Phase 2 randomized study of high-risk metachronous oligometastatic prostate cancer with high-risk mutations treated with metastasis-directed therapy and niraparib/abiraterone acetate plus prednisone (KNIGHTS) trial.
Authors: Deek Matthew Pierre , Shi Xiaolei , Radwan Noura , Eggleston Caitlin , Baker Kaysee , Rana Zaker Hamid , Ferris Matthew J. , Kwok Young , Bentzen Soren , Ennis Ronald D , Hathout Lara , Saraiya Biren , Mayer Tina M. , Mannuel Heather Dorothy , Hussain Arif , Abramowitz Matthew , Berlin Alejandro , Mishra Mark V. , Tran Phuoc T. , Molitoris Jason K. 
Published: February 2025

TPS283

Background:
Some patients with oligometastases may have the potential for long-term disease-free survival with just aggressive local therapy as shown by randomized trials for total consolidation of macroscopic metastases using metastasis-directed therapy (MDT). Long-term outcomes of pooled STOMP and ORIOLE trials in oligorecurrent metastatic castration-sensitive prostate cancer (omCSPC) demonstrated MDT improved progression free survival. However, men with high-risk mutations, including pathogenic alterations in
ATM
,
BRCA1/2
,
Rb1
, and
TP53
, did poorly. Additional data suggests men with metastatic castration-resistant prostate cancer and similar mutations are sensitive to PARP inhibition (PARPi) with niraparib. We are launching a first-in-man biomarker-driven trial in omCSPC patients with high-risk mutations to evaluate the efficacy of MDT + androgen deprivation therapy (ADT)
versus
MDT + ADT + niraparib/abiraterone acetate plus prednisone (nira/AAP).
Methods:
This study is a multi-site, non-blinded, randomized phase II trial in patients with omCSPC. Men with histologically confirmed (at any site) omCSPC (≤3 metastases on standard imaging or ≤5 on Axumin/Choline/PSMA-PET/CT) and germ-line/somatic high-risk mutations (
TP53, BRCA1/2, PALB2, ATM, BRIP1, CHEK2, FANCA, RAD51B, RAD54L, MUTYH
) will be randomized (1:1) to MDT + 6- months ADT
versus
MDT + 6-months ADT + 6-months nira/AAP. A range of MDT radiation fractionation regimens are permitted. Subjects who meet eligibility criteria and qualify for enrollment will be stratified according to: (i) institution; (ii) conventional/enhanced imaging, (iii) PSADT <6-months, (iv) initial surgery/radiation, and (v)
BRCA1/2
status. This study has been IRB approved (NCT06212583). We assume an accrual time of 24 months, with 18 months of additional follow-up time, and will randomize a total of 88 patients (44 patients in each arm). The primary endpoint will be to assess frequency of PSA failure (> 0.2 ng/mL post primary surgery or nadir + 2 post definitive radiation) with testosterone >100 ng/dl at 18-months after randomization (powered for 20% improvement over control arm by Fisher’s exact test). Secondary endpoints will include toxicity, health-related quality of life (HRQoL), time to locoregional progression, time to distant progression, time to new metastasis, radiographic progression-free survival, and duration of response. Discovery correlatives associated with clinical outcome will be assessed by collection of including, but not limited to, cell free DNA, circulating-tumor cells, immunologic biomarkers, microbiota and radiomics. Clinical trial information:
NCT06212583
.