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Using an adaptive trial design to minimize the exposure of patients to inactive agents and to detect more active regimens sooner, investigators found that adding veliparib and carboplatin to standard therapy improved outcome in triple-negative breast cancer. Breast cancer is genetically and clinically heterogeneous, which makes it challenging to identify effective patient-specific therapies. Although mortality due to breast cancer in the United States has decreased, more than 40,000 women in the United States still die from this disease each year. 1 Further decreases in mortality will require therapeutic options that target biologic properties of tumors and can be delivered early enough in the disease course to make a clinical difference. The neoadjuvant approach facilitates the evaluation of an individual patient's response to treatment and holds promise for the development of experimental therapies for disease while it is still . . .

Poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors as maintenance therapy after first-line chemotherapy have improved progression-free survival in women with advanced ovarian cancer; however, not all PARP inhibitors can provide benefit for a biomarker-unselected population. Senaparib is a PARP inhibitor that demonstrated antitumor activity in patients with solid tumors, including ovarian cancer, in phase 1 studies. The multicenter, double-blind, phase 3 trial FLAMES randomized (2:1) 404 females with advanced ovarian cancer (International Federation of Gynecology and Obstetrics stage III–IV) and response to first-line platinum-based chemotherapy to senaparib 100 mg ( n  = 271) or placebo ( n  = 133) orally once daily for up to 2 years. The primary endpoint was progression-free survival assessed by blinded independent central review. At the prespecified interim analysis, the median progression-free survival was not reached with senaparib and was 13.6 months with placebo (hazard ratio 0.43, 95% confidence interval 0.32–0.58; P  < 0.0001). The benefit with senaparib over placebo was consistent in the subgroups defined by BRCA1 and BRCA2 mutation or homologous recombination status. Grade ≥3 treatment-emergent adverse events occurred in 179 (66%) and 27 (20%) patients, respectively. Senaparib significantly improved progression-free survival versus placebo in patients with advanced ovarian cancer after response to first-line platinum-based chemotherapy, irrespective of BRCA1 and BRCA2 mutation status and with consistent benefits observed between homologous recombination subgroups, and was well tolerated. These results support senaparib as a maintenance treatment for patients with advanced ovarian cancer after a response to first-line chemotherapy. ClinicalTrials.gov identifier: NCT04169997 . In a prespecified interim analysis of the multicenter, randomized, phase 3 FLAMES trial, maintenance therapy with a PARP inhibitor in patients with ovarian cancer showed prolonged progression-free survival compared with placebo in all subgroups defined by BRCA or homologous recombination status.

Rucaparib, a poly(ADP-ribose) polymerase inhibitor, has anticancer activity in recurrent ovarian carcinoma harbouring a BRCA mutation or high percentage of genome-wide loss of heterozygosity. In this trial we assessed rucaparib versus placebo after response to second-line or later platinum-based chemotherapy in patients with high-grade, recurrent, platinum-sensitive ovarian carcinoma. In this randomised, double-blind, placebo-controlled, phase 3 trial, we recruited patients from 87 hospitals and cancer centres across 11 countries. Eligible patients were aged 18 years or older, had a platinum-sensitive, high-grade serous or endometrioid ovarian, primary peritoneal, or fallopian tube carcinoma, had received at least two previous platinum-based chemotherapy regimens, had achieved complete or partial response to their last platinum-based regimen, had a cancer antigen 125 concentration of less than the upper limit of normal, had a performance status of 0–1, and had adequate organ function. Patients were ineligible if they had symptomatic or untreated central nervous system metastases, had received anticancer therapy 14 days or fewer before starting the study, or had received previous treatment with a poly(ADP-ribose) polymerase inhibitor. We randomly allocated patients 2:1 to receive oral rucaparib 600 mg twice daily or placebo in 28 day cycles using a computer-generated sequence (block size of six, stratified by homologous recombination repair gene mutation status, progression-free interval after the penultimate platinum-based regimen, and best response to the most recent platinum-based regimen). Patients, investigators, site staff, assessors, and the funder were masked to assignments. The primary outcome was investigator-assessed progression-free survival evaluated with use of an ordered step-down procedure for three nested cohorts: patients with BRCA mutations (carcinoma associated with deleterious germline or somatic BRCA mutations), patients with homologous recombination deficiencies (BRCA mutant or BRCA wild-type and high loss of heterozygosity), and the intention-to-treat population, assessed at screening and every 12 weeks thereafter. This trial is registered with ClinicalTrials.gov, number NCT01968213; enrolment is complete. Between April 7, 2014, and July 19, 2016, we randomly allocated 564 patients: 375 (66%) to rucaparib and 189 (34%) to placebo. Median progression-free survival in patients with a BRCA-mutant carcinoma was 16·6 months (95% CI 13·4–22·9; 130 [35%] patients) in the rucaparib group versus 5·4 months (3·4–6·7; 66 [35%] patients) in the placebo group (hazard ratio 0·23 [95% CI 0·16–0·34]; p<0·0001). In patients with a homologous recombination deficient carcinoma (236 [63%] vs 118 [62%]), it was 13·6 months (10·9–16·2) versus 5·4 months (5·1–5·6; 0·32 [0·24–0·42]; p<0·0001). In the intention-to-treat population, it was 10·8 months (8·3–11·4) versus 5·4 months (5·3–5·5; 0·36 [0·30–0·45]; p<0·0001). Treatment-emergent adverse events of grade 3 or higher in the safety population (372 [99%] patients in the rucaparib group vs 189 [100%] in the placebo group) were reported in 209 (56%) patients in the rucaparib group versus 28 (15%) in the placebo group, the most common of which were anaemia or decreased haemoglobin concentration (70 [19%] vs one [1%]) and increased alanine or aspartate aminotransferase concentration (39 [10%] vs none). Across all primary analysis groups, rucaparib significantly improved progression-free survival in patients with platinum-sensitive ovarian cancer who had achieved a response to platinum-based chemotherapy. ARIEL3 provides further evidence that use of a poly(ADP-ribose) polymerase inhibitor in the maintenance treatment setting versus placebo could be considered a new standard of care for women with platinum-sensitive ovarian cancer following a complete or partial response to second-line or later platinum-based chemotherapy. Clovis Oncology.

