The efficacy of androgen deprivation therapy for
prostate adenocarcinoma has been known for more than 50 years.
Within the past 10 years, however, there has been an
increasingly robust understanding of systemic side effects of such therapies.
Much work has been done to find new management strategies to ameliorate these
adverse effects, as well as new therapeutics to attenuate clinical
Two of these — intermittent androgen deprivation
therapy (ADT) and the use of denosumab (Xgeva, Amgen) — are highlighted by
a recent patient case.
A 53-year-old man developed hematuria, prompting further
investigation. Initial laboratory testing included a PSA, which was 5.9 ng/mL.
The only other symptom he was experiencing was occasional pain in the perineal
region, but he had no urinary difficulty. Biopsy revealed prostate
adenocarcinoma, and subsequent radical prostatectomy documented a Gleason 4+5,
T2c N0 M0 adenocarcinoma.
He had an uncomplicated postoperative course, with an
undetectable PSA level 1 year later. However, at that point, the PSA began to
rise to 0.18 ng/mL. He underwent salvage radiotherapy, but 9 months later, the
PSA rose to 1.2 ng/mL. The only symptomatology during this time was
intermittent right hip pain. Scans were negative for any suspicious lesions. He
was started on androgen deprivation with leuprolide, and his PSA dropped to 0.4
He sustained this response over the next year, although
the PSA fluctuated between 0.3 ng/mL and 1 ng/mL.
Most disconcerting for the patient, however, was the
fact he was experiencing a number of new symptoms consistent with side effects
of ADT. These included fatigue, insomnia, sexual side effects (difficulty with
erection) and the development of osteoporosis. The patient recently had gotten
married and, hence, naturally had concerns about his quality of life on
At the time of these symptoms, the patient had a PSA
value of 0.24 ng/mL and a testosterone level of less than 10 ng/dL. Given the
presentation, the option of intermittent ADT was discussed with the patient,
and he chose to take that approach. As such, leuprolide was held while
monitoring his symptoms and lab studies.
After 4 months, the serum testosterone returned to the
normal range at 396.1 ng/dL. His symptoms gradually began to improve, as well.
He reported better energy and fewer sexual side effects. During the subsequent
6 months, the PSA fluctuated between 0.7 ng/mL and 1.4 ng/mL, and it most
recently was recorded at 1.03 ng/mL.
Concomitantly, the patient was begun on denosumab for skeletal event
prevention, as he has documented osteoporosis and continues on hormonal therapy
— albeit now intermittently — for prostate cancer. He continues to do
well without bone pain, and he also is on calcium and vitamin D
The patient shares several common predicaments that many
prostate cancer patients on ADT face.
Although his PSA has been fairly well controlled, he has
multiple concerning side effects affecting his quality of life, including
osteoporosis in the setting of ongoing hormonal therapy. Fortunately, data have
emerged within the past year to support better management options for these
A large phase 3 randomized trial evaluated intermittent
vs. continuous androgen suppression. The trial involved 1,386 patients who were
randomly assigned between the two groups.
Results were reported at the 2011 ASCO annual meeting.
The primary endpoint, OS, was equivalent between the
groups: 8.8 years for those in the intermittent group vs. 9.1 years for those
in the continuous group (HR=1.02; 95% CI, 0.86-1.21).
Multiple quality-of-life measures were superior in the
intermittent therapy group, including physical function, fatigue, desire for
sexual activity and erectile function (P<.01 for all). No differences
were seen in the rate of myocardial events or osteoporotic fractures.
Interestingly, the time to hormone resistance was better
in the intermittent androgen suppression arm, although this was not the primary
endpoint (HR=0.8; 95% CI, 0.67-0.98). Overall, 35% of patients in the
intermittent therapy arm had testosterone levels return to normal range.
Bone health is another critical management issue for
patients on hormonal therapy. In the aforementioned phase 3 trial, the results
showed no difference in the rate of osteoporotic fractures.
Skeletal events also have been known to be a common
clinical event in prostate cancer, and they have potentially serious
consequences. To this end, a RANK ligand inhibitor, denosumab, was evaluated in
patients with prostate cancer undergoing ADT.
In a phase 3, double blind trial, 1,468 patients who had
been on ADT for at least 12 months were randomly assigned between denosumab 60
mg subcutaneously every 6 months and placebo. The primary endpoint was change
in bone mineral density at the lumbar spine at 24 months.
Results showed that lumbar spine bone mineral density
improved 5.6% with denosumab, whereas it fell 1% on placebo
(P≤001). Significant improvements also were seen in secondary
endpoints, including bone mineral density in the femoral neck and hip. In
addition, there was a decreased incidence of new vertebral fractures at 36
months (1.5% in the denosumab group vs. 3.9% in the placebo group). Serious
adverse events were equal between groups, and no cases of osteonecrosis of the
jaw were seen in this study.
These are two practice-changing clinical trials, and
they address important treatment-related issues that often present in prostate
This data, along with the availability of new
therapeutic agents, allows more nuanced and improved management in this large
- Crook JM. Abstract #4514. Presented at: the ASCO Annual Meeting;
June 3-7, 2011; Chicago.
- Smith MR. N Engl J Med. 2009;361:745-755.
For more information:
- Amit Mehta, MD, is an attending physician at Regional Cancer Care
in Durham, N.C. He also is a member of the HemOnc Today Editorial Board.
Disclosure: Dr. Mehta reports no relevant financial disclosures.