This randomized, phase II, double-blind, dose-finding study compared the effects of two dose levels of POMx on PSA kinetics in men with a rising PSA following radiation or radical pro-statectomy. The study met its primary objective as hypothesized, with a lengthening of PSADT ≥6 months (11.9–18.5 months, P =0.001), with no significant difference between dose groups. PSADT increases were noted by patients across the range of baseline PSADT values, although shortening of PSADT was recorded in 20 (19.8%) patients, as might be expected with a broad patient population. In clinically reviewing patients with shortening of PSADT, none experienced clinical harm. Several transitioned to subsequent treatments and accounted for early withdrawal, moving primarily to androgen deprivation therapy.
The study accrued quickly, in part because patients were disposed to forgo androgen deprivation therapy therapy to avoid associated toxicities.7,8
The majority of patients stayed on treatment per protocol, but 42% of patients left prematurely over the 18-month study. Patients who left early showed evidence of PSA progression, but often did not meet the protocol definition of a rise of 5 ng dl−1
, after 6 months on treatment. Premature departure of patients often reflected investigator and/or patient anxiety concerning disease progression due to rising PSA values, however, 70% of patients remained on study for a year providing adequate on-study PSA values to calculate PSADT reliably. A total of 28 patients in the low-dose arm and 27 patients in the high-dose arm entered the high-dose, open-label extension study and 37 patients remained on study after 18 months of treatment in the open-label extension. Only 8% of patients left the study prior to completing 6 months, and nearly 60% completed protocol, as planned. This level of completion of the 18-month protocol reflects a disease that continues to progress, and PSA increases can be concerning. When progression occurs, patients frequently ask for access to treatments that could result in a decrease in PSA. Researchers may want to consider shorter trial duration in future studies in this patient population.
These observations of lengthening of PSADT in patients treated with POMx are consistent with the results of the Pantuck et al
study of pomegranate juice in a more narrowly defined patient population (0.2<PSA<5 ng ml−1
, Gleason score ≤7). At 24 months of treatment, the change from median baseline PSADT to median post-baseline PSADT was 11.5–19.9 versus 11.9– 18.5 months at 18 months treatment in our study. Pantuck’s patients were more homogenous and had baseline PSAs ≤5 ng ml−1
, whereas 31% of patients in our study had baseline PSA levels >5 ng ml−1
, ranging up to 32 ng ml−1
. The percentage of patients who had a decreasing PSA on study was roughly similar (18% for Pantuck and 13% in our study). Pantuck’s analytical methodology excluded subjects with negative post-baseline PSADT from analysis, thereby underestimating the reported effects. We included any patient with on-study PSA measurements and those coming off quickly may have led to over- or underestimates of the effects of POMx on PSADT. To enable inclusion of all subjects in the ITT population and avoid underestimating the median, we included patients with declining PSA values by converting their negative PSADT to the highest PSADT experienced by study participants, as was done in previous trials.3,17
The lack of dose response requires discussion because it may imply that changes in PSADT were not brought about by the compound. An alternative explanation is that the lower dose was sufficient and the higher dose exceeded a threshold for ‘drug’ activity. Such a result is not uncommon in the use of dietary supplements where dose-limiting toxicities are not found.18,19
The higher rate of diarrhea in the high-dose group suggests the possibility of reduced absorption and if true, would correlate with decreased bioavailability. However, we did not measure pharma-cokinetics and only 13% of patients in the high-dose group had diarrhea. Therefore, dose-ranging studies like this could benefit from evaluation of bioavailability with markers such as urolithin A, which has been found to be present in urine 24 h after administration of pomegranate juice.20
The major limitation of our study is the lack of a placebo arm. A placebo arm was considered, but given the perceived positivity of pomegranate juice, a placebo control was felt to pose difficulties for patient accrual. A dose-response study was an alternative. The US Food and Drug Administration describes dose-response studies as ‘one kind of adequate and well-controlled trial that can provide primary clinical evidence of effectiveness’ consistent with Code of Federal Regulations Title 21, Section 314.126.21
In this study, no effect of dose was seen, suggesting that the change in PSADT may be due to chance. Only a placebo-controlled trial could provide the evidence needed to have confidence that the effect was treatment-related. In three prior trials in similar patient populations, patients on the placebo arms experienced substantial lengthening of PSADT while on study. In a Rosiglitazone trial involving 106 patients, 73% of patients on placebo had an increase of PSADT in excess of 100%, and 31% exceeded 200% in PSADT lengthening.22
In an Atrasentan trial involving 222 patients, 78% of the patients on placebo had a lengthening of PSADT.23
In a celecoxib trial involving 78 patients, 20% of the patients on placebo had >200% increase of PSADT.24
In our study, 46% of the low-dose and 41% of the high-dose group showed PSADT increases ≥100%, and 28% and 37%, respectively, exceeded 200%. The high levels of PSADT lengthening seen in placebo arms of prior studies along with the lack of a significant dose-related effect in our study raise the question whether these results could be due to statistical variation and/or placebo effect. Though our study was positive as designed, our results do not definitively show that changes in PSADT can be related to POMx administration. The lack of dose effect that we hypothesized suggests that future studies should be placebo-controlled and use of low-dose POMx appears appropriate. A phase III, 180 patient, placebo-controlled, 2:1 randomized study of POM juice is maturing (NCT00732043). In addition, a randomized, placebo-controlled, pre-surgical phase II trial involving 70 patients will measure the effects of POMx consumption on oxidative damage, proliferation and localization of urolithins in prostate tissue (NCT00719030).
Variations in measurement of PSA values may contribute to variability in results. Baseline PSADT values were calculated using PSA levels collected at irregular intervals ≥1 month apart within the year prior to study initiation using site-specific laboratories; on-study measurements were obtained consistently every 3 months using a central laboratory. A period of rigorous measurement of PSA values, using a central laboratory, prior to randomization may enable more accurate assessment of baseline PSADT. Further investigation is warranted to illuminate statistical variability in PSA measurement and the placebo effect in trials of therapeutic agents in this patient population.
A related issue is whether changes in PSADT are acceptable end points for clinical trials. Retrospective studies have shown that PSADT is a strong predictor of metastasis-free survival25
and overall survival3,26
However, prospective studies are needed to provide confirmation that PSA declines accompanying drug administration correspond with improved metastasis-free survival and overall survival.
No significant changes were seen in testosterone levels, and although significant increases were seen in estradiol in the high-dose group, there was high variability in the measurements. Plants such as pomegranate, which contain phytoestrogens, may raise estrogen levels and theoretically could cause clinically significant estrogenic effects. In this study, estradiol levels fluctuated, sometimes rising just above the reference upper limit of 50 pg ml−1
and subsequently declining while still on study, suggesting that the fluctuations were unrelated to the study compound.27
No clinically significant estrogen-related side effects, such as breast enlargement, were reported. In addition, no significant difference in change in PSADT was seen between the low- and high-dose POMx groups, despite the measurably different increase in estradiol in the high-dose POMx group. In other words, changes in PSADT do not seem to be affected by increases in estradiol. However, given the small sample size, estradiol should be monitored in future studies of POMx.
This randomized, double-blind, dose-finding study in PCA patients with rising PSA attempted to rigorously examine a widely consumed natural product under an Investigational New Drug Application. PSADT lengthened in men on this study, independent of dose level without adverse effects, but questions remain as to causality secondary to POMx. This study confirms the need for placebo-controlled trials when assessing PSADT and ultimately for using clinically meaningful end points such as metastasis-free survival and overall survival before recommending the use of POMx by PCA patients.