This Phase 1b / 2 study will examine the effects of the study drugs, avelumab, binimetinib and talazoparib when given in a 2 (doublet) or 3 (triplet) drug combination, in patients with locally advanced or metastatic RAS-mutant solid tumors. The Phase 1b part of the study will assess if the different study drugs can be given together safely and which doses to use for further research. Phase 2 will test if the study treatments have an effect on tumor size and growth, and gather more information about potential side effects.

Zie voor meer studies met talazoparib op Cancer Research

A Study of Talazoparib in Men With DNA Repair Defects and Metastatic Castration-Resistant Prostate Cancer

For the multinational phase II TALAPRO-1 trial, 128 patients with progressive metastatic castration-resistant prostate cancer were enrolled between June 4, 2017 and March 20, 2020. All had at least a monoallelic DDR gene deleterious alteration likely to sensitize them to PARP inhibition identified from an 11-gene panel (ATM, ATR, BRCA1, BRCA2, CHEK2, FANCA, MLH1, MRE11A, NBN, PALB2, and RAD51C). Positive DDR gene alteration status was defined as detection of homozygous deletions, putative deleterious genomic alterations, or a combination, in at least one gene. The patients had previously received one to two taxane-based chemotherapy regimens and at least one hormonal therapy with enzalutamide and/or abiraterone acetate given in the metastatic setting.

The patients received 1 mg oral talazoparib daily, or 0.75 mg daily if moderate renal impairment was present, until radiographic progression, unacceptable toxicity, consent withdrawal, or death. Radiographic assessments were performed every 8 weeks during the first 24 weeks, then every 12 weeks thereafter.

The primary endpoint was confirmed objective response rate (ORR) by blinded independent central review, while key secondary endpoints included time to objective response, response duration, radiographic progression-free survival (PFS), overall survival (OS), prostate-specific antigen (PSA) decrease of at least 50%, circulating tumor cell count conversion, and safety. Antitumor activity endpoints were analyzed by DDR groups, where patients were separated hierarchically by DDR gene alterations (BRCA1/2 > PALB2 > ATM > others). Dr. De Bono presented antitumor activity and tolerability results, with data cut-off on September 4, 2020.

The safety population (n = 127) included all patients who received at least one dose of talazoparib and a small number of patients with non-measurable disease who were enrolled in an earlier version of the protocol. The efficacy population (n = 104) included all patients with measurable soft tissue disease who had predefined tumor DDR gene alterations and had received at least one dose of talazoparib.

Baseline characteristics between both safety and efficacy populations were similar. Among all 127 patients, 48% had received more than one prior taxane-based regimen. Median duration of talazoparib treatment was 6.1 months in the safety population and 6.2 months in the efficacy population.

The ORR was 29.8% in the efficacy population (95% confidence interval 21.2–39.6). It was 45.6% for the BRCA2 alteration group, 50.0% for the BRCA1 group, 25.0% for the PALB2 group, and 11.8% for the ATM group. Reduction in tumor burden (79.8%), PSA (71.9%), and circulating tumor cell count (82.2%) was observed in most patients. These reductions were especially apparent in BRCA-altered cancers but were also found in PALB2- and ATM-altered cancers.

Time to objective response was 3.4 months (range 1.6–7.5 months), and median duration of response was 12.8 months in the efficacy population. The longest confirmed objective response was observed in patients with BRCA2 alterations. Twelve patients had an ongoing response at data cut-off. Median radiographic PFS was 5.6 months. It was 11.2 months for patients with BRCA1/2 alterations, 3.5 months for those with non-BRCA alterations, 5.6 months for those with PALB2 alterations, and 3.5 months for those with ATM alterations. Similar patterns were observed for OS and time to PSA progression.

The tolerability of talazoparib was consistent with previous reports. Of all 127 patients, 95.3% reported any all-causality treatment-emergent adverse events, the most common of which were anemia (48.8%), nausea (33.1%), decreased appetite (28.3%), and asthenia (23.6%). The most common grade 3/4 treatment-emergent adverse events were anemia (30.7%), thrombocytopenia (8.7%), and neutropenia (7.9%). Serious treatment-emergent adverse events were reported in 33.9%, which primarily included pulmonary embolism (6.3%), anemia (3.9%), disease progression (3.1%), urinary tract infection (2.4%), and pneumonia (2.4%). Permanent discontinuation of talazoparib due to treatment-emergent adverse events occurred in 11.8% of patients.

“Talazoparib monotherapy has important, substantial, and durable antitumor activity in DDR-mutated advanced metastatic castration-resistant prostate cancer in patients who have had prior taxane and novel hormonal therapy, most impressively in the BRCA-altered cancers, but also with antitumor activity in the PALB2- and ATM-altered cancers,” concluded Dr. De Bono.

The TALAPRO-1 trial was sponsored by Pfizer Inc.

TALAPRO-2: Phase 3 study of talazoparib (TALA) + enzalutamide (ENZA) versus placebo (PBO) + ENZA as first-line (1L) treatment in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC).

Authors

Neeraj Agarwal

Huntsman Cancer Institute, University of Utah (NCI-CCC), Salt Lake City, UT

info_outline

Neeraj Agarwal, Arun Azad, Joan Carles, Andre P. Fay, Nobuaki Matsubara, Daniel Heinrich, Cezary Szczylik, Ugo De Giorgi, Jae Young Joung, Peter C.C. Fong, Eric Voog, Robert J Jones, Neal D. Shore, Curtis Dunshee, Stefanie Zschaebitz, Xun Lin, Cynthia G. Healy, Nicola Di Santo, Fabian Zohren, Karim Fizazi

Organizations

Huntsman Cancer Institute, University of Utah (NCI-CCC), Salt Lake City, UT, Peter MacCallum Cancer Centre, Melbourne, Australia, Vall d’Hebron University Hospital, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain, PUCRS School of Medicine Grupo Oncoclínicas, Porto Alegre, MA, Brazil, National Cancer Center Hospital East, Chiba, Japan, Innlandet Hospital Trust, Gjøvik, Norway, European Health Centre, Otwock & Postgraduate Medical Education Center, Warsaw, Poland, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) Dino Amadori, Meldola, Italy, National Cancer Center, Goyang, South Korea, Auckland City Hospital, Auckland, New Zealand, Clinique Victor Hugo Centre Jean Bernard, Le Mans, France, School of Cancer Sciences, University of Glasgow, Beatson West of Scotland Cancer Centre, Glasgow, United Kingdom, Carolina Urologic Research Center, Myrtle Beach, SC, Urological Associates of Southern Arizona, Tucson, AZ, National Center for Tumor Diseases (NCT), Heidelberg University Hospital, Heidelberg, Germany, Pfizer Inc., La Jolla, CA, Pfizer Inc., Collegeville, PA, Pfizer, Inc., Durham, NC, Institut Gustave Roussy, University of Paris-Saclay, Villejuif, France

Abstract Disclosures

Research Funding

Pharmaceutical/Biotech Company

Pfizer, Astellas

Background:TALAPRO-2 (NCT03395197) is the first phase 3 study to combine the poly(ADP-ribose) polymerase inhibitor TALA with the androgen receptor inhibitor ENZA. Pts unselected for genetic alterations in DNA damage repair pathways, directly or indirectly involved with homologous recombination repair (HRR), received either TALA + ENZA or PBO + ENZA as 1L treatment for mCRPC.Methods:Pts randomized 1:1 to TALA 0.5 mg or PBO (all pts received ENZA 160 mg daily) were stratified by prior abiraterone or docetaxel for castration-sensitive PC and HRR gene alteration status. Key eligibility criteria: mildly or asymptomatic mCRPC with disease progression at study entry, ECOG PS ≤1, ongoing androgen deprivation therapy, no prior life-prolonging therapy for CRPC. Primary endpoint: imaging-based progression-free survival (ibPFS) by BICR per RECIST 1.1 and PCWG3.Results:402 pts were randomized to receive TALA + ENZA and 403 PBO + ENZA. Of these 805 pts, enrollment was informed by tumor tissue for 804 (99.9%), by tumor tissue and blood for 114 (14.2%), and by blood only for 1 (0.1%). Median ibPFS by BICR was significantly improved in the TALA + ENZA vs PBO + ENZA arm (not reached vs 21.9 months, respectively; HR, 0.63; 95% CI, 0.51–0.78; P< 0.001). ibPFS was significantly improved in HRR-deficient (HR, 0.46; 95% CI, 0.30–0.70; P< 0.001), HRR-non-deficient or unknown (HR, 0.70; 95% CI, 0.54–0.89; P= 0.004), and HRR-non-deficient pts by tumor tissue testing (HR, 0.66; 95% CI, 0.49–0.91; P= 0.009) in the TALA + ENZA vs PBO + ENZA arm. Overall survival data are immature; 30.6% (TALA) and 32.0% (PBO) pts had died; HR (0.89 [95% CI, 0.69–1.14; P= 0.35]) favored the TALA + ENZA arm. Objective response rates, PSA response ≥50%, and time to PSA progression and use of subsequent cytotoxic chemotherapy and antineoplastic therapy significantly favored the TALA + ENZA vs PBO + ENZA arm. In pts, 71.9% (TALA + ENZA) and 40.6% (PBO + ENZA) had grade 3-4 treatment-emergent adverse events (TEAEs). The most common grade ≥3 TEAEs were anemia, low neutrophil, and low platelet counts (TALA + ENZA), and hypertension, anemia, and fatigue (PBO + ENZA). TEAEs led to discontinuation of TALA in 19.1% of pts (vs PBO in 12.2%). Discontinuation rates of ENZA were 10.8% in the TALA + ENZA vs 11.0% in PBO + ENZA arm. Median time to definitive clinically meaningful deterioration in global health status/quality of life (GHS/QoL) was significantly longer with TALA + ENZA vs PBO + ENZA (30.8 vs 25.0 months, respectively; HR, 0.78; 95% CI, 0.62–0.99; P= 0.04).Conclusions:TALA + ENZA demonstrated statistically significant and clinically meaningful improvement in ibPFS over standard of care ENZA as 1L treatment in pts with mCRPC regardless of HRR status, while delaying time to worsening in GHS/QoL. There were no new safety signals; toxicity was generally manageable. Clinical trial information: NCT03395197.