AstraZeneca and MSD Inc., Kenilworth, N.J., US (MSD: known as Merck & Co., Inc. inside the US and Canada) today announced that the companies have received marketing authorisation from China’s National Medical Products Administration (NMPA) for Lynparza (olaparib) as a 1st-line maintenance treatment of adult patients with newly diagnosed advanced germline or somatic BRCA mutated (gBRCAm or sBRCAm) epithelial ovarian, fallopian tube or primary peritoneal cancer who are in complete or partial response to 1st-line platinum-based chemotherapy.

AstraZeneca and MSD Inc., Kenilworth, N.J., US (MSD: known as Merck & Co., Inc. inside the US and Canada) today announced that Lynparza (olaparib) has been approved in Japan as a maintenance treatment after 1st-line chemotherapy in patients with BRCA-mutated (BRCAm) advanced ovarian cancer, as detected by an approved companion diagnostic test.

AusPAR...Olaparib is indicated as monotherapy for the maintenance treatment of patients with platinum-sensitive relapsed BRCA-mutated (germline or somatic) high grade serous epithelial ovarian, fallopian tube or primary peritoneal cancer who are in response (complete response or partial response) after platinum-based chemotherapy.

AstraZeneca Canada announced today that Health Canada has approved LYNPARZA (olaparib) capsules as a maintenance treatment for patients with platinum-sensitive relapsed BRCA-mutated (germline or somatic) high grade serous epithelial ovarian, fallopian tube or primary peritoneal cancer.

Lynparza is indicated as monotherapy for the...maintenance treatment of adult patients with advanced (FIGO stages III and IV) BRCA1/2-mutated (germline and/or somatic) high-grade epithelial ovarian, fallopian tube or primary peritoneal cancer who are in response (complete or partial) following completion of first-line platinum-based chemotherapy.

Lynparza is a poly (ADP-ribose) polymerase (PARP) inhibitor indicated:...for the maintenance treatment of adult patients with deleterious or suspected deleterious germline or somatic BRCA-mutated advanced epithelial ovarian, fallopian tube or primary peritoneal cancer who are in complete or partial response to first-line platinum-based chemotherapy. Select patients for therapy based on an FDA-approved companion diagnostic for Lynparza....for the treatment of adult patients with deleterious or suspected deleterious germline BRCA-mutated (gBRCAm) advanced ovarian cancer who have been treated with three or more prior lines of chemotherapy. Select patients for therapy based on an FDA approved companion diagnostic for Lynparza.

Newly Diagnosed Ovarian Cancer….Recommendation 2.1...For those with germline or somatic pathogenic or likely pathogenic variants in BRCA1 or BRCA2 genes, options should include olaparib (300 mg orally every 12 hours for 2 years), niraparib (200-300 mg orally daily for 3 years) or rucaparib (600 mg twice a day for 2 years).

Women with newly diagnosed stage III-IV EOC that is in complete or partial response to first-line platinum-based chemotherapy should be offered PARPi maintenance therapy with olaparib (for those with germline or somatic pathogenic or likely pathogenic variants in BRCA1 or BRCA2 genes)...

PARP inhibitors (olaparib, niraparib and rucaparib) when given as maintenance therapy following a response to platinum-based second or higher line of treatment have proven benefit with respect to PFS and could be recommended. The benefit is greatest in, but is not limited to, patients with a BRCA mutation....PARP inhibitors (rucaparib*, olaparib) are active as monotherapy in patients with a BRCA mutation and could be considered.

Olaparib has been added as an option for patients with a CR/PR and germline or somatic BRCA1/2 mutation

Results indicate a clinically meaningful, albeit not statistically significant according to prespecified criteria, improvement in OS with maintenance olaparib in patients with newly diagnosed advanced ovarian cancer and a BRCA mutation and support the use of maintenance olaparib to achieve long-term remission in this setting; the potential for cure may also be enhanced. No new safety signals were observed during long-term follow-up.

