13 Interestingly, in our analysis assessing patients treated with PARPi, we found that among BRCA1 patients, those with the greatest benefit had mutations in the RING domain (located outside the exon 11), and no-exon 11 patients had a reduced risk of recurrence.

Regarding BRCA2 mutation carriers in FDs, we found that individuals with mutations in RAD51-BD had significantly longer PFS when treated with olaparib, in accordance with previous data.13 In the PAOLA-1 analysis, it was found that the BRCA2 DNA-BD group had the better survival outcomes, regardless of whether they had received olaparib–bevacizumab or not.13 In the setting of recurrence, patients harboring mutations involving BRCA1 DNA-BD and BRCT domains showed longer PFS during PARPi maintenance in comparison with those with RING domain alterations.34

In our BRCA1/2 DNA-BD-mutated population, a significant improvement with olaparib was not observed. However, the mutation of DNA-BD appeared to be associated with better survival, regardless of the administration of olaparib, in comparison with other FDs. Therefore, it is challenging to determine whether the good prognosis is intrinsically due to the DNA-BD BRCA1/2 mutation or attributable to the effect of PARPi therapy. Moreover, in our study, patients were treated with PARPi alone (compared with no maintenance) and did not receive bevacizumab. We cannot rule out the possibility that in the PAOLA-1 analysis, bevacizumab’s antiangiogenic effect may have interfered with the sensitivity of olaparib.13 Additionally, both in the PAOLA-1 analysis and in our study, the sample sizes were small and, although a power calculation was carried out in the PAOLA-1 study, the authors themselves suggest that a larger sample size is necessary for a comprehensive analysis with sufficient statistical power.13

In the PAOLA-1 study, none of the mutation types were found to affect the benefits of olaparib plus bevacizumab (interaction P > 0.01).13 Excluding data obtained from patients with splicing mutations due to the small numbers, we observed an advantage in PFS across the different mutation types. However, we did find that missense ones, regardless of the genes involved, had a very positive outcome. This was surprising because in the PAOLA-1 study, patients with missense mutations did not seem to benefit from the addition of olaparib to bevacizumab. As a result, we revisited the missense mutations and discovered that our population was enriched with the specific missense mutation p.(Ala1708Glu). This is noteworthy because this specific mutation, in addition to p.(Gly1706Glu), has already been proven to be particularly sensitive to olaparib,35 due to its specific effect on the DNA repair pathway.

Recently, biphasic recruitment of the BRCA1 tumor suppressor into DNA damage sites was described.36 The early recruitment requires PAR recognition by the BRCA1–BARD1 protein complex, while the late phase depends on several specific functions, firstly on the functional BRCA1–BRCT domain.

Olaparib was shown to block the early recruitment phase of DNA repair by inhibiting PAR synthesis and late recruitment by decreasing the interaction between the BRCA1-A complex and BRCT. These mechanisms make the cell more dependent on the other functions of the late recruitment stages. In cells with BRCA1 missense mutations, both defective and normal BRCA proteins are produced37: the altered ones could compete with the wild type, hindering the late recruitment path to repair DNA. Conversely, heterozygous truncating mutations lead to degradation of the mutated mRNA and the mutated protein frequently is not produced.37 Thus, the remaining wild-type proteins maintain their function in the DNA repair through the late recruitment phase and the effect of PARPi is less pronounced.

Coherently, in an in vitro study, the recruitment of the BRCA1 protein toward cH2AX (indispensable for the initial recognition of DNA breaks38) was proved to be lower in cells with missense mutations p.(Ala1708Glu) and p.(Gly1706Glu) than in wild-type cells and those with truncating mutations.35 Notably, while these mutations accounted for 28% of all missense mutations in our study, the population in the PAOLA-1 study only had 15% of these specific mutations.13 Besides, in PAOLA-1, one case (5%) of p.(Gly1706Glu) mutation was reported,13 and none in our series, suggesting that the mutation distribution might differ across different populations. This emphasizes the importance of considering the type and site of genetic mutations when investigating these issues, especially in BRCA mutation carriers. We did not correlate BRCA mutation site and type to overall survival since overall survival data are still immature in our population and will require longer follow-up.

We acknowledge some limitations to our study, including its retrospective nature and the relatively small number of patients in each mutation category. However, to our knowledge, our study is the only real-life study comparing PARPi alone with no maintenance, providing a direct analysis of olaparib efficacy independent of platinum sensitivity.

Conclusions

In conclusion, we have provided additional evidence that the effectiveness of olaparib varies across different types and sites of BRCA mutation. We observed that specific missense mutations in the BRCT region of the BRCA1 gene are particularly sensitive to olaparib treatment, potentially opening up to a new possible research on PARPi sensitivity. Integrating knowledge about the type and the site of mutation may identify patients for whom PARPi are essential and sufficient and others for whom PARPi may not be entirely effective, who may require combination with antiangiogenic agents. Furthermore, for a more personalized approach, this varying benefit from PARPi based on BRCA1/2 mutation could justify a possible de-escalation of duration, identifying patients for whom maintenance of even <2 or 3 years might be enough.

