Elsevier

The Lancet Oncology

Volume 22, Issue 9, September 2021, Pages 1250-1264
The Lancet Oncology

Articles
Talazoparib monotherapy in metastatic castration-resistant prostate cancer with DNA repair alterations (TALAPRO-1): an open-label, phase 2 trial

https://doi.org/10.1016/S1470-2045(21)00376-4Get rights and content

Summary

Background

Poly(ADP-ribose) polymerase (PARP) inhibitors have antitumour activity against metastatic castration-resistant prostate cancers with DNA damage response (DDR) alterations in genes involved directly or indirectly in homologous recombination repair (HRR). In this study, we assessed the PARP inhibitor talazoparib in metastatic castration-resistant prostate cancers with DDR-HRR alterations.

Methods

In this open-label, phase 2 trial (TALAPRO-1), participants were recruited from 43 hospitals, cancer centres, and medical centres in Australia, Austria, Belgium, Brazil, France, Germany, Hungary, Italy, the Netherlands, Poland, Spain, South Korea, the UK, and the USA. Patients were eligible if they were men aged 18 years or older with progressive, metastatic, castration-resistant prostate cancers of adenocarcinoma histology, measurable soft-tissue disease (per Response Evaluation Criteria in Solid Tumors version 1.1 [RECIST 1.1]), an Eastern Cooperative Oncology Group performance status of 0–2, DDR-HRR gene alterations reported to sensitise to PARP inhibitors (ie, ATM, ATR, BRCA1, BRCA2, CHEK2, FANCA, MLH1, MRE11A, NBN, PALB2, RAD51C), had received one or two taxane-based chemotherapy regimens for metastatic disease, and progressed on enzalutamide or abiraterone, or both, for metastatic castration-resistant prostate cancers. Eligible patients were given oral talazoparib (1 mg per day; or 0·75 mg per day in patients with moderate renal impairment) until disease progression, unacceptable toxicity, investigator decision, withdrawal of consent, or death. The primary endpoint was confirmed objective response rate, defined as best overall soft-tissue response of complete or partial response per RECIST 1.1, by blinded independent central review. The primary endpoint was assessed in patients who received study drug, had measurable soft-tissue disease, and had a gene alteration in one of the predefined DDR-HRR genes. Safety was assessed in all patients who received at least one dose of the study drug. This study is registered with ClinicalTrials.gov, NCT03148795, and is ongoing.

Findings

Between Oct 18, 2017, and March 20, 2020, 128 patients were enrolled, of whom 127 received at least one dose of talazoparib (safety population) and 104 had measurable soft-tissue disease (antitumour activity population). Data cutoff for this analysis was Sept 4, 2020. After a median follow-up of 16·4 months (IQR 11·1–22·1), the objective response rate was 29·8% (31 of 104 patients; 95% CI 21·2–39·6). The most common grade 3–4 treatment-emergent adverse events were anaemia (39 [31%] of 127 patients), thrombocytopenia (11 [9%]), and neutropenia (ten [8%]). Serious treatment-emergent adverse events were reported in 43 (34%) patients. There were no treatment-related deaths.

Interpretation

Talazoparib showed durable antitumour activity in men with advanced metastatic castration-resistant prostate cancers with DDR-HRR gene alterations who had been heavily pretreated. The favourable benefit–risk profile supports the study of talazoparib in larger, randomised clinical trials, including in patients with non-BRCA alterations.

Funding

Pfizer/Medivation.

Introduction

The poly(ADP-ribose) polymerase (PARP) enzymes PARP1 and PARP2 are key components of the DNA damage response (DDR) mechanism.1 PARP inhibitors selectively kill specific cancer cells via so-called synthetic lethality, a mechanism whereby deficiency in function of one gene or gene product has little effect alone but is toxic in combination with deficiency in function of a second gene or gene product.1 PARP inhibition is synthetically lethal in cells with homozygous deletions or deleterious alterations, or both, in DDR genes involved either directly or indirectly in homologous recombination repair (HRR).1 Germline or somatic DDR alterations occur in 23–27% of men with prostate cancer,2, 3 and are associated with worse outcomes.4, 5, 6