Olaparib treatment led to an improvement in progression-free survival compared with placebo (hazard ratio = 0.44, 95% confidence interval: 0.17–1.19; median = 13.8 vs. 5.5 months)….Efficacy and safety findings in the China SOLO2 cohort support the use of olaparib (300 mg twice daily) as maintenance treatment for Chinese patients with platinum-sensitive relapsed ovarian cancer and a BRCA mutation.

Between 2018 and 2020, 225 patients were enrolled, and 224 received olaparib; 35.7% had received {greater than or equal to}3 lines of chemotherapy, 35.3% had achieved complete response to their last line of platinum-based chemotherapy, and 41.1% had a platinum-free interval {less than or equal to}12 months. At primary data cutoff (December 25, 2020), overall mPFS was 16.1 months; mPFS was 21.2 and 11.0 months in BRCA-mutated and wild-type BRCA subgroups, respectively...Olaparib maintenance therapy was highly effective and well tolerated in Asian patients.

No significant difference in the magnitude of progression-free survival (PFS) benefit from olaparib for older patients (N = 40, hazard ratio [HR]≥65 0.43, 95%-confidence interval [CI] 0.24–0.81) as compared with younger patients (N = 155, HR<65 0.31 (95%-CI 0.22–0.43) was seen (interaction P = 0.33). The overall survival (OS)benefit seen in younger patients in the olaparib arm was not observed in older patients. Results of this large phase III cohort of BRCA1/2-mutated PSOC patients treated with olaparib underline impressive efficacy of olaparib maintenance...

A 5-year follow-up of patients in the ongoing SOLO1 trial showed that patients with advanced BRCA-mutated ovarian cancer who had finished platinum-based chemotherapy had a significantly longer median progression-free survival when they received 2 years of olaparib as a maintenance therapy instead of placebo-56 months versus 13.8 months, respectively.

n this post-hoc analysis, median progression-free survival was 56·0 months (95% CI 41·9–not reached) with olaparib versus 13·8 months (11·1–18·2) with placebo (hazard ratio 0·33 [95% CI 0·25–0·43]). For patients with newly diagnosed advanced ovarian cancer and a BRCA mutation, after, to our knowledge, the longest follow-up for any randomised controlled trial of a PARP inhibitor in this setting, the benefit derived from 2 years' maintenance therapy with olaparib was sustained beyond the end of treatment, extending median progression-free survival past 4·5 years.

In pts with HRRmt, median PFS was 12.3, 13.1, and 20.4 mos for chemo, olap, and ced/olap, with HR 0.78 (95% CI 0.48-1.27) for olap to chemo and HR 0.55 (0.32-0.95) for ced/olap….HRR status was predictive of olap response vs chemo (p = 0.0176) but not of ced/olap vs chemo (p = 0.1009)....In NRG-GY004 pts, HRR status was driven by BRCAmt, correlated with overall prognosis, and was predictive of olap response vs chemo.

279 pts were enrolled from 17 countries (mean age: 64 years); 253 pts (90.7%) were confirmed non-gBRCAm. At data cut-off (Oct 2, 2020), median PFS was 9.2 mo (95% CI 7.6–10.9), with 210 PFS events (75.3% maturity). 65.3%, 38.5% and 24.3% of pts were progression-free (PF) at 6, 12 and 18 mo, respectively...Our findings support the use of olaparib maintenance therapy in non-gBRCAm PSR OC pts, consistent with our interim analysis and previous trials in this setting.

...endometrioid ovarian cancer, primary peritoneal cancer, or fallopian tube cancer with a BRCA mutation...Mean quality-adjusted progression-free survival (olaparib 29·75 months [95% CI 28·20–31·63] vs placebo 17·58 [15·05–20·18]; difference 12·17 months [95% CI 9·07–15·11], p<0·0001) and the mean duration of TWiST (olaparib 33·15 months [95% CI 30·82–35·49] vs placebo 20·24 months [17·36–23·11]; difference 12·92 months [95% CI 9·30–16·54]; p<0·0001) were significantly longer with olaparib than with placebo.

