Modest Effects of Intense Therapy for Prostate Ca

Chemoradiation (CRT) plus androgen deprivation therapy (ADT) for high-risk localized prostate cancer modestly improved survival compared with radiation plus ADT, results of a randomized trial showed.

Patients randomized to CRT with docetaxel had a 4-year survival of 93% versus 89% for patients who received RT plus ADT. Disease-free survival at 6 years was 65% with chemotherapy and 55% without.

Fewer patients in the chemotherapy group developed distant metastases or died of prostate cancer, reported Seth A. Rosenthal, MD, of Sutter Medical Group and Sutter Cancer Centers in Sacramento, California, and colleagues in the Journal of Clinical Oncology (JCO).

However, they acknowledged that the trial did not demonstrate a clear advantage over other potential treatment strategies.

“Although there are multiple management options, on the basis of the results of this trial, adjuvant chemotherapy with docetaxel can be reasonably discussed for selected men with high-risk localized prostate cancer who are fit for chemotherapy,” the authors concluded.

Another JCO study showed that intense neoadjuvant ADT with enzalutamide (Xtandi) and abiraterone (Zytiga) before prostatectomy led to pathologic complete response (pCR) or minimal residual disease (MRD) almost twice as often as did ADT with enzalutamide. However, the difference did not achieve statistical significance, reported Mary-Ellen Taplin, MD, of Dana-Farber Cancer Institute in Boston, and colleagues.

The studies represented just two of several different intensified treatment strategies being evaluated in patients with high-risk localized prostate cancer, said Eric Klein, MD, of the Cleveland Clinic, who was not involved in either study. On the basis of the results reported, the impact of treatment was fairly modest, and neither strategy clearly distinguished itself from other possible strategies.

In contrast to intensified strategies, emerging precision-medicine approaches to prostate cancer offer the potential to change the treatment landscape.

“We’re in an era where we can test the genomics and gene expression of prostate cancer on biopsy, or on prostatectomy specimens, and understand the biology far better than we used to,” Klein told MedPage Today. “There are tests on the market that will allow us to determine whether a cancer is likely to respond to androgen deprivation therapy, whether it’s likely to respond to chemotherapy, whether it’s likely to respond to radiation therapy.”

“We’re really on the doorstep of an era where we will be better able to individualize treatment based on that genomic characterization of the tumor,” he added. “I’m more excited about that, honestly, than I am about sort of shotgun approaches of hormones before surgery or chemotherapy before hormones and radiation. That’s a more precision medicine kind of approach, and we will be doing that in the future.”

High-Risk Localized Prostate Cancer

Many patients with localized prostate cancer have good outcomes, including survival, with early diagnosis and modern treatment. Improved risk stratification facilitates identification of patients with high-risk disease and an increased likelihood of prostate cancer death. Patients with high-risk localized disease are candidates for intensified therapy. One accepted strategy for high-risk prostate cancer is radiotherapy and long-term ADT, Rosenthal and colleagues noted.

Docetaxel-based chemotherapy has been shown to improve overall survival (OS) in both castration-resistant and hormone-sensitive prostate cancer. Clinical experience with other types of cancer suggested that chemotherapy might be more effective if used earlier in the disease course, the authors continued. In the adjuvant setting, a reduced tumor burden may minimize the potential for malignant cells to develop resistance to therapy. Additionally, chemotherapy might target hormone-resistant cells, potentially complementing the effects of ADT.

With the preceding background information, investigators for NRG Oncology conducted the RTOG (Radiation Therapy Oncology Group) 0521 trial to test the hypothesis that adding docetaxel to radiation therapy and ADT would improve disease control and survival in high-risk localized prostate cancer, as compared with radiation and ADT.

Investigators at 154 sites enrolled patients with newly diagnosed, clinically localized prostate cancer, using standard criteria for high risk: Gleason score 9-10; Gleason score 7-8 with PSA level ≥20 ng/mL; or Gleason score 8, PSA <20 ng/mL, and T stage ≥2. All patients received 8 weeks of ADT, followed by external-beam radiation therapy to a total dose of 72-75.6 Gy and 24 months of adjuvant ADT. Patients were randomized to adjuvant docetaxel or no chemotherapy.

The trial had a primary endpoint of OS, and data analysis included 563 evaluable patients. The patients had a median PSA of 15.1 ng/mL, 53% had Gleason 9-10 disease, and 27% had cT3-cT4 disease.

After a median follow-up of 5.7 years, the 4% absolute difference in 4-year survival translated into a statistically significant 31% reduction in the survival hazard ratio (90% CI 0.49-0.97, P=0.034). Sixteen patients in the docetaxel arm died of prostate cancer versus 23 in the control group. The 6-year incidence of distant metastasis was 9% with docetaxel and 14% without it (HR 0.60, 95% CI 0.37-0.99, P=0.044). The 10% absolute difference in 6-year DFS represented a 24% reduction in the hazard ratio (95% CI 0.58-0.99, P=0.043).

Intensified ADT

The study by Taplin and colleagues continued a line of clinical investigation that begun several years ago with the neoadjuvant combination of abiraterone and standard ADT for men with high-risk localized prostate cancer. The current study included 75 patients with clinically localized prostate cancer associated with Gleason score ≥4+3=7, PSA >20 ng/mL, or T3 disease.

The patients were randomized 2:1 to receive enzalutamide and leuprolide with or without abiraterone and prednisone, followed by radical prostatectomy. The primary endpoint was pCR or MRD.

The data showed that 30% of patients randomized to receive both enzalutamide and abiraterone attained pCR or MRD, as compared with 16% of patients who received enzalutamide (P=0.263). Rates of ypT3 disease, positive surgical margins, and positive lymph nodes were similar between the two groups. Analysis of residual tumor showed similar levels of ERG, PTEN, androgen receptor PSA, and glucocorticoid receptor expression. ERG positivity and PTEN loss were associated with a greater volume of residual disease.

“Neoadjuvant hormone therapy followed by radical prostatectomy ion locally advanced prostate cancer resulted in favorable pathologic responses in some patients, with a trend toward improved pathologic outcomes with [enzalutamide and abiraterone],” the authors concluded. “Longer-follow-up is necessary to evaluate the impact of therapy on recurrence rates.”