SPOP Mutations in Veterans With Prostate Cancer and Outcomes With Doublet and Triplet Therapy in De Novo Metastatic...

Inactivating missense mutations in the tumor suppressor gene speckle-type pox virus and zinc finger protein (SPOP) occur in 5%-15% of men with prostate cancer (PC). SPOP mutations increase androgen receptor-mediated transcription and enhance sensitivity to hormonal therapies. Here we describe the clinical characteristics, outcomes, and mutational patterns in Veterans with SPOP-mutated PC.

This retrospective cohort was defined as men diagnosed with PC between January 1, 2000 and September, 30 2024 in the Veterans Affairs health care system with an SPOP mutation identified on genomic testing. The primary and secondary outcomes were overall survival (OS) from date of metastasis and metastatic castration-resistant PC (mCRPC) to death or censoring on December 31, 2024, and adjusted for left truncation.

Of 984 Veterans with SPOP-mutated PC, most Veterans (78.4%) received at least one androgen receptor pathway inhibitor (ARPI) and 20.2% received docetaxel. Median OS from date of metastasis (n = 898) was 42.0 mo (95% CI: 38.1-48.2). Median OS from mCRPC diagnosis (n = 425) was 23.5 mo (95% CI: 19.4-29.5). We also identified a subgroup of 114 patients with de novo metastatic hormone-sensitive PC (mHSPC), 96 who received androgen deprivation therapy (ADT) + ARPI (doublet) and 18 who received ADT + ARPI + docetaxel (triplet) as initial therapy. Median OS from diagnosis to death was 48.3 mo (CI not estimable) in the doublet subgroup and not estimable in the triplet subgroup. The most common co-occurring genetic alterations with SPOP in de novo mHSPC were APC (21.9%; 25/114), TP53 (18.4%; 21/114), and PTEN (8.3%; 8/114).

This is the largest cohort of men with SPOP mutations, including those with de novo mHSPC treated with an ARPI, reported to date. Further prospective study of SPOP-mutated PC may help guide which patients with de novo mHSPC may either benefit from or can forego the addition of chemotherapy.