...pts with a BRCAm and newly diagnosed advanced ovarian cancer, the benefit derived from 2 years of maintenance olaparib was sustained beyond the end of treatment, and after 5 years, almost half of pts were progression free…

Olaparib provided a median overall survival benefit of 12·9 months compared with placebo in patients with platinum-sensitive, relapsed ovarian cancer and a BRCA1/2 mutation.

After a median follow-up overall of ~41 months, the risk of disease progression/death per investigator was significantly reduced with olaparib versus placebo in the higher-risk group (HR 0.34, 95% CI 0.24–0.48; 66% reduction) and the lower-risk group (HR 0.33, 95% CI 0.20–0.52; 67% reduction) (figure 1)....In this exploratory analysis of data from the SOLO1 study, maintenance olaparib provided a substantial PFS benefit over placebo in patients with both higher-risk and lower-risk newly diagnosed advanced ovarian cancer and a BRCAm...

AstraZeneca and Merck (NYSE: MRK), known as MSD outside the United States and Canada, today announced positive five-year follow-up data from the Phase 3 SOLO-1 trial which demonstrated a long-term progression-free survival (PFS) benefit of LYNPARZA versus placebo as a first-line maintenance treatment in patients with newly diagnosed, advanced BRCA-mutated (BRCAm) ovarian cancer who were in complete or partial response to platinum-based chemotherapy.

Maintenance olaparib demonstrated activity in non-gBRCAm PSR OC pts.

Pts with PSROC and a BRCAm who had received ≥2 lines of treatment and were in response to their most recent platinum-based chemotherapy received maintenance olaparib (300 mg bid tablets) or placebo...A long-term treatment benefit was seen with olaparib vs placebo with an OS HR of 0.74 (95% confidence interval [CI] 0.54–1.00) in the full analysis set (FAS; unadjusted for crossover; 38.4% of placebo pts crossed over to a PARP inhibitor) (Table).

In gBRCA pts, HR for PFS was 0.55 (95% CI 0.73-1.30) for C+O vs SOC, and 0.63 (95% CI 0.37-1.07) for O vs SOC. In non-gBRCA pts, HR for these comparisons was 0.97 (95% CI 0.73-1.30) and 1.41 (1.07-1.86). No OS differences between arms were observed at 44% events.

SOLO1 is a randomized, controlled, double-blind trial. Eligible pts had newly diagnosed, FIGO stage III–IV, high-grade serous or endometrioid ovarian, primary peritoneal and/or fallopian tube cancer with a BRCAm….Maintenance olaparib led to a substantial, unprecedented improvement in PFS, with an estimated difference in median PFS for olaparib versus placebo of approximately 3 years.

Olaparib tablet maintenance treatment provided a significant progression-free survival improvement with no detrimental effect on quality of life in patients with platinum-sensitive, relapsed ovarian cancer and a BRCA1/2 mutation.

The use of maintenance therapy with olaparib provided a substantial benefit with regard to progression-free survival among women with newly diagnosed advanced ovarian cancer and a BRCA1/2 mutation, with a 70% lower risk of disease progression or death with olaparib than with placebo.

Pts with gBRCAm PSR OC receiving olaparib monotherapy had a significant, clinically relevant improvement in ORR and PFS vs TPC, with no new safety signals.

...Documented absence of somatic and germline mutations of BRCA 1 /2.6. ...

...- Documented mutation in BRCA1 or BRCA2 that is predicted to be deleterious or suspected deleterious (known or predicted to be detrimental/lead to loss of function)....

...- Documented gBRCA1/2 mutation status...

...Documented germline or somatic mutation in BRCA1 or BRCA2 genes that is predicted to be deleterious or suspected deleterious (known or predicted to be detrimental/lead to loss of function) [Genetic counselling for patients with germline BRCA mutations should be performed according to local regulations] Or Tumour BRCAwt status and documented qualifying mutation in any of 13 genes involved in the HRR pathway, excluding BRCA1 and BRCA2 (ATM, BARD1, BRIP1,CDK12, CHEK1, CHEK2, FANCL, PALB2, PPP2R2A, RAD51B, RAD51C, RAD51D,and RAD54L), identified by the Lynparza HRR Assay in archival tumour tissue (i.e.,BRCA-independent HRRm) 4....

