Chemotherapy and Androgen Suppression for MEN WITH

(1) METASTATIC PROSTATE CANCER AND
(2) HIGH-RISK CANCER AT INITIAL PRESENTATION

In the New England Journal of Medicine in October 2004 the pivotal TAX-327 clinical trial reported the efficacy of docetaxel (Taxotere) in prolonging median survival by 2.4 months in men with castration resistant prostate cancer (CRPC) to 18.9 v. 16.5 months for mitoxantrone. This success spawned several investigations which addressed the question as to whether introducing docetaxel earlier in cancer management would yield even superior results.   Underlying this proposed schema was a more basic biological supposition.

In their editorial in Expert Rev. Anticancer Ther. 2015, “Should docetaxel be administered earlier in prostate cancer therapy?” Drs.Thomas Beers and Julie Graff comment, “The driving hypothesis of these trials is that castration-resistant cells are present at diagnosis and that targeting both castration-sensitive and castration-resistant clones at diagnosis is beneficial.”

Three clinical trials have recently been reported each designed to address this issue. Two trials used docetaxel and androgen deprivation therapy (ADT) v. ADT alone in men who had metastatic prostate cancer at diagnosis. The other trial followed the same design and analyzed outcome in men who presented at diagnosis with cancer predicted to have a high risk of recurrence.

These findings are likely to be practice changing but, as usual, proper patient selection calls for a shared discussion and sound clinical judgment.

1. Results of Two Trials Treating Men with De Novo Hormone-Naive Metastatic Cancer. 

Results of the CHAARTED and STAMPEDE trials comparing ADT and docetaxel v. ADT alone in men with hormone-naive de novo metastatic disease:

Note: With appropriate PSA screening there should be no men presenting with metastatic disease. The Prostate Cancer Prevention Trial found that only 5-6% of men showed high-grade cancer by the end of the study and none were metastatic. In an unscreened population, however, high-grade disease is found in about 15%, and some of them have metastases at diagnosis. (With the lapse of screening following USPSTF recommendation to cease PSA screening, unfortunately this number will increase.) So the findings of these two studies will address only a limited … and hopefully decreasing, number of men. However, as a “proof of principle” the results are very significant.

The CHAARTED trial results were reported in the New England Journal of Medicine in August, 2015.

  • The 790 participants were randomized to either the combination therapy or ADT alone.
  • Docetaxel was started at the same time as ADT and consisted of six 3-week cycles of docetaxel (Taxotere).
  • Each arm was further stratified between “low tumor burden” and “high tumor burden.” The latter group was defined as having visceral metastases or > 4 lesions on bone scan, one or more of which were required to be beyond the axial skeleton, a recognized indicator of more aggressive disease. High-burden disease was seen in 65% of men; 60% had Gleason score > 8 and 15% had visceral metastases.
  • The mean PSA at entry was 51ng/ml.

Results: Men in both tumor burden groups receiving combination therapy benefited compared to ADT alone. The median follow-up time was short at 28.9 months. However, at this time the median overall survival for both arms in the combined treatment group was 57.6 v. 44.0 months for the ADT alone arm, a 13.6 month improvement. In the low-burden group there was a trend toward benefit for combined treatment, but the median survival had not been reached. The benefit in the high-burden arm was impressive — 49.2 v. 32.2 months, a 17 month improvement.

It is of note that by the time of the data analysis, 74% of the men who relapsed on the ADT arm received docetaxel later in their treatment when they had become castration resistant. This subsequent use of chemotherapy in the CRPC setting did not compensate for the benefit from the initial application of docetaxel treatment when the patients were hormone naive.

As commented on by Voskoboynik in “ ‘Charting a new course for prostate cancer’ – currying favor for docetaxel in hormone-sensitive metastatic prostate cancer,” (Expert Review of Anticancer Therapy, Sept 2015), “The results from CHAARTED show an improvement in overall survival that has been never seen in metastatic prostate cancer and is rarely seen in clinical trials for metastatic solid malignancies.”

The STAMPEDE trial is ongoing and involves a complex design of 9 different treatment arms, but essentially compares the early use of chemotherapy/ADT to ADT alone in two groups of men, those with locally advanced cancer and those with metastatic, hormone-naive cancer. At 42 months of follow-up the comparison of the median overall survival for the combination therapy v. ADT alone in all arms favored the duo by 10 months. “For the subset of patients [presenting] with metastatic disease the average improvement in overall survival was even higher, 22 months (from 43 vs 65 months” (ASCO Post, May 2015).

Lead author, Nicholas James MD, states “We hope our finding will encourage doctors to offer docetaxel to men newly diagnosed with metastatic prostate cancer, if they are healthy enough for chemotherapy. Men with locally advanced, nonmetastatic prostate cancer may also consider docetaxel as part of upfront therapy, as it clearly delays relapse.”

2. Results of the RTOG 0521 comparing adjuvant ADT and docetaxel v. ADT alone in men with high-risk cancer following primary radiation therapy.

RTOG 0521: The results of this trial were reported as an abstract (LBA5002) at the 2015 season of the ASCO annual meeting.  High-risk was defined as:

  1. Gleason score 7-8, any T-stage, and PSA >20 ng/ml;
  2. Gleason 8, > T2 stage, any PSA;
  3. Gleason 9-10, any T-stage, any PSA.

These trial results are likely to have wide applicability, since these categories are commonly encountered in clinical practice and frequently treated with radiation (RT) and adjuvant ADT.

In the study:

  • 53% had Gleason score 9-10; 31% Gleason score 8; 16% Gleason 7; and 27% had stage cT3-4 disease.
  • The median PSA at entry was 15.1ng/ml. The radiation therapy dose was acceptably high at 75.6 Gy.
  • Once again, docetaxel chemotherapy (CT) was administered for six 3-week cycles plus prednisone starting 28 days after RT.
  • Androgen deprivation therapy (ADT) was continued for 24 months.
  • Median follow-up for the 562 men was 5.5 years.

Results: The 6-year disease-free survival rate [i.e., no PSA progression] was 65% for the ADT+RT+CT arm and 55% for ADT+RT. At four years the overall survival rate was 93% v 89% favoring the ADT+RT+CT group. Additional follow-up is pending.

Expert comment by Ian Tannock, MD, PhD, DSc (ASCO Post, June 2015): “For the first time, a large randomized trial has suggested that overall survival is improved by the addition of adjuvant chemotherapy to androgen suppression and radiotherapy in men with localized, high-risk, hormone-sensitive prostate cancer.”

Chemotherapy and Androgen Suppression

BOTTOM LINE:  The findings in these three studies have direct clinical applicability. The CHAARTED and STAMPEDE studies demonstrate a clear survival advantage from the early addition of chemotherapy to ADT in patients with de novo metastatic disease.  The RTOG 5021 trial found an improvement in disease-free and overall survival by adding early chemotherapy to the standard radiation/ADT regimen in men with high-risk cancer at diagnosis.

Considering the known, but variable, toxicity of chemotherapy, not all men with these disease presentations will be appropriate for the addition of chemotherapy. Patient selection, as usual, will require sound clinical judgment as well as an informed patient/physician discussion.

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