Impact of Pathogenic Germline DNA Damage Repair alterations on Response to Intense Neoadjuvant Androgen Deprivation Therapy in High-risk Localized Prostate Cancer

Eur Urol. 2021 Sep;80(3):295-303. doi: 10.1016/j.eururo.2021.03.031. Epub 2021 Apr 19.


Background: Intense neoadjuvant androgen deprivation therapy (ADT) before radical prostatectomy (RP) is an investigational approach to reduce recurrence rates in men with high-risk localized prostate cancer (PCa). The impact of germline DNA damage repair (gDDR) gene alterations on response to intense neoadjuvant ADT is not known.

Objective: To evaluate the prevalence of gDDR alterations among men with localized PCa at high risk of recurrence and evaluate their impact on response to intense neoadjuvant ADT.

Design, setting, and participants: We performed germline panel sequencing for 201 men with intermediate- and high-risk localized PCa from five randomized multicenter clinical trials of intense neoadjuvant ADT before RP.

Intervention: Intense neoadjuvant ADT followed by RP.

Outcome measurements and statistical analysis: The prevalence of pathogenic gDDR alterations and their association with exceptional pathologic response (complete response or minimal residual disease, defined as residual tumor with the largest cross-section dimension ≤5 mm) to intense neoadjuvant ADT and rates of post-RP biochemical recurrence.

Results and limitations: Pathogenic gDDR alterations were detected in 19 (9.5%) of the 201 PCa patients. The most frequently altered genes were BRCA2 (n = 6; 3.0%) and ATM (n = 4; 2.0%). Patients with gDDR alterations exhibited similar rates of exceptional pathologic response (26% vs 22%), pT3 disease (42% vs 53%), lymph node involvement (5.3% vs 10%), extraprostatic extension (35% vs 54%), and positive margins (5.3% vs 13%) to patients without gDDR alterations (all p > 0.05). The 3-yr biochemical recurrence-free survival was also similar at 45% (95% confidence interval 7.9-78%) for men with gDDR alterations and 55% (95% confidence interval 44-64%) for men without gDDR alterations.

Conclusions: gDDR alterations are common among men with intermediate- and high-risk localized PCa. Men with gDDR alterations appear to have a comparable response to intense neoadjuvant ADT to that among men without gDDR alterations and should not be excluded from consideration for this treatment approach.

Patient summary: Intense therapy to inhibit the production of androgen hormones (eg, testosterone) before surgery may minimize the risk of cancer recurrence for men with high-risk localized prostate cancer. Inherited mutations in certain DNA repair genes are associated with particularly high rates of recurrence. We found that men with these mutations respond equally well to this intense androgen inhibition before surgery as men without the mutations.

Keywords: Biochemical recurrence; Biomarkers; DNA damage repair; Germline alterations; Germline sequencing; Hormone therapy; Neoadjuvant therapy; Pathologic response; Prostate cancer.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, Non-U.S. Gov't