If further studies support our findings, we could develop a more effective algorithm for managing BRCA-mutated ovarian cancer, selecting patients who will most benefit from PARPi and personalizing their care based on a ‘detailed genetic profile’.

Acknowledgments

ACKNOWLEDGEMENTS

This work was supported by Italian MoH - RC2025.

Funding

None declared.

Disclosures

CM has received grants or contracts from GSK, Pharmamar, Merck Sharpe & Dohme (MSD), Menarini, and AstraZeneca; has received consulting fees from GSK, Pharmamar, Clovis, MSD, AstraZeneca, and Arquer Diagnostics; has received support for attending meetings and/or travel from AstraZeneca and Roche; and has participated on a data safety monitoring board or advisory board for GSK, Pharmamar, Clovis, MSD, and AstraZeneca.

AF has received grants or contracts from AstraZeneca and MSD; has received consulting fees from GSK, Pharmamar, Johnson & Johnson, and Fondazione Internazionale Menarini; and has received payment or honoraria for lectures, presentations, speaker's bureaus, manuscript writing, or educational events from Pharmamar and GSK.

CC has received consulting fees and payment or honoraria for lectures from and has participated on a data safety monitoring board or advisory board for AstraZeneca, GSK, Pharmamar, and MSD.

LI has received payment or honoraria for lectures, presentations, speaker's bureaus, manuscript writing, or educational events from Ipsen and BMS.

MTP has received support for attending meetings and/or travel from MSD and AstraZeneca.

CMS has received consulting fees from GSK and AstraZeneca and has received support for attending meetings and/or travel from Pharmamar.

EG has received payment or honoraria for lectures, presentations, speaker's bureaus, manuscript writing, or educational events from GSK and AstraZeneca, and has received support for attending meetings and/or travel from MSD.

LV has received consulting fees from GSK and Pharmamar.

SMB has received consulting fees from GSK, Pharmamar, and AstraZeneca, and has received support for attending meetings and/or travel from Pharmamar.

VS has received consulting fees from MSD, GSK, Immunogen, and Menarini Stemlines, and has received payment or honoraria for lectures, presentations, speaker's bureaus, manuscript writing, or educational events from GSK, AstraZeneca, and MSD.

MGF has received consulting fees from MSD Italia S.r.l., GSK, and AstraZeneca.

CN has received consulting fees from Illumina and Guardant Health, MSD, GSK, AstraZeneca, Altems, and Veeva, and has received support for attending meetings and/or travel from MSD, Illumina, Menarini, and AstraZeneca.

LM has received consulting fees from MSD and AstraZeneca.

AR has received payment or honoraria for lectures, presentations, speaker's bureaus, manuscript writing, or educational events from Roche Diagnostics and has participated on a data safety monitoring board or advisory board for Bristol Myers Squibb, Pfizer, Bayer, and Kyowa Kirin.

GS has received grants or contracts from Novartis, Lyra, Sofar, Galileo Research, Olympus, Merck KGAA, AstraZeneca, Celgene Corporation, Roche, Pharma Mar, Shionogi, Morphotek, Linnea, Cryolife, Celldex, Pfizer, Millenium, GSK, Llc, Princess Margaret Cancer Centre, Central And Eastern European Gynecologic Oncology Group (CEEGOG), K-Group Beta, Inc., S&R Pharmaceutic, MSD, Karyopharm Therapeutics, Novocure Ltd, Seattle Genetics Inc., Clovis Oncology, Inc, Immunogen, Inc, Bayer Ag, Inovio Pharmaceuticals Inc, Aeterna Zentaris Gmbh, Glycotope Gmbh, Eli Lilly, Sanofi-Aventis Recherche Et Développement, Tesaro, Inc., Novocure Ltd, Oncoquest Pharmaceuticals Inc, Kiromic, Medtronic, Advenchen Laboratories, Merck, Debiopharm, Arcagy Gineco, Consorzio Oncotech, Oncoquest Inc., Transenterix Italia S.R.L.; has received consulting fees from Menarini, Olympus Europa, Intuitive Surgical, GSK, Covidien AG (Med Company), Baxter Healthcare, AstraZeneca, and MSD; has received support for attending meetings and/or travel from Olympus Europa, Intuitive Surgical Inc, GSK, Covidien A (Medtronic company), Baxter Healthcare, AstraZeneca, and MSD.

DL has received grants or contracts from Pharmaand, GSK, and MSD; has received consulting fees from GSK, MSD, AstraZeneca, Immunogen, Regeneron, Sutro, Genmab; has received payment or honoraria for lectures, presentations, speaker's bureaus, manuscript writing, or educational events from GSK and MSD.

All remaining authors have declared no conflicts of interest.

Supplementary data

Supplemental Material
mmc1.docx (339.3KB, docx)

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Supplemental Material
mmc1.docx (339.3KB, docx)

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