Talazoparib potently inhibits PARP catalytic activity and is the most efficient PARP inhibitor at trapping PARP1 and PARP2 on DNA single-strand break sites, preventing DNA replication and transcription, and leading to double-strand DNA breaks and cell death.7, 8, 9, 10 Talazoparib is approved for treating germline BRCA1-mutated and BRCA2-mutated human epidermal growth factor receptor 2 (HER2, ErbB-2) negative metastatic or locally advanced breast cancer.11, 12 To our knowledge, TALAPRO-1 is the first international phase 2 trial to assess the antitumour activity and tolerability of talazoparib monotherapy in men with metastatic castration-resistant prostate cancers and HRR gene alterations who have been heavily pretreated.

Research in context

Evidence before this study

In the planning phase for TALAPRO-1, we searched PubMed in late 2015 to early 2016 for relevant preclinical or clinical research published on so-called BRCAness, DNA damage response, DNA damage repair (DDR), homologous recombination repair (HRR), synthetic lethality, poly(ADP-ribose) polymerase (PARP) inhibitors, and advanced prostate cancer. Prostate cancer remains the second most common cause of cancer-related death in men, with no curative treatment options available once patients develop metastatic castration-resistant prostate cancer. At study initiation, treatment options for men with metastatic castration-resistant prostate cancers included novel hormonal therapies (eg, enzalutamide, abiraterone), taxanes (docetaxel, cabazitaxel), radium-223, and sipuleucel-T. An unmet medical need remains for men with metastatic castration-resistant prostate cancers who have already received novel hormone therapy and taxane-based chemotherapy; some of these tumours carry alterations in DDR genes involved directly or indirectly in HRR that can sensitise to PARP inhibitors. Those alterations have been linked to worse prognosis. Several PARP inhibitors are being assessed for the treatment of metastatic castration-resistant prostate cancers with defective HRR gene alterations. The toxicity profile and efficacy or duration of sensitivity to PARP inhibitors might differ depending on specific HRR gene alterations; therefore, continued research with PARP inhibitors is warranted.

Added value of this study

To our knowledge, this study is the first international phase 2 trial to assess the antitumour activity and tolerability of talazoparib in men with metastatic castration-resistant prostate cancers with alterations in DDR genes involved in HRR who have been heavily pretreated. Antitumour activity was most notable against tumours with BRCA2 alterations, although partial or complete responses, stable disease, and prostate-specific antigen responses were also seen in tumours with alterations in BRCA1, PALB2, and ATM, which affirms that PARP inhibition has antitumour activity beyond the BRCA1 and BRCA2 subset. Our finding that homozygous loss is associated with enhanced antitumour activity might be crucial to interpreting antitumour activity results in gene-by-gene analyses from prostate cancer PARP inhibitor studies using multi-gene panels, including the TALAPRO-1 study.

Implications of all the available evidence

These data suggest that talazoparib has durable antitumour activity against lethal prostate cancers with various DNA repair defects that directly or indirectly impact HRR. This antitumour activity was observed even in men with very advanced prostate cancer who have exhausted most available treatment options. The favourable benefit–risk profile of talazoparib monotherapy against metastatic castration-resistant prostate cancers with alterations in DDR genes either directly or indirectly involved in HRR in men previously treated with taxanes and novel hormone therapy supports the study of talazoparib in larger, randomised clinical trials, including in men with non-BRCA alterations.

Section snippets

Study design and participants

TALAPRO-1 is an open-label, phase 2 trial that enrolled patients at 43 hospitals, cancer centres, and medical centres in 14 countries (Australia, Austria, Belgium, Brazil, France, Germany, Hungary, Italy, the Netherlands, Poland, Spain, South Korea, the UK, and the USA). Patients were eligible if they were men aged 18 years or older with progressive metastatic castration-resistant prostate cancers of adenocarcinoma histology. Progressive disease was defined as a minimum of three increasing

Results

The first patient's first visit occurred on July 4, 2017, with prescreening ending on Feb 21, 2020; study enrolment officially closed on March 20, 2020. Of 1425 screened patients, 1297 did not have HRR gene alterations or did not meet other eligibility criteria (figure 1; appendix p 3). Between Oct 18, 2017, and March 20, 2020, 128 men were enrolled, of whom 23 (18%) had non-measurable disease or were not HRR deficient and one (1%) patient did not receive talazoparib, leaving 127 patients in