Single-agent maintenance poly(ADP-ribose) polymerase (PARP) inhibition may represent an effective strategy in patients with advanced/metastatic endometrial cancer responding to platinum-based chemotherapy, including for molecular subtypes with suboptimal options. To explore this approach, we initiated the randomized phase IIb UTOLA trial (NCT03745950). Female patients without progression following front-line platinum-based chemotherapy for advanced/metastatic endometrial cancer were randomized 2:1 to twice-daily maintenance oral olaparib 300 mg or placebo until progression or intolerance, stratified by p53 status, mismatch repair status, and response to initial chemotherapy. The primary endpoint was progression-free survival (PFS) in the intention-to-treat population. Secondary endpoints were PFS in subgroups, time to second progression or death, time to first and second subsequent therapy, objective response rate, overall survival, patient-reported outcomes, and safety. In the intention-to-treat population ( n  = 145), there was no PFS difference between olaparib and placebo (median 5.6 vs. 4.0 months, respectively; hazard ratio 0.94, 95% confidence interval 0.65–1.35; p  = 0.74). However, intriguing numerical PFS effects were observed in exploratory analyses of pre-specified subgroups (p53-abnormal, complete response to initial chemotherapy, chromosomal instability). There was no overall survival difference between treatments. Grade 3/4 adverse events occurred in 36% versus 10% of olaparib- versus placebo-treated patients and were consistent with the olaparib safety profile in other cancers. Maintenance olaparib did not improve PFS, but promising numerical effects in subsets of patients warrant prospective evaluation. Single-agent maintenance PARP inhibition may represent an effective strategy for advanced/metastatic endometrial cancer treatment. Here this randomized phase IIb UTOLA trial evaluates the efficacy and safety of orally administered olaparib in female patients ( n = 145) without progression following front-line platinum-based chemotherapy for advanced/metastatic endometrial cancer.

