Talazoparib In Patients Research Articles

Study to Evaluate Sacituzumab Govitecan in Combination With Talazoparib in Patients With Metastatic Breast Cancer.

Study to Evaluate Sacituzumab Govitecan in Combination With Talazoparib in Patients With Metastatic Breast Cancer.

Talazoparib beyond BRCA: A phase II trial of talazoparib monotherapy in BRCA1 and BRCA2 wild-type patients with advanced HER2-negative breast cancer or other solid tumors with a mutation in homologous recombination (HR) pathway genes.

3006 Background: Talazoparib, a PARP inhibitor, is active in germline BRCA1/2 mutant advanced HER2-negative breast cancer, but its activity beyond BRCA1/2 is unknown. We conducted a single institution phase II trial to evaluate talazoparib in patients (pts) with advanced HER2-negative breast cancer or other solid tumors with a germline (g) or somatic (s) alteration in HR pathway genes not including BRCA1/2. Methods: Eligible pts had measurable disease, lacked a germline or somatic mutation in BRCA1/2, received at least one prior therapy for advanced HER2-negative breast cancer or other solid tumor and had a HR pathway gene mutation: PALB2, CHEK2, ATM, NBN, BARD1, BRIP1, RAD50, RAD51C, RAD51D, MRE11, ATR, PTEN, FANCA, FANCC, FANCD2, FANCE, FANCF, FANCG, FANCL. Pts with no progression on or within 8 weeks of their last platinum dose were eligible. Pts were treated with talazoparib 1 mg po daily until disease progression. Response was assessed every 8 +/- 1 weeks. If 2 or more responses were observed in 10 pts in stage I, the study would proceed to stage II and enroll 10 additional pts. The null hypothesis of a ≤ 5% objective response rate would be rejected if at least 3 of 20 respond. Results: Twenty pts were enrolled; 13 breast cancer (12 HR+/HER2-, 1 TNBC) and 7 non-breast cancer (pancreas, colon, uterine, testicular, parotid salivary). Median age was 54 years. Of 12 response evaluable pts with breast cancer, 3 had a RECIST response (ORR = 25%, 2 g PALB2, 1 g CHEK2/g FANCA/sPTEN) and 3 additional pts (g PALB2, s ATR, s PTEN) had SD ≥ 6 months (CBR = 50%). No responses were seen in non-breast tumors; 2 (g CHEK2 testicular, g ATM colon) had SD ≥ 6 months. Talazoparib was well tolerated; 5 patients required dose reduction for hematologic toxicity. Results of tumor HR deficiency status assessment from metastatic biopsies and serial ctDNA profiling will be presented. Conclusions: In this proof-of-concept phase II study, single agent talazoparib demonstrated activity in HER2-negative advanced breast cancer pts with a HR pathway mutation beyond BRCA1/2. Further evaluation of talazoparib in this population is warranted. Clinical trial information: NCT02401347.

Major clinical research advances in gynecologic cancer in 2018.

Nineteen topics were selected as major clinical research advances in gynecologic oncology in 2018. For cervical cancer, the importance of human papillomavirus (HPV) testing alone as primary cervical cancer screening method and negative survival impact of minimally invasive surgery in early-stage cervical cancer were addressed. For ovarian cancer, cost-effectiveness of genetic testing to prevent cancer, use of analgesics and oral pill to reduce cancer risk, efficacy of secondary cytoreductive surgery and hyperthermic intraperitoneal chemotherapy, update in the use of poly (ADP-ribose) polymerase inhibitor, and efficacy of anti-angiogenic targeted treatments, including bevacizumab and tyrosine kinase inhibitors, were reviewed. For corpus cancer, sentinel lymph node mapping technique, adjuvant therapy in high-risk endometrial cancer (PORTEC-3), and targeted therapy in recurrent disease were covered. For the field of radiation oncology, survival outcomes of chemoradiation compared with chemotherapy alone in metastatic cervical cancer and new findings regarding the use of neoadjuvant chemotherapy in locally advanced cervical cancer were introduced. Lastly, for breast cancer, the use of talazoparib in patients with germline BRCA1/2 mutation, ovarian suppression for premenopausal patients, adjuvant chemotherapy guided by 21-gene assay, and combination therapy of atezolizumab and nab-paclitaxel for triple-negative cancer as well as promising overall survival results of palbociclib and fulvestrant in advanced breast cancer were briefly mentioned.