...Patients are eligible to undergo BRCA testing even if they have - Documented germline mutation in Breast Cancer susceptibility genes: BRCA1 and/or BRCA2 that is predicted to be deleterious or suspected deleterious (known or predicted to be detrimental/lead to loss of function) - At least one lesion that can be accurately assessed at baseline by CT/MRI and is suitable for repeated assessment. ...

...time from start of maintenance olaparib to the date of first documented disease progression or death from any cause, whichever occurs first, of olaparib for the BRCA1 or BRCA2 mutant (germline or somatic) HR deficient group, the non BRCA mutant HR deficient group and the HR proficient group`time from start olaparib to death (any cause).`...

...Documented mutation in BRCA1 or BRCA2 germline and/or somatic that is predicted to be deleterious or suspected deleterious (known or predicted to be detrimental/lead to loss of function); 4....

...b) Male or female with histologically confirmed, metastatic breast cancer and documented BRCA1 or BRCA2 germline mutation, regardless of tumour steroid hormone receptor or HER-2 status OR...

...• Biological effects in the primary tumour following a short pre-operative course of treatment with Olaparib in patients with platinum sensitive relapsed ovarian cancer; the biological effects are assess in terms of the degree of PAR or PARP-1 inhibition (in tissue and ctDNA) • Germline HRD mutations and tissue mutation with respect to BRCA1/2, RAD51B, RAD51C, RAD51D, PPM1D, FANCM, BRIP1, PALB2 and BARD1 (in tissue and ctDNA)• Generate initial clinical efficacy data for future studies (RECIST 1.1)...

...Documented mutation in BRCA1 or BRCA2 that is predicted to be deleterious or suspected deleterious from germline or a tumour specimen, prior to provision of informed consent 5....

...- All participants must have documented BRCA 1/2 mutant or other HRD+ in solid tumor, which is identified through a validated sequencing test...

...- Documented mutation in BRCA1 or BRCA2 that is predicted to be deleterious or suspected deleterious (known or predicted to be detrimental/lead to loss of function)....

...Difference in levels of PAR or PARP-1 before and after study treatment`Mutations in BRCA1/2, RAD51B, RAD51C, RAD51D, PPM1D, FANCM, BRIP1, PALB2 and BARD1 in germline tissue compared to tumor tissue...

...- Documented BRCA mutations (germline and/or somatic mutation in BRCA1 (Breast Cancer gene 1) and/or BRCA2 (Breast Cancer gene 2) that is predicted to be deleterious or suspected deleterious (known or predicted to be detrimental/lead to loss of function))...

...Documented absence of somatic and germline mutations of BRCA 1 /2....

...Documented absence of somatic and germline mutations of BRCA1 or BRCA2 genes, that is predicted to be deleterious or suspected deleterious 4....

...Histologically proven advanced cancer, either locally or metastatic, harboring a specific pathogenic genetic alteration (with the exception of breast, pancreas, or prostate cancer patients harboring a BRCA1/2 mutation and HRD ovarian cancer) 4....

...Men with BRCA1/2 mutation and metastatic breast cancer will be eligible for study....

...For patients enrolling in the sporadic serous epithelial ovarian cancer group, Group B, a negative family history (BRCAPRO score less than or equal to 20% or negative BRCA1/2 mutation test)....

...1- Provision of informed consent prior to any study specific procedures 2- Female or male aged > 18 years 3- Histologically proven advanced cancer, either locally or metastatic, harboring a specific pathogenic genetic alteration (with the exception of breast, pancreas, ovarian or prostate cancer patients harboring a BRCA1/2 mutation) 4- No approved targeted therapy for the specific genetic alteration in the specific tumor type 5- No other genomic driven phase I, II or III trial available for the specific genomic alteration in the specific tumor type 6- Available tumor tissue for verification of the mutation by Sanger sequencing. ...

...Documented mutation in BRCA1 or BRCA2 germline and/or somatic that is predicted to be deleterious or suspected deleterious (known or predicted to be detrimental/lead to loss of function);4. ...

