Apa/Enza-short Study: Shorter Treatment With Androgen Receptor Pathway Inhibitor in Patients With Low-volume Metastatic Castration-sensitive Prostate Cancer

Official title

Apa/Enza Short Study: Shortened 12 Months Duration of Androgen Receptor Signaling Agent in Combination With Androgen Deprivation Therapy in Patients With Low Volume Castration-sensitive Prostate Cancer: a Randomized Nationwide Study

Overview

The goal of this clinical trial is to evaluate the outcomes of a shorter treatment duration (12 months) with an androgen receptor pathway inhibitor (ARPI), in this study Apalutamide or Enzalutamide, in patients with low-volume, hormone-sensitive metastatic prostate cancer (mCSPC), with the possibility to restart treatment if needed. The main research question is whether discontinuation of ARPI therapy after 12 months, with the option to restart treatment upon disease progression, is non-inferior to continued ARPI therapy, potentially reducing toxicity and costs. Eligible patients will be randomized after completing 12 months of ARPI treatment, to one of the following two arms: 1. ADT + continued ARPI (Apalutamide or Enzalutamide) 2. ADT + ARPI discontinued after 12 months, with the option to resume ARPI in case of a confirmed PSA rise. The confirmatory PSA sample must be obtained at least 4 weeks after the initial rise. This study aims to minimize toxicity associated with prolonged use of ARPIs in patients with low-volume, hormone-sensitive metastatic prostate cancer.

Interventions

• Drug ADT plus only 12 months of ARPI
  ADT plus only 12 months of ARPI (apalutamide/enzalutamide) with the possibility to resume treatment with ARSI in case of a confirmed PSA rise.
• Drug ADT plus continued ARPI
  ADT plus continued ARPI (apalutamide/enzalutamide) to the moment of progression

Primary outcome measures

• Time to clinical progression free survival (cPFS) in both arms. [Time frame: From inclusion to the last day of treatment or moment of progression (whichever occurs first). Subjects will participate for 5 years, after randomization. In total, patients will participate for 6 years.]

Eligibility criteria

Inclusion criteria

• Male and ≥18 years of age
• Capable of understanding and complying with protocol requirements and able to understand and sign the informed consent form
• Histological diagnosis of prostate adenocarcinoma
• Low volume de novo metastatic disease (M1a or M1b) defined as anything other than fitting the criteria for high-volume metastatic disease, e.g., four or more bone lesions with one or more lesions in any body structure beyond the spine or pelvis, or visceral disease (non-nodal). This has been assessed by either bone scan and computed tomography (CT), or PSMA-PET scan. Low-volume disease has subsequently been confirmed by the local (multidisciplinary) team after consideration of the available imaging results as per the standard imaging protocol for the site.
• ADT initiated within 6 weeks prior to inclusion
• Eastern Cooperative Oncology Group (ECOG) performance scale status of 0, 1 or 2
• Fit for treatment with apalutamide or enzalutamide according to treating physician

Exclusion criteria

• Pathological finding consistent with small cell, ductal or neuroendocrine carcinoma of the prostate
• Other prior malignancy less than or equal to 5 years prior to randomization except for squamous or basal cell skin carcinoma or non-invasive superficial bladder cancer
• History of seizures or medications known to lower seizure threshold
• Any other prior treatment for prostate cancer other than ADT (e.g., other next generation anti-androgens or other CYP17 inhibitors, chemotherapy, immunotherapy, or radiopharmaceutical agents)
• ADT started more than 6 weeks before inclusion

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Supportive care

Study locations

Netherlands · 26 centers

• Noordwest Ziekenhuisgroep — Alkmaar
• Meander MC Amersfoort — Amersfoort
• Amsterdam Universitair Medisch Centrum — Amsterdam
• Antoni van Leeuwenhoek — Amsterdam
• Wilhelmina Ziekenhuis Assen — Assen
• Rode Kruis Ziekenhuis — Beverwijk
• Deventer Ziekenhuis — Deventer
• Catharina Ziekenhuis — Eindhoven
• … and 18 more centers