Poly (ADP-ribose) polymerase inhibitors (PARPi) exploit DNA repair deficiency in germline BRCA1 and BRCA2 pathogenic variant (gBRCAm) cancers. Haematological toxicity limits chemotherapy-PARPi treatment combinations. In preclinical models we identified a schedule combining olaparib and carboplatin that avoids enhanced toxicity but maintains anti-tumour activity. We investigated this schedule in a neoadjuvant, phase II-III, randomised controlled trial for gBRCAm breast cancers (ClinicalTrials.gov ID:NCT03150576; PARTNER). The research arm included carboplatin (Area Under the Curve 5, 3-weekly); paclitaxel (80 mg/m 2 , weekly) day 1, plus olaparib (150 mg twice daily) day 3-14 (4 cycles), followed by anthracycline-containing chemotherapy (3 cycles); control arm gave chemotherapy alone. The primary endpoint, pathological complete response rate, showed no statistical difference between research 64.1% (25/39); control 69.8% (30/43) ( p  = 0.59). However, estimated survival outcomes at 36-months demonstrated improved event-free survival: research 96.4%, control 80.1% ( p  = 0.04); overall survival: research 100%, control 88.2% ( p  = 0.04) and breast cancer specific survival: research 100%, control 88.2% ( p  = 0.04). There were no statistical differences in relapse-free survival and distant disease-free survival, both were: research 96.4%, control 87.9% ( p  = 0.20). Similarly, local recurrence-free survival and time to second cancer were both: research 96.4%, control 87.8% ( p  = 0.20). The PARTNER trial identified a safe, tolerable schedule combining neoadjuvant chemotherapy with olaparib. This combination demonstrated schedule-dependent overall survival benefit in early-stage gBRCAm breast cancer. This result needs confirmation in larger trials. Toxicities limit combination of PARP inhibitors (PARPi) and chemotherapy in patients with germline BRCA1 and BRCA2 pathogenic variant (gBRCAm) breast cancer. Here, the authors report a preclinical study followed by a randomised phase II/III clinical trial investigating the addition of a gap between chemotherapy (carboplatin and paclitaxel) and PARPi (olaparib), in patients with early gBRCAm breast cancer.

In ARIEL3, rucaparib maintenance treatment significantly improved progression-free survival versus placebo. Here, we report prespecified, investigator-assessed, exploratory post-progression endpoints and updated safety data. In this ongoing (enrolment complete) randomised, placebo-controlled, phase 3 trial, patients aged 18 years or older who had platinum-sensitive, high-grade serous or endometrioid ovarian, primary peritoneal, or fallopian tube carcinoma and an Eastern Cooperative Oncology Group performance status of 0 or 1 who had received at least two previous platinum-based chemotherapy regimens and responded to their last platinum-based regimen were randomly assigned (2:1) to oral rucaparib (600 mg twice daily) or placebo in 28-day cycles using a computer-generated sequence (block size of six with stratification based on homologous recombination repair gene mutation status, progression-free interval following penultimate platinum-based regimen, and best response to most recent platinum-based regimen). Patients, investigators, site staff, assessors, and the funder were masked to assignments. The primary endpoint of investigator-assessed progression-free survival has been previously reported. Prespecified, exploratory outcomes of chemotherapy-free interval (CFI), time to start of first subsequent therapy (TFST), time to disease progression on subsequent therapy or death (PFS2), and time to start of second subsequent therapy (TSST) and updated safety were analysed (visit cutoff Dec 31, 2017). Efficacy analyses were done in all patients randomised to three nested cohorts: patients with BRCA mutations, patients with homologous recombination deficiencies, and the intention-to-treat population. Safety analyses included all patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov, NCT01968213. Between April 7, 2014, and July 19, 2016, 564 patients were enrolled and randomly assigned to rucaparib (n=375) or placebo (n=189). Median follow-up was 28·1 months (IQR 22·0–33·6). In the intention-to-treat population, median CFI was 14·3 months (95% CI 13·0–17·4) in the rucaparib group versus 8·8 months (8·0–10·3) in the placebo group (hazard ratio [HR] 0·43 [95% CI 0·35–0·53]; p<0·0001), median TFST was 12·4 months (11·1–15·2) versus 7·2 months (6·4–8·6; HR 0·43 [0·35–0·52]; p<0·0001), median PFS2 was 21·0 months (18·9–23·6) versus 16·5 months (15·2–18·4; HR 0·66 [0·53–0·82]; p=0·0002), and median TSST was 22·4 months (19·1–24·5) versus 17·3 months (14·9–19·4; HR 0·68 [0·54–0·85]; p=0·0007). CFI, TFST, PFS2, and TSST were also significantly longer with rucaparib than placebo in the BRCA-mutant and homologous recombination-deficient cohorts. The most frequent treatment-emergent adverse event of grade 3 or higher was anaemia or decreased haemoglobin (80 [22%] patients in the rucaparib group vs one [1%] patient in the placebo group). Serious treatment-emergent adverse events were reported in 83 (22%) patients in the rucaparib group and 20 (11%) patients in the placebo group. Two treatment-related deaths have been previously reported in this trial; there were no new treatment-related deaths. In these exploratory analyses over a median follow-up of more than 2 years, rucaparib maintenance treatment led to a clinically meaningful delay in starting subsequent therapy and provided lasting clinical benefits versus placebo in all three analysis cohorts. Updated safety data were consistent with previous reports. Clovis Oncology.

