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

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.

Sex

Male

Minimum age

18 Years

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

• BACKGROUNDIan, 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.
• BACKGROUNDBelic 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
• BACKGROUNDAngus 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 29. PMID 33514525
• BACKGROUNDMendelaar 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: 10.1002/1878-0261.13196. Epub 2022 Mar 17. PMID 35181986
• BACKGROUNDBettegowda 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 GJ, Sartore-Bianchi A, Schmidt K, Shih lM, Oba-Shinjo SM, Siena S, Theodorescu D, Tie J, Harkins TT, Veronese S, Wang TL, Weingart JD, Wolfgang CL, Wood LD, Xing D, Hruban RH, Wu J, Allen PJ, Schmidt CM, Choti MA, Velculescu VE, Kinzler KW, Vogelstein B, Papadopoulos N, Diaz LA Jr. Detection of circulating tumor DNA in early- and late-stage human malignancies. Sci Transl Med. 2014 Feb 19;6(224):224ra24. doi: 10.1126/scitranslmed.3007094.