Publications

• Ian, D.D., et al., Updated overall survival outcomes in ENZAMET (ANZUP 1304), an international, cooperative group trial of enzalutamide in metastatic hormone-sensitive prostate cancer (mHSPC). Journal of Clinical Oncology, 2022. 40(17_suppl): p. LBA5004-LBA5004.
• Belic J, Koch M, Ulz P, Auer M, Gerhalter T, Mohan S, Fischereder K, Petru E, Bauernhofer T, Geigl JB, Speicher MR, Heitzer E. Rapid Identification of Plasma DNA Samples with Increased ctDNA Levels by a Modified FAST-SeqS Approach. Clin Chem. 2015 Jun;61(6):838-49. doi: 10.1373/clinchem.2014.234286. Epub 2015 Apr 20. PMID 25896989
• Angus L, Deger T, Jager A, Martens JWM, de Weerd V, van Heuvel I, van den Bent MJ, Sillevis Smitt PAE, Kros JM, Bindels EMJ, Heitzer E, Sleijfer S, Jongen JLM, Wilting SM. Detection of Aneuploidy in Cerebrospinal Fluid from Patients with Breast Cancer Can Improve Diagnosis of Leptomeningeal Metastases. Clin Cancer Res. 2021 May 15;27(10):2798-2806. doi: 10.1158/1078-0432.CCR-20-3954. Epub 2021 Jan PMID 33514525
• Mendelaar PAJ, Robbrecht DGJ, Rijnders M, de Wit R, de Weerd V, Deger T, Westgeest HM, Aarts MJB, Voortman J, Martens JWM, van der Veldt AAM, Nakauma-Gonzalez JA, Wilting SM, Lolkema M. Genome-wide aneuploidy detected by mFast-SeqS in circulating cell-free DNA is associated with poor response to pembrolizumab in patients with advanced urothelial cancer. Mol Oncol. 2022 May;16(10):2086-2097. doi: 1 PMID 35181986
• Bettegowda C, Sausen M, Leary RJ, Kinde I, Wang Y, Agrawal N, Bartlett BR, Wang H, Luber B, Alani RM, Antonarakis ES, Azad NS, Bardelli A, Brem H, Cameron JL, Lee CC, Fecher LA, Gallia GL, Gibbs P, Le D, Giuntoli RL, Goggins M, Hogarty MD, Holdhoff M, Hong SM, Jiao Y, Juhl HH, Kim JJ, Siravegna G, Laheru DA, Lauricella C, Lim M, Lipson EJ, Marie SK, Netto GJ, Oliner KS, Olivi A, Olsson L, Riggins PMID 24553385
• Vandekerkhove G, Struss WJ, Annala M, Kallio HML, Khalaf D, Warner EW, Herberts C, Ritch E, Beja K, Loktionova Y, Hurtado-Coll A, Fazli L, So A, Black PC, Nykter M, Tammela T, Chi KN, Gleave ME, Wyatt AW. Circulating Tumor DNA Abundance and Potential Utility in De Novo Metastatic Prostate Cancer. Eur Urol. 2019 Apr;75(4):667-675. doi: 10.1016/j.eururo.2018.12.042. Epub 2019 Jan 10. PMID 30638634
• Evans CP, Higano CS, Keane T, Andriole G, Saad F, Iversen P, Miller K, Kim CS, Kimura G, Armstrong AJ, Sternberg CN, Loriot Y, de Bono J, Noonberg SB, Mansbach H, Bhattacharya S, Perabo F, Beer TM, Tombal B. The PREVAIL Study: Primary Outcomes by Site and Extent of Baseline Disease for Enzalutamide-treated Men with Chemotherapy-naive Metastatic Castration-resistant Prostate Cancer. Eur Urol. 2016 PMID 27006332
• Nadal R, Taplin ME, Bellmunt J. Enzalutamide for the treatment of prostate cancer: results and implications of the AFFIRM trial. Future Oncol. 2014 Feb;10(3):351-62. doi: 10.2217/fon.13.275. PMID 24559444

Identifiers

NCT: NCT07260435 · EU CT 2023-506698-36

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