Addition of anti-angiogenic inhibitors has the potential to enhance the efficacy of poly(ADP-ribose) polymerase (PARP) inhibitors; however, clinical evidence for their use in breast cancer is scarce. The FABULOUS study assessed fuzuloparib (an oral PARP inhibitor) with or without apatinib (an oral angiogenesis inhibitor) for breast cancer. FABULOUS was an open-label, randomised, phase 3 trial done at 40 sites in China. Eligible patients were women aged 18–75 years, with HER2-negative metastatic breast cancer with deleterious or suspected deleterious germline BRCA1 or BRCA2 (BRCA1/2) mutations and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients were randomly assigned (1:1:1) to receive oral fuzuloparib 100 mg twice daily plus oral apatinib 500 mg once daily, oral fuzuloparib 150 mg twice daily, or chemotherapy of the physician's choice (either oral capecitabine 1000–1250 mg/m2 twice daily on days 1–14 of each 21-day cycle or intravenous vinorelbine 25–30 mg/m2 on days 1 and 8 of each 21-day cycle). Randomisation was done via a centralised interactive web-response system using block randomisation (block size of six), stratified by the number of previous chemotherapy regimens for metastatic disease, hormone receptor status, and previous use of platinum-based therapy. The primary endpoint was progression-free survival per blinded independent central review (BICR). Herein, we reported the findings of prespecified interim analysis. Efficacy was assessed in the intention-to-treat population. Safety was analysed in patients who received at least one dose of study medication. This study is registered with ClinicalTrials.gov (NCT04296370). Recruitment and follow-up are ongoing to achieve the target sample size and obtain long-term efficacy and safety data. Between Oct 12, 2020, and Dec 13, 2023, 203 eligible patients were enrolled and assigned to receive fuzuloparib–apatinib (n=70), fuzuloparib (n=67), or chemotherapy (n=66). 191 (94%) patients were Han Chinese, and 12 (6%) were other ethnicity Chinese. At the present interim analysis, median time from randomisation to cutoff date was 24·2 months (IQR 13·2–31·8). Median progression-free survival per BICR was 11·0 months (95% CI 8·4–13·1) with fuzuloparib–apatinib, 6·7 months (4·2–7·6) with fuzuloparib, and 3·0 months (1·6–5·3) with chemotherapy. Compared with chemotherapy, fuzuloparib–apatinib (HR 0·27 [95% CI 0·17–0·43]; one-sided p<0·0001) or fuzuloparib alone (0·49 [0·32–0·75]; p=0·0004]) groups had significantly longer progression-free survival. Additionally, the fuzuloparib–apatinib group had significantly longer progression-free survival than fuzuloparib (0·60 [0·40–0·91]; p=0·0079). The most common grade 3–4 treatment-related adverse events were decreased neutrophil count (nine [13%]) and hypertension (nine [13%]) in the fuzuloparib–apatinib group; anaemia (25 [37%]) and decreased neutrophil count (14 [21%]) in the fuzuloparib group; and decreased neutrophil count (14 [24%]) and decreased white blood cell count (11 [19%]) in the chemotherapy group. Serious treatment-related adverse events occurred in nine (13%), 12 (18%), and eight (14%) patients in the fuzuloparib–apatinib, fuzuloparib, and chemotherapy groups, respectively. There were no treatment-related deaths in the fuzuloparib–apatinib and chemotherapy groups, and one (1%) patient in the fuzuloparib group died due to a treatment-related adverse event (septic shock). Fuzuloparib, either as monotherapy or in combination with apatinib, provided statistically significant improvements in progression-free survival compared with chemotherapy in patients with HER2-negative metastatic breast cancer with germline BRCA1/2 mutations, presenting as new treatment options. Jiangsu Hengrui Pharmaceuticals, Natural Science Foundation of China, National Key Research and Development Program of China, Guangdong Science and Technology Department, Science and Technology Program of Guangzhou, Bureau of Science and Technology of Guangzhou, and Program for Guangdong Introducing Innovative and Entrepreneurial Teams.

