According to results of a phase 3 clinical trial, the 3-year biochemical progression-free survival (BPFS) of men with localized, high-risk prostate cancer undergoing radical prostatectomy (RP) was not significantly improved by the administration of docetaxel and androgen-deprivation therapy (ADT) in the neoadjuvant setting. These findings were published in the Journal of Clinical Oncology.1

Rationales for undertaking a study of neoadjuvant chemohormonal therapy in men with localized, high-risk prostate cancer included their increased risks of a worse outcome following RP compared with patients without high-risk disease features, previous findings related to the benefit of ADT when administered to these patients in association with radiation therapy, and results of early-phase clinical trials showing a beneficial effect of docetaxel in this setting.

Inclusion criteria for enrollment in this open-label, phase 3 study (Alliance; Clinicaltrials.gov Identifier: NCT00430183) included clinical stage T1-3a disease without evidence of disease metastasis on radiographic imaging of the abdomen and pelvis, a negative bone scan, as well as a less than 60% probability of absence of biochemical disease progression at 5 years following surgery according to the Kattan nomogram2 or a biopsy Gleason score of 8 to 10.

In this study, 788 eligible patients were randomly assigned in a 1:1 ratio to receive RP with or without 6 cycles of docetaxel plus 18 to 24 weeks of a leutinizing hormone-releasing agonist or antagonist. Study arms were stratified with respect to Kattan nomogram score and biopsy Gleason score.


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The primary study endpoint was 3-year BPFS, with biochemical failure defined as a serum prostate-specific antigen (PSA) level greater than 0.2 ng/mL that increases in 2 subsequent consecutive measurements separated by at least 3 months. Secondary study endpoints including 5-year BPFS, overall BPFS, metastasis-free survival (MFS), prostate cancer-specific mortality, and overall survival (OS).  

Seventy percent of patients had a Kattan risk score of 3 or 4, and a biopsy Gleason score of 8 to 10 was observed in approximately 85% to 90% of patients. Only 13% of patients had previously received ADT.  Clinical stage was T1 or T2 in over 80% of patients in both arms, and the median patient age was approximately 62 years to 63 years.  

Significant pathologic downstaging, as well as significantly fewer positive surgical margins, were observed for the group who received neoadjuvant therapy vs the group that did not.

However, at a median follow-up of 6.1 years, this study failed to meet the primary study endpoint, with a 3-year BPFS of 0.89 observed for the patients treated with neoadjuvant therapy vs 0.84 for those who underwent surgery alone (P =.11).

A study limitation mentioned by the authors was the use of salvage therapy prior to meeting the primary endpoint, typically radiation therapy with or without ADT, in 43% and 52% of those receiving neoadjuvant therapy and surgery alone, respectively. Hence, they suggested that the requirement for early censoring of these patients may have compromised the power of the study.

Of note, a subsequent analysis of event-free survival (EFS) in these 2 groups, in which patients receiving salvage therapy were considered to have experienced treatment failure, showed significantly longer EFS for men treated with neoadjuvant therapy compared with surgery alone (hazard ratio [HR], 0.61, 95% CI, 0.48-0.78).

Regarding secondary study end points, no significant differences were observed between the 2 study arms regarding 5-year BPFS and prostate-cancer specific mortality, although neoadjuvant therapy was associated with significant improvements in overall BPFS, MFS and OS.

Although no patient deaths were associated with receipt of neoadjuvant therapy, 26% and 19% of those undergoing this treatment experienced a grade 3 or grade 4 adverse event, respectively. In particular, grade 4 neutropenia/granulocytopenia occurred in 17% of patients treated with neoadjuvant chemohormonal therapy.

In their concluding comments, the study authors noted that “although some improvement was seen in secondary end points, any potential benefit must be weighed against toxicity.”

They further added that “our findings indicate that the combination of neoadjuvant docetaxel with androgen-deprivation therapy before radical prostatectomy should not be considered as a treatment option for men with clinically localized, high-risk prostate cancer at this time.”

References

  1. Eastham JA, Heller G, Halabi S, et al. Cancer and Leukemia Group B 90203 (Alliance): Radical prostatectomy with or without neoadjuvant chemohormonal therapy in localized, high-risk prostate cancer [published online July 24, 2020]. J Clin Oncol. doi: 10.1200/JCO.20.00315
  2. Kattan MW, Eastham JA, Stapleton AM, et al: A preoperative nomogram for disease recurrence following radical prostatectomy for prostate cancer. J Natl Cancer Inst. 1998;90:766-771.