Quality of life with talazoparib after platinum or multiple cytotoxic non-platinum regimens in patients with advanced breast cancer and germline BRCA1/2 mutations: patient-reported outcomes from the ABRAZO phase 2 trial

BackgroundTalazoparib (1 mg/day) exhibited promising efficacy and safety in patients with advanced breast cancer during ABRAZO (NCT02034916); this study evaluated patient-reported outcomes (PROs). Patients and methodsABRAZO is a two-cohort, two-stage, phase 2 study of talazoparib in patients with advanced breast cancer after a response to prior platinum-based therapy (cohort 1 [C1], n = 49) or ≥3 platinum-free cytotoxic-based regimens (cohort 2 [C2], n = 35). PROs were assessed on day 1 (baseline), every 6 weeks for an initial 24 weeks, and every 12 weeks thereafter until progression, using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (QLQ-C30) and its breast cancer module, QLQ-BR23. ResultsGlobal health status/quality of life (GHS/QoL) was maintained from baseline across all time points for both C1 and C2. For C1 and C2, median time to deterioration (TTD) of GHS/QoL (95% confidence interval [CI]) was 2.8 (2.1, 3.0) and 5.5 (4.2, 5.7) months, respectively. Median TTD for all QLQ-C30 functional scales for C1 and C2 ranged 2.1–3.1 months and 4.2–5.6 months, respectively; median TTD for all QLQ-BR23 symptom scales ranged 2.6–4.0 months and 4.2–5.6 months, respectively. There were no statistically significant differences in estimated overall change from baseline in the GHS/QoL scale for both cohorts (C1: −2.6 [95% CI, −7.8, 2.5]; C2: 1.2 [95% CI, −5.5, 8.0]). Significant overall improvements in the breast symptoms and arm symptoms and the future perspective of patients in C1 and C2 were observed, despite the statistically significant and clinically meaningful overall deterioration among patients regarding their role functioning (in C1) and dyspnoea symptoms (in C2). ConclusionDespite the statistically significant and clinically meaningful overall deterioration among patients regarding their role functioning (in C1) and dyspnoea symptoms (in C2), patients in both C1 and C2 reported significant overall improvements in their breast symptoms, arm symptoms and future perspective, and their GHS/QoL was maintained from baseline.

Talazoparib in Patients with Advanced Breast Cancer and a Germline BRCA Mutation

BackgroundThe poly(adenosine diphosphate–ribose) inhibitor talazoparib has shown antitumor activity in patients with advanced breast cancer and germline mutations in BRCA1 and BRCA2 (BRCA1/2).MethodsWe conducted a randomized, open-label, phase 3 trial in which patients with advanced breast cancer and a germline BRCA1/2 mutation were assigned, in a 2:1 ratio, to receive talazoparib (1 mg once daily) or standard single-agent therapy of the physician’s choice (capecitabine, eribulin, gemcitabine, or vinorelbine in continuous 21-day cycles). The primary end point was progression-free survival, which was assessed by blinded independent central review.ResultsOf the 431 patients who underwent randomization, 287 were assigned to receive talazoparib and 144 were assigned to receive standard therapy. Median progression-free survival was significantly longer in the talazoparib group than in the standard-therapy group (8.6 months vs. 5.6 months; hazard ratio for disease progression or death, 0.54; 95% confidence interval [CI], 0.41 to 0.71; P<0.001). The interim median hazard ratio for death was 0.76 (95% CI, 0.55 to 1.06; P=0.11 [57% of projected events]). The objective response rate was higher in the talazoparib group than in the standard-therapy group (62.6% vs. 27.2%; odds ratio, 5.0; 95% CI, 2.9 to 8.8; P<0.001). Hematologic grade 3–4 adverse events (primarily anemia) occurred in 55% of the patients who received talazoparib and in 38% of the patients who received standard therapy; nonhematologic grade 3 adverse events occurred in 32% and 38% of the patients, respectively. Patient-reported outcomes favored talazoparib; significant overall improvements and significant delays in the time to clinically meaningful deterioration according to both the global health status–quality-of-life and breast symptoms scales were observed.ConclusionsAmong patients with advanced breast cancer and a germline BRCA1/2 mutation, single-agent talazoparib provided a significant benefit over standard chemotherapy with respect to progression-free survival. Patient-reported outcomes were superior with talazoparib. (Funded by Medivation [Pfizer]; EMBRACA ClinicalTrials.gov number, NCT01945775.)

Abstract P5-19-05: Health-related quality of life during a phase 2 study of talazoparib in patients with advanced breast cancer and germline BRCA1/2 mutations (ABRAZO)

Abstract Background: Talazoparib (TALA; 1 mg/d) was well tolerated and exhibited promising antitumor activity in ABRAZO, a 2-cohort, 2-stage, open-label phase 2 study (NCT02034916) in patients (pts) with locally advanced or metastatic breast cancer and gBRCA1/2 mutations following platinum-based therapy (cohort 1 [C1]) or ≥3 platinum-free cytotoxic-based regimens (cohort 2 [C2]). This analysis evaluates health-related quality of life (QoL) for both cohorts. Methods: QoL was assessed on day 1 (baseline) and every 6 weeks for the initial 24 weeks and every 12 weeks thereafter, or sooner if progression was clinically suspected, using the EORTC QLQ-C30 and its breast cancer module, QLQ-BR23. For all scales, results were summarized using descriptive statistics for each cohort and at each time point, based on Characters (max 3400 including title, body and table [including spaces]): 3363 No abbreviations in title; title sentence case; define acronyms; no figures Category: Psychosocial, QOL, and Educational Aspects – Other 2 observed values and changes from baseline (clinically meaningful defined as ≥10-point change from baseline). Time to deterioration (TTD; defined as ≥10-point decrease in global health status [GHS]/functional scales or increase in symptom scales) analyses using survival analysis methods were carried out on the GHS/functional scales of QLQ-C30 and symptom scales of QLQ-BR23. Results:GHS was maintained from baseline across all time points for both C1 and C2 except at week 24 in C2, when a statistically significant but not clinically meaningful improvement in GHS was observed. In C1, statistically significant and clinically meaningful improvement was observed at specific time points in 4 functional scales (body image, week 6; sexual functioning, week 24; sexual enjoyment, week 36; and future perspective, weeks 6, 18, and 24) and in 3 symptom scales (dyspnea, week 24; insomnia, week 24; and breast symptoms, weeks 6 and 36). Statistically significant and clinically meaningful deterioration in C1 was observed in 2 functional scales (emotional functioning, week 12 and end of treatment, and role functioning, end of treatment) and in 1 symptom scale (fatigue, week 6). In C2, statistically significant and clinically meaningful improvement was observed at specific time points in 4 functional scales (role functioning, week 24; social functioning, week 24; sexual enjoyment, week 18; and future perspective, weeks 6, 12, and 18) and in 5 symptom scales (nausea/vomiting, week 18; pain, weeks 12, 18, and 24; insomnia, week 24; breast symptoms, weeks 12 and 18; and arm symptoms, week 48). For C2, no statistically significant and clinically meaningful deterioration was observed for any functional or symptoms scales across all time points, except in the dyspnea symptom scale at week 18. For C1 and C2, the median (95% confidence interval) TTD of GHS was 2.8 (2.1-3.0) and 5.5 (4.2-5.7) months, respectively. The median TTD for all QLQ-C30 functional scales for C1 and C2 ranged 2.1-3.1 and 4.2-5.6 months, respectively; the median TTD for all QLQ-BR23 symptoms scales ranged 2.6-4.0 and 4.2-5.6 months, respectively. Conclusions: The QoL of TALA-treated patients during ABRAZO was maintained. QoL is being evaluated among atients with germline BRCA1/2 mutated advanced BC treated with TALA vs physician's choice chemotherapy in the phase 3 EMBRACA trial (NCT01945775). Citation Format: Hurvitz SA, Turner NC, Telli ML, Rugo HS, Mailliez A, Ettl J, Grischke E-M, Mina LA, Balmaña J, Fasching PA, Tudor C, Quek RGW, Hannah AL, Robson ME, Wardley AM. Health-related quality of life during a phase 2 study of talazoparib in patients with advanced breast cancer and germline BRCA1/2 mutations (ABRAZO) [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P5-19-05.

A feasibility study of neoadjuvant talazoparib for operable breast cancer patients with a germline BRCA mutation demonstrates marked activity

This study was undertaken to determine the feasibility of enrolling breast cancer patients on a single-agent-targeted therapy trial before neoadjuvant chemotherapy. Specifically, we evaluated talazoparib in patients harboring a deleterious BRCA mutation (BRCA+). Patients with a germline BRCA mutation and ≥1 cm, HER2-negative primary tumors were eligible. Study participants underwent a pretreatment biopsy, 2 months of talazoparib, off-study core biopsy, anthracycline, and taxane-based chemotherapy ± carboplatin, followed by surgery. Volumetric changes in tumor size were determined by ultrasound at 1 and 2 months of therapy. Success was defined as 20 patients accrued within 2 years and <33% experienced a grade 4 toxicity. The study was stopped early after 13 patients (BRCA1 + n = 10; BRCA2 + n = 3) were accrued within 8 months with no grade 4 toxicities and only one patient requiring dose reduction due to grade 3 neutropenia. The median age was 40 years (range 25–55) and clinical stage included I (n = 2), II (n = 9), and III (n = 2). Most tumors (n = 9) were hormone receptor-negative, and one of these was metaplastic. Decreases in tumor volume occurred in all patients following 2 months of talazoparib; the median was 88% (range 30–98%). Common toxicities were neutropenia, anemia, thrombocytopenia, nausea, dizziness, and fatigue. Single-agent-targeted therapy trials are feasible in BRCA+ patients. Given the rapid rate of accrual, profound response and favorable toxicity profile, the feasibility study was modified into a phase II study to determine pathologic complete response rates after 4–6 months of single-agent talazoparib.

A phase I study of carboplatin and talazoparib in patients with and without DNA repair mutations.

2527 Background: Talazoparib is a novel PARP inhibitor (PARPi) in clinical development. Synergistic anti-tumor effects of PARPi and chemotherapy have been observed in preclinical models. Overlapping toxicity may limit tolerability in patients with germline DNA repair defects. Methods: In a dose escalation Phase 1 trial, we tested the safety, tolerability, pharmacokinetics (PK), and efficacy of talazoparib and carboplatin in patients with and without germ line mutations. Results: 24 patients with solid tumors were enrolled in 4 cohorts evaluating talazoparib 0.75 or 1 mg daily and carboplatin AUC 1 or 1.5 mg/mL/min 2 or 3 weeks of a 3-week cycle. Dose-limiting toxicities included grade 3 fatigue and grade 4 thrombocytopenia. Other grade 3/4 toxicities included fatigue (13%), neutropenia (63%), thrombocytopenia (29%), and anemia (38%). Post cycle 2 hematologic toxicities required dose delays/reductions in all patients. One complete and two partial responses occurred in germline BRCA1/2 (gBRCA1/2) patients. Of the 4 patients with stable disease beyond 4 months, 3 had somatic BRCA mutations and 1 had a BRIP1 germline mutation suggesting greater benefit in tumors with DNA repair mutations. PK-toxicity modeling suggests that after 3 cycles of carboplatin AUC 1.5 weekly and talazoparib 1 mg daily, the percent decrease in neutrophil counts from baseline was significantly more pronounced in gBRCA carriers; -78% (95% CI: -87 to -68%) vs. non-carriers; -63% (95% CI: -72 to -55%), p-value &lt; 0.001. This modeling also showed that 2-4 fold dose reductions for each drug are needed to improve tolerability of this combination. Pulse dosing of talazoparib may be more tolerable in gBRCA carriers. Conclusions: The combination of carboplatin and talazoparib showed responses in gBRCA carriers but also had increased hematologic toxicity in gBRCA carriers. PK toxicity modeling was used to determine alternate dosing strategies based on carrier status. Clinical trial information: NCT02317874.

Abstract OT1-03-17: ABRAZO: An international phase 2 (2-stage, 2-cohort) study of the oral PARP inhibitor talazoparib (BMN 673) in BRCA mutation subjects with locally advanced and/or metastatic breast cancer

Abstract Background: Cancer cells with deleterious mutations in breast cancer susceptibility genes 1 and 2 (BRCA1/2) are deficient in the DNA double-strand break repair mechanism, rendering them highly dependent on the single-strand break repair pathway, which is initiated by poly-(ADP-ribose) polymerase (PARP) [1-3]. In cells with deleterious BRCA1/2 mutations, PARP inhibition is synthetically lethal because of accumulation of irreparable DNA damage [1-3]. Talazoparib (BMN 673) exhibits a novel two-pronged approach in treating BRCA1/2-mutant tumors: 1) potent catalytic inhibition of the PARP enzyme; and 2) trapping of PARP at sites of DNA damage [4-7]. The capacity to trap PARP-DNA complexes varies widely across PARP inhibitors and is not correlated with catalytic inhibition potency [4-7]. In preclinical models, trapping PARP on DNA is more potent at inducing cancer cell death than enzymatic inhibition of PARP alone [4,7]. Talazoparib is the most potent clinical-stage PARP inhibitor tested to date with the highest efficacy at trapping PARP-DNA complexes [7]. Talazoparib has shown single-agent antitumor efficacy in several solid tumor types and was generally well tolerated in a phase 1/2 clinical study [8]. Methods: This 2-stage, 2-cohort, phase 2 international study (ABRAZO) evaluates the safety and efficacy of talazoparib in patients with a deleterious germline BRCA1 or BRCA2 mutation with locally advanced and/or metastatic breast cancer. Eligible subjects will be assigned to one of two cohorts based on prior chemotherapy for metastatic disease. Cohort 1 (n=70) includes patients with a complete response (CR) or partial response (PR) to platinum-containing regimens for metastatic disease. Cohort 2 (n=70) includes patients who have received &amp;gt;2 prior chemotherapy regimens in the metastatic setting but have not had prior platinum therapy for locally advanced or metastatic disease (prior adjuvant or neoadjuvant therapy with a platinum is allowed). The primary objective is objective response rate (ORR). Secondary objectives include clinical benefit response (CBR) rate, duration of response (DOR), progression-free survival (PFS), and overall survival (OS). Health-related quality of life (QoL) assessments are an exploratory objective. Eligible subjects will receive oral talazoparib (1 mg/day, 21-day cycles) until disease progression or unacceptable toxicity. This trial is currently enrolling patients from the United States and Europe (NCT02034916). This study is funded by BioMarin Pharmaceutical Inc.