Background Patients with BRCA1 -like tumors correlate with improved response to DNA double-strand break-inducing therapy. A gene expression-based classifier was developed to distinguish between BRCA1 -like and non- BRCA1 -like tumors. We hypothesized that these tumors may also be more sensitive to PARP inhibitors than standard treatments. Methods A diagnostic gene expression signature ( BRCA1 ness) was developed using a centroid model with 128 triple-negative breast cancer samples from the EU FP7 RATHER project. This BRCA1 ness signature was then tested in HER2-negative patients ( n  = 116) from the I-SPY 2 TRIAL who received an oral PARP inhibitor veliparib in combination with carboplatin (V-C), or standard chemotherapy alone. We assessed the association between BRCA1 ness and pathologic complete response in the V-C and control arms alone using Fisher’s exact test, and the relative performance between arms (biomarker × treatment interaction, likelihood ratio p  < 0.05) using a logistic model and adjusting for hormone receptor status (HR). Results We developed a gene expression signature to identify BRCA1 -like status. In the I-SPY 2 neoadjuvant setting the BRCA1 ness signature associated significantly with response to V-C ( p  = 0.03), but not in the control arm ( p  = 0.45). We identified a significant interaction between BRCA1 ness and V-C ( p  = 0.023) after correcting for HR. Conclusions A genomic-based BRCA1 -like signature was successfully translated to an expression-based signature ( BRC1A ness). In the I-SPY 2 neoadjuvant setting, we determined that the BRCA1 ness signature is capable of predicting benefit of V-C added to standard chemotherapy compared to standard chemotherapy alone. Trial registration I-SPY 2 TRIAL beginning December 31, 2009: Neoadjuvant and Personalized Adaptive Novel Agents to Treat Breast Cancer (I-SPY 2), NCT01042379 .

Background Olaparib is poorly soluble, requiring advanced drug delivery technologies for adequate bioavailability. Sixteen capsules/day are required for the approved 400 mg twice-daily dose; a tablet formulation was developed to reduce pill burden. This clinical trial evaluated the optimal dose and administration schedule of the tablet formulation. Patients and Methods Two stages of sequentially enrolled cohorts: stage 1, pharmacokinetic properties of tablet and capsule formulations were compared in patients with advanced solid tumours; stage 2, tablet dose escalation with expansion cohorts at doses/schedules of interest in patients with solid tumours and BRCA m breast/ovarian cancers. Results Olaparib 200 mg tablets displayed similar C max,ss , but lower AUC ss and C min,ss than 400 mg capsules. Following multiple dosing, steady-state exposure with tablets ≥300 mg matched or exceeded that of 400 mg capsules. After dose escalation, while 400 mg twice daily was the tablet maximum tolerated dose based on haematological toxicity, 65 % of patients in the randomized expansion phase eventually required dose reduction to 300 mg. Intermittent tablet administration did not significantly improve tolerability. Tumour shrinkage was similar for 300 and 400 mg tablet and 400 mg capsule cohorts. Conclusions The recommended monotherapy dose of olaparib tablet for Phase III trials was 300 mg twice daily, simplifying drug administration from 16 capsules to four tablets per day. Clinical Trial Number NCT00777582 (ClinicalTrials.gov)

BackgroundCombining poly(ADP-ribose) polymerase (PARP) inhibitors with antiangiogenic agents appeared to enhance activity vs PARP inhibitors alone in a randomized phase II trial.Materials and methodsIn AVANOVA (NCT02354131) part 1, patients with measurable/evaluable high-grade serous/endometrioid platinum-sensitive ovarian cancer received bevacizumab 15 mg/kg every 21 days with escalating doses of niraparib capsules (100, 200, or 300 mg daily) in a 3 + 3 dose-escalation design. Primary objectives were to evaluate safety and tolerability and to determine the recommended phase II dose (RP2D).ResultsThree of 12 enrolled patients had germline BRCA2 mutations. In cycle 1, nine patients experienced grade 3 toxicities: five with hypertension, three with anemia, and one with thrombocytopenia. There was one dose-limiting toxicity (grade 4 thrombocytopenia with niraparib 300 mg), thus the RP2D was bevacizumab 15 mg/kg with niraparib 300 mg. The response rate was 50%; disease was stabilized in a further 42%. Median progression-free survival was 11.6 (95% confidence interval 8.4–20.1) months. Niraparib pharmacokinetics were consistent with historical single-agent data. Overlapping exposure was observed across the dose ranges tested on days 1 and 21.ConclusionsThere was one dose-limiting toxicity; other adverse events were typical PARP inhibitor and antiangiogenic class effects. Niraparib–bevacizumab showed promising activity; Part 2 (vs bevacizumab) was recently reported and phase III comparison with standard-of-care therapy is planned.