Biochemically-relapsed, non-metastatic, hormone-naïve prostate cancer represents a unique disease state [16
]. As many as 70,000 men per year in the United States fall into this category where a rising PSA is the only manifestation of illness [17
]. In men with PSA progression after local therapy, management options include surveillance, initiation of androgen deprivation therapy (ADT), dietary intervention, or clinical trial participation. A subset of patients may benefit from salvage radiation therapy. However, no definite survival benefit has been demonstrated with the early institution of ADT in this population. Given the adverse effects of ADT, many men choose to avoid or delay medical castration for a rising PSA alone. Developing alternative options for patients with “PSA-only” prostate cancer is therefore highly desirable.
Evaluating drugs to treat prostate cancer poses unique challenges. The natural history of the disease often spans decades. The Prostate-Specific Antigen Working Group (PSAWG) has described eligibility criteria and trial design considerations for patients in the state of a rising PSA after local therapy [19
]. While changes in PSA have not been endorsed as a surrogate marker of clinical benefit or survival, modulation of PSA levels is considered to be an indicator of biological drug effects that could help screen for agents that might alter the natural history of the disease. The current study adhered to the concepts described by the PSAWG and was designed to determine the proportion of patients who remained PSA progression-free for 24 weeks. This may help us predict clinical responses in patients with biochemically-relapsed prostate cancer.
We designed this randomized phase II study in order to screen for clinical activity of ATN-224, and to guide the conduct of future studies. Overall, 54% of evaluable patients were PSA progression-free at 24 weeks suggesting that ATN-224 may have biological activity in this patient population. When examining each dose-level separately, it appeared that the low-dose arm had greater effects on PSA parameters than the high-dose arm. However, differences between the two arms cannot be interpreted, as the study lacked power for comparative efficacy analyses. In addition, it is not known if modulation of PSA parameters is related to true clinical benefits. Interpretation of the results is further complicated by the baseline patient characteristic analysis suggesting that there were less high-Gleason patients in the low-dose group.
Data from a retrospective cohort of patients with clinically localized prostate cancer treated with either radical prostatectomy or radiation therapy suggested that a short post-treatment PSADT (<3 months) is a useful surrogate endpoint for all-cause mortality and prostate cancer-specific mortality after biochemical recurrence[20
]. In men who had a rising PSA after radical prostatectomy, a PSADT shorter than the median value of 10 months was the most significant predictor for metastatic progression[21
]. Similarly, a short post-treatment PSADT after radiation therapy predicted progression to metastatic disease[22
]. The PSA velocity was also related significantly to survival in men with rising PSA after external beam radiotherapy[24
In this study, we found that compared to pre-treatment values, post-treatment PSADT was statistically longer after low-dose ATN 224 treatment but not after high-dose therapy. PSA slope was also significantly decreased post-treatment in the low-dose arm. One explanation for this could be the different baseline populations as mentioned above. However, it is also impossible to prove that the same effects could not have been seen with a placebo treatment. To this end, in a placebo-controlled trial evaluating the effect of celecoxib on PSADT in a similar patient population, 20% of 40 men in the placebo group had post-treatment PSADT ≥200% of baseline PSADT[25
]. A separate study of rosiglitazone versus placebo in a similar population showed that 40% of men in the placebo group had a post-treatment PSADT >150% of baseline[26
]. In our study, 8 patients (33%) in low-dose group and 3 men (13%) in the high-dose group had PSADT >200% of baseline after 6 months of treatment. Certainly there are differences in baseline PSADT characteristics in our study compared to these prior trials (e.g.
PSADTs were between 6 and 24 months[25
] or <24 months[26
] in the other studies, and <12 months in the current study), and therefore direct comparisons of our study with the prior trials is not possible. Therefore, in the absence of a placebo-control, it is difficult to interpret the significance of the PSA changes reported here.
Surrogate endpoints for future studies evaluating investigational agents in this patient population need to be validated. PSADT and PSA kinetics changes may be acceptable for phase II studies, but would have questionable significance in larger phase III studies in the absence of clinical endpoints (e.g.
metastasis-free survival or overall survival). Metastasis-free survival as a surrogate for the survival endpoint is currently being discussed in the clinical research community and may be reasonable for studies requiring prolonged follow-up. Interestingly, a preliminary evaluation of several PSA measures in the “PSA-only” population seems to suggest that changes in PSA kinetics induced by treatments with a variety of experimental agents correlate significantly with metastatic progression[27
], although these data require prospective confirmation.
SOD1 as a target for cancer therapeutics should be revisited as well. Studies have shown that over-expression of SOD in vitro
increases cell differentiation, decreases cell growth and proliferation, and can reverse a malignant phenotype[28
]. Other in vivo
studies showed that SOD could be highly expressed in aggressive human solid tumors[30
]. Furthermore, high SOD expression has occasionally been associated with a poor prognosis and with resistance to cytotoxic drugs and radiation[33
]. It is suggested that most of the apparent conflicts between the above in vitro
and in vivo
observations can be reconciled by considering the net redox status of tumor cells in different environments[35
]. It is possible that the baseline net cell redox balance will determine the sensitivity of cancer cells to a SOD1 inhibitor such as ATN-224. Regrettably, evaluation of SOD1 expression was not conducted as part of this trial.
ATN-224 may also mediate antitumor effects by lowering systemic copper levels, as reflected by serum Cp. Although ATN-224 decrease Cp level as expected, there was only a weak correlation between Cp levels and PSA alterations. SOD1 activity in erythrocytes has also been proposed as a biomarker for copper status in humans[36
]. It may give us some information to explain why the low-dose ATN-224 group achieved a higher degree of PSA progression-free survival.
This study has several limitations. First, there was no placebo control in this trial. It has been reported that in similar patient populations, placebo-treated patients can have stable disease for many weeks. In addition, it is not possible to assess whether post-treatment PSA changes would have also occurred to the same degree on a placebo arm, due to factors such as more frequent PSA measurements captured on-treatment with a consequent regression of PSADT values towards the mean. Second, the baseline patient factors in this study were not all well balanced between groups, with more high-risk patients observed in the high-dose group. This makes interpretation of the data difficult, especially because Gleason sum has been shown to be a predictor of progression and survival. It is possible that ATN-224 may be more efficacious in patients with low-risk disease. Third, the sample size here was not large enough to permit an adequately-powered comparative analysