Metastasis-directed therapy (MDT) plus androgen deprivation therapy (ADT) for oligometastatic prostate cancer (omPC): Primary results of the EXTEND continuous ADT (cADT) basket plus combined analysis with the updated intermittent ADT (iADT) basket and immune correlatives.
Authors: Sherry Alexander Dean , Haymaker Cara L , Fellman Bryan M. , Bathala Tharakeswara K. , Medina-Rosales Marina N. , Liu Suyu , Chun Stephen G. , Mayo Lauren L. , Choi Seungtaek , Phillips Ryan , Deek Matthew Pierre , Aparicio Ana , Zurita Amado J. , Pilié Patrick Glen , Siddiqui Bilal Ahmed , Subudhi Sumit Kumar , Reuben Alexandre , Corn Paul Gettys , Tran Phuoc T. , Tang Chad 
Published: February 2025

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Background:
In the phase II EXTEND iADT omPC basket, MDT+iADT improved progression-free survival (PFS) vs iADT. Here we present the primary results of the EXTEND cADT omPC basket. We further report a pre-specified combined analysis with updated results from the iADT basket and examine the effects of MDT on immunity.
Methods:
Patients with 1 to 5 omPC metastases were randomized 1:1 to MDT+cADT vs cADT (NCT03599765). MDT consisted of definitive local therapy. cADT consisted of ADT +/- second-generation anti-androgens. The primary endpoint was per-protocol PFS, defined by biochemical criteria (Prostate Cancer Working Group 3), radiologic measures (RECIST v1.1), clinical progression, or death. 87 patients were needed to show superiority at a one-sided
P
of 0.10 by log-rank test. CDR3 regions in rearranged T cell receptor (TCR) β-chains from pre- and post-enrollment peripheral blood were sequenced with immunoSEQ (Adaptive Biotech). TCR repertoire modulation was defined as having TCR expansion plus contraction using a false-discovery-corrected betabinomial model. TCR sequencing from the ORIOLE trial (NCT02680587) was assessed for external validation.
Results:
From 2018 to 2022, 87 randomized patients were treated per protocol (MDT+cADT: 45; cADT: 42). 39% had castrate resistant omPC. MDT was definitive radiotherapy in all cases. With median follow-up of 31 mo, median PFS was 47 mo after MDT+cADT vs 22 mo after cADT (HR 0.50; 95% CI 0.23 to 1.08; one-sided
P
= 0.036). In the combined analysis (N=174) with median follow-up of 42 mo, MDT+ADT improved PFS (HR 0.45; 95% CI 0.30 to 0.69;
P
< 0.001), radiologic PFS (HR 0.63; 95% CI 0.40 to 0.97;
P
= 0.038), and castration-resistance free-survival (HR 0.40; 95% CI 0.19 to 0.82;
P
= 0.013). MDT+ADT had higher odds of TCR repertoire modulation vs ADT (55% vs 15%,
P
< 0.001). This finding was validated in the ORIOLE trial (MDT: 57% vs observation: 19%,
P
= 0.03). Among the subset of patients with extreme responses, random forest modeling of 37 clinical/immune variables identified TCR repertoire modulation as the variable with highest importance; further, MDT+ADT induced TCR repertoire modulation in all patients with favorable responses (i.e. PFS > 4 years) and none with unfavorable responses (i.e. PFS < 1 year). Among all patients randomized to MDT+ADT, TCR repertoire modulation was associated with longer PFS (HR 0.21; 95% CI 0.06 to 0.76;
P
= 0.02).
Conclusions:
MDT+cADT met the PFS primary endpoint of the phase II EXTEND trial, warranting phase III testing. From the combined analysis, MDT+ADT may also improve longer term outcomes including radiologic PFS and castration-resistance-free survival. Improved outcomes may result from MDT-induced immunomodulation, with implications for future trial design. Clinical trial information:
NCT03599765
.