10% of patients received olaparib for ≥5 years. Median PFS was 14.3 months (95% CI 12.2–18.0). Median overall survival was 35.4 months (95% CI 29.2–47.1)….This real-word study supports efficacy and tolerability of olaparib maintenance therapy after PBC in patients with BRCAm PSROC.

For patients with a BRCA mutation who did not have the opportunity to receive a PARPi in first-line, this exploratory analysis of SOLO2 in patients with first recurrence showed that maintenance olaparib following a response to chemotherapy leads to a clinically meaningful survival benefit. These results support the recommended use of olaparib in this patient subgroup.

177 patients received olaparib. At the primary data cut-off (17 April 2020), the median follow-up for PFS in the BRCAm cohort was 22.3 months. The median PFS (95% CI) in BRCAm, sBRCAm, gBRCAm and non-BRCA HRRm cohorts was 18.0 (14.3-22.1), 16.6 (12.4-22.2), 19.3 (14.3-27.6) and 16.4 (10.9-19.3) months, respectively. Most patients with BRCAm reported improvements (21.8%)....Maintenance olaparib had similar clinical activity in PSR OC patients with sBRCAm and those with any BRCAm....ORZORA further supports use of maintenance olaparib in all patients with BRCA-mutated, including sBRCA-mutated, PSR OC.

We present the results of a national real-world study on the effectiveness of olaparib in relapsed BRCA-mutated EOC patients….The median PFS was 17.0 months (95%CI=14.7-21.3) in the EMA label population and 15.5 months (95% CI=12.6-18.1) in the whole population (Figure 1)....The median OS in the EMA label population and in the whole population was 34.9 months (95%CI=27.2-46.4) and 33.6 months (95%CI=28.7-40.3), respectively (Figure 2). The 1-year OS rate was 88.4% (95% CI=79.6-93.6) in the EMA label population and 87.9% (95% CI=80.8-92.5) in the whole study cohort; the 2-year OS rate was 66.14% (95% CI=55.1-75.1) and 65.8% (95% CI=56.7-73.5).

260 pts were randomized to olaparib and 131 to pbo (median treatment duration 24.6 vs 13.9m, respectively). At OS data maturity of 38.1% (data cut-off 7 Mar 2022), median OS was not reached in olaparib pts vs 75.2m in pbo pts, with an OS HR of 0.55 (95% CI 0.40–0.76; unadjusted for crossover; 44.3% of pbo pts received a PARP inhibitor in a subsequent line of therapy) (Table). At 7y, 45.3% of olaparib pts vs 20.6% of pbo pts were alive and had still not received a first subsequent treatment (KM estimates). The incidence of MDS/AML remained low and new primary malignancies remained balanced between arms. 2y of maintenance olaparib provided a clinically meaningful improvement in OS over pbo in pts with newly diagnosed advanced OC and a BRCAm. At 7y, 67.0% of olaparib pts vs 46.5% of pbo pts were alive; no new safety signals were detected. These data provide the longest f/u for any PARP inhibitor in this setting and support use of maintenance olaparib to achieve long-term remission and enhance the potential for cure.

This real world study complements SOLO-1 RCT data by demonstrating prolonged benefit of 1L olaparib in newly diagnosed pts with BRCAm AOC in terms of lower likelihood of progression (tx switch/death).

At DCO (June 25, 2021), median OS follow-up in censored pts was 42.6 mo in BRCAm and 39.3 mo in non-BRCA HRRm pts. OS and PFS2 are reported in the Table. PBC was received as a subsequent therapy by 33.1% BRCAm, 32.7% sBRCAm, 33.3% gBRCAm, and 45.5% non-BRCA HRRm pts...In final OS analyses, maintenance olaparib capsules showed consistent clinical activity in BRCAm and sBRCAm PSROC pts...

Adding bevacizumab to olaparib was associated with a numerical improvement in PFS compared with olaparib alone (hazard ratio [HR] 0.71; 95% confidence interval [CI] 0.45-1.09). Statistically significant improvements in PFS were seen with olaparib alone versus placebo plus bevacizumab (HR 0.48; 95% CI 0.30-0.75), olaparib plus bevacizumab versus placebo (0.23; 0.14-0.34), and placebo plus bevacizumab versus placebo (0.65; 0.43-0.95). Results of this hypothesis-generating PA-ITC analysis support the use of maintenance olaparib alone or with bevacizumab in patients with newly diagnosed, advanced ovarian cancer and a BRCAm.

