ADT as a stand alone treatment

a layman’s version…
…how SBRT (Stereotactic body radiotherapy) works…A bunch of x ray beams are sent towards a metastatic spot. This is done via a very high tech radiation machine (True beam or Cyberknife) Now, these beams of x ray converge and form a cone…eventually reaching a very high velocity very pointed "super bean" which hits the metastatic spot. This causes severe injury to cancer cells breaking their DNA strands. Cancer cells stay alive for a while but they are severely crippled. Slowly over weeks and months these crippled cells start dying and crippled cells also lose their capacity to reproduce (“mitotic catastrophe”)slowing tumor growth. The dead cells while busting and dying, release substances which attract all kind of natural killer cells, phagocytes, macrophages...they all start munching on cancer cells in the area. Some neighboring cells die just due to fear watching their fellow cancer cells DNA cracking and breaking...This interesting phenomenon is called "Abscopal Effect" Because cancer killing effect of SBRT is a very slow process, you might see changes in PSMA PET-CT and /or PSA in many months sometimes in 2 or 3 years.

What about metastasis-directed therapy in the mHSPC disease setting?
STOMP was a phase II trial of oligorecurrent mHSPC with three or less lesions on choline PET/CT. Patients randomized to MDT, in the form of SABR or surgery, had significantly prolonged ADT-free survival (21 versus 13 months).6

ORIOLE similarly evaluated MDT (SABR) in oligorecurrent mHSPC patients with 3 or less lesions on conventional imaging. Patients treated with MDT had significantly improved 6-month progression rates (61% versus 19%). This benefit was most pronounced in patients who had all PET-detected lesions targeted by MDT treatment plans.7

A pooled analysis of the two trials published in 2022 demonstrated that there was a proportion of these mHSPC patients (15-20%) treated with MDT who had PFS beyond 4 years. Notably, the median rPFS with MDT and in the no high-risk mutations cohort was 25.3 months.8

The recently published EXTEND trial evaluated the utility of adding MDT to IADT. This phase II trial randomized patients with oligometastatic hormone-sensitive or resistant prostate cancer (0-5 lesions) to six months of hormonal therapy followed by intermittent hormonal therapy with or without MDT. This trial met its primary endpoint with prolonged PFS in the MDT arm (HR: 0.25, p< 0.001). Notably, a benefit was observed in the mHSPC subgroup (HR: 0.22), with consistent benefits across subgroups, including: synchronous versus metachronous and ADT + ARSI versus ADT alone.9 Significantly, eugonadal PFS (i.e., PFS in those who recovered normal testosterone levels following intermittent hormone therapy suspension) was significantly prolonged in the MDT group (HR: 0.32, 95% CI: 0.11 – 0.91, p=0.03).

In this randomized clinical trial, PFS and eugonadal PFS were significantly improved with combination treatment compared with hormone treatment only in men with oligometastatic PCA.

Combination of MDT with IADT may allow for excellent disease control while facilitating prolonged eugonadal testosterone intervals

Kevin