Discussion

TALAPRO-1 is an open-label, phase 2 trial of single-agent talazoparib in men with metastatic castration-resistant prostate cancers with alterations of DDR genes involved directly or indirectly in HRR and who have been heavily pretreated with novel hormone therapy and taxane chemotherapy. In this population, talazoparib had robust antitumour activity, which was most notable and durable against tumours with BRCA1 or BRCA2 gene alterations. Responses were also confirmed in patients with tumours

Data sharing

Upon request, and subject to specific criteria, conditions, and exceptions, which are available online, Pfizer will provide access to individual de-identified participant-level data from Pfizer-sponsored global interventional clinical studies conducted for medicines, vaccines, and medical devices for indications that have been approved in the USA or Europe and in programmes that have been terminated (eg, development for all indications has been discontinued). Pfizer will also consider requests

Declaration of interests

JSdB reports consulting fees from Astellas Pharma, AstraZeneca, Bayer, BioXcel Therapeutics, Boehringer Ingelheim, Celgene, Daiichi Sankyo, Eisai, Genmab, GSK, Janssen Oncology, Menarini Silicon Biosystems, Merck Serono, MSD, Orion Pharma GmbH, Pfizer, Roche/Genentech, Sanofi, Sierra Oncology, and Taiho Pharmaceutical; funding or support to his institution for laboratory and clinical work from Astex Pharmaceuticals, AstraZeneca, Bayer, Celgene, Cellcentric, Daiichi Sankyo, Genentech, GSK,

References (32)

  • R Lozano Mejorada et al.

    612MO Clinical impact of somatic alterations in prostate cancer patients with and without previously known germline BRCA1/2 mutations: results from PROREPAIR-A study

    Ann Oncol

    (2020)
  • A Neeb et al.

    Advanced prostate cancer with ATM loss: PARP and ATR inhibitors

    Eur Urol

    (2021)
  • CJ Lord et al.

    PARP inhibitors: synthetic lethality in the clinic

    Science

    (2017)
  • JH Chung et al.

    Prospective comprehensive genomic profiling of primary and metastatic prostate tumors

    JCO Precis Oncol

    (2019)
  • J Armenia et al.

    The long tail of oncogenic drivers in prostate cancer

    Nat Genet

    (2018)
  • E Castro et al.

    PROREPAIR-B: a prospective cohort study of the impact of germline DNA repair mutations on the outcomes of patients with metastatic castration-resistant prostate cancer

    J Clin Oncol

    (2019)
  • IE Kim et al.

    Similar incidence of DNA damage response pathway alterations between clinically localized and metastatic prostate cancer

    BMC Urol

    (2019)
  • J Murai et al.

    Trapping of PARP1 and PARP2 by clinical PARP inhibitors

    Cancer Res

    (2012)
  • Y Shen et al.

    Trapping poly(ADP-ribose) polymerase

    J Pharmacol Exp Ther

    (2015)
  • J Murai et al.

    Stereospecific PARP trapping by BMN 673 and comparison with olaparib and rucaparib

    Mol Cancer Ther

    (2014)
  • L Zandarashvili et al.

    Structural basis for allosteric PARP-1 retention on DNA breaks

    Science

    (2020)
  • Talzenna (talazoparib) prescribing information

  • JK Litton et al.

    Talazoparib in patients with advanced breast cancer and a germline BRCA mutation

    N Engl J Med

    (2018)
  • HI Scher et al.

    Trial design and objectives for castration-resistant prostate cancer: updated recommendations from the Prostate Cancer Clinical Trials Working Group 3

    J Clin Oncol

    (2016)
  • JX Sun et al.

    A computational approach to distinguish somatic vs germline origin of genomic alterations from deep sequencing of cancer specimens without a matched normal

    PLoS Comput Biol

    (2018)
  • CH Marshall et al.

    Therapeutic targeting of the DNA damage response in prostate cancer

    Curr Opin Oncol

    (2020)
  • Cited by (141)

    View all citing articles on Scopus
    View full text