Analysis shows olaparib is safe and effective maintainance treatment in BRCA1/2 relapsed epithelial ovarian cancer…

Overall, OLA users showed significantly better progression-free survival (PFS) than BEV users (median, 23.8 vs. 17.4 months; p=0.004). Before matching, PFS improved in the OLA intent group but marginal statistical significance (p=0.057). Compared to BEV, intention-to-treat OLA and actual use of OLA maintenance therapy were significantly associated with decreased disease recurrence risk in patients with BRCA-mutated, PSR HGSOC.

Of 272 enrolled pts, 271 received olaparib...Consistent with the primary analysis, the 18-mo OS rate was highest in the BRCAm cohorts (similar OS in g and sBRCAm); among pts without a BRCAm, 18-mo OS was highest in the HRD +ve cohort.

A total of 181 pts were enrolled in ORZORA (BRCAm n = 145 [s n = 55; g n = 87; n = 3 s vs g status unknown]; HRRm n = 33; unassigned n = 3) . Pt characteristics were similar between s and g cohorts: ≥3 prior lines of chemotherapy (38% vs 48%, respectively); partial response to prior platinum (45% vs 49%); tumor BRCA1-mutated (65% vs 64%)....Results highlight that PSROC pts beyond those with a gBRCAm can benefit from maintenance olaparib.

We included HGSOC p treated with ssq CT after progression to maintenance PARPi...56p were identified (32p BRCAmut; 1p BRIP1mut). 4p (7.1%) received PARPi after 1st line CT, 26 (46.4%) after 2nd line and 26 (46.4%) after ≥3rd line. 34p (60.7%) received olaparib and 22 (39.3%) niraparib...m-PARPi-PFS in the recurrent setting was 7.5 mo (longer in BRCAmut: 10.1 vs 5.5 mo, p 0.03). m-PARPi-PFS2 was 15.8 mo (longer in BRCAmut: 20.9 vs 15.4 mo, p 0.07).

260 pts were randomized to olaparib; 131 to pbo (median treatment duration 24.6 vs 13.9 m, respectively). After a median of 4.8 and 5.0 y of f/u, median PFS was 56 vs 14 m (Table). Among pts in CR at baseline, risk of disease recurrence or death was reduced by 63%....For pts with a BRCAm and newly diagnosed advanced OC the benefit derived from 2 y of maintenance olaparib was sustained beyond the end of treatment and after 5y almost half of pts were progression-free vs 20% with pbo. Over 50% of pts in CR after first-line platinum-based chemotherapy remained free from relapse 5y later.

For pts with a BRCAm and newly diagnosed advanced OC the benefit derived from 2 y of maintenance olaparib was sustained beyond the end of treatment and after 5 y almost half of pts were progression-free vs 20% with pbo. Over 50% of pts in CR after first-line platinum-based chemotherapy remained free from relapse 5 y later. 5-y f/u is the longest for any PARP inhibitor in this setting and no new safety signals were observed.

SOLO2 (ENGOT Ov-21; NCT01874353) demonstrated that maintenance olaparib (O) in patients (pts) with platinum-sensitive relapsed EOC and a BRCA1/2 mutation led to clinically significant survival benefit. We report on the efficacy of subsequent chemotherapy at the time of disease progression...106/195 (54%) and 80/99 (81%) pts had a RECIST progression in the O and P arms respectively. Pt baseline demographics were balanced between both arms. Overall, 161/186 (87%) pts received a first subsequent therapy, including a chemotherapy in 150/161 (93%) and a PARP inhibitor in 29/161 (18%, all in the P arm). In the P arm, 33/75 (44%) and 42/75 (56%) pts received a non-platinum and a platinum-based chemotherapy respectively vs 32/86 (37%) and 54/86 (63%) in the O arm. Overall, in pts receiving subsequent treatment, TTSP was longer in the placebo compared to the O arm: 11.1 vs 7 months (HR 1.93; 95% CI [1.35-2.76]). TTSP was 14.3 vs 7m with platinum-based chemotherapy and 8.3 vs 5.5m with non-platinum chemotherapy in the P and O arm respectively.

Overall, 128 pts were included in the analysis and 89 were treated according to EMA label. Main reasons to be given olaparib off-label were absence of radiological response following platinum-based chemotherapy (n=22) and non high-grade serous EOC subtype (n=14). BRCA1/2 mutation was present in 126 pts (98%). Most pts (68%) received olaparib after 3 or more lines of platinum-based chemotherapy. Median follow up was 41.8 months. Median PFS in ptsEMA was 17.0 months (95% CI: 14.7-21.3). Median PFS and overall survival (OS) in the whole population were 15.5 months (95% CI: 12.6-18.1) and 33.6 months (95% CI: 28.7; 40.3), respectively. Fourteen (11.2%) pts stopped olaparib for toxicity reason and 75 (58.6%) had at least one dose reduction or one dose interruption. Related myelodysplastic syndrome and second cancers were diagnosed in respectively n=5 and n=1 pts. Number of previous lines of systemic therapy ≤2 was associated with prolonged PFS.

Olaparib treatment demonstrated activity across all cohorts. As observed in the maintenance setting, similar efficacy was seen in the gBRCAm and sBRCAm cohorts.

Nine different cancer types were included: prostate (n=11), breast (n=4), ovarian (n=2), pancreatic (n=3), colorectal (n=2), biliary tract (n=2), kidney (n=1), adrenal gland (n=1) and endometrial (n=1). The primary endpoint was clinical benefit (CB: objective response or stable disease (SD) ≥ 16 weeks). CB was observed in pts with both somatic and germline BRCA alterations and across tumor types.

Platinum-free interval ≥ 12 months, complete response and normalized CA-125 levels after ultimate platinum-based chemotherapy are associated with prolonged PFS and OS in relapsing BRCA mutated ovarian cancer patients who received olaparib as maintenance therapy.

The PFS benefit in pts with a tBRCAm and in HRD-positive pts was substantial.

Twenty (40%; 95% CI, 26% to 55%) achieved Response Evaluation Criteria in Solid Tumors (RECIST) complete or partial responses and/or tumor marker (CA125) responses, and three (6.0%) maintained RECIST disease stabilization for more than 4 months, giving an overall clinical benefit rate of 46% (95% CI, 32% to 61%)....Olaparib has antitumor activity in BRCA1/2 mutation ovarian cancer, which is associated with platinum sensitivity.

In this updated analysis, median PFS remained significantly longer with cediranib/olaparib compared with olaparib alone (16.5 versus 8.2 months, hazard ratio 0.50; P = 0.007)…PFS and OS appeared similar between the two arms in gBRCAm patients….Subset analyses suggest this margin of benefit is driven by PFS prolongation in patients without gBRCAm.

...12 of the 19 (63%) had a clinical benefit from treatment with olaparib, with radiologic or tumor-marker responses or meaningful disease stabilization (stable disease for a period of 4 months or more). Nine BRCA carriers had a response according to RECIST, with the response sustained for more than 76 weeks in one patient (Figure 2C and Table 4)....Overall, eight patients with advanced ovarian cancer had a partial response on radiology, according to RECIST...

Olaparib proved to be a safe and effective option for the treatment of a patient with multidrug-resistant, BRCA1-mutated EOC with CNS metastases.

Here, we investigated the ability of paraspeckle component 1 (PSPC1), as an additional synthetic lethal partner with BRCA1/2, to enhance olaparib sensitivity in preclinical models of BRCA1/2-mutated breast and ovarian cancers. In vitro, the combined olaparib and PSPC1 small interfering RNA (siRNA) exhibited synergistic anti-proliferative activity in BRCA1/2-mutated breast and ovarian cancer cells. The combination therapy also demonstrated synergistic tumor inhibition in a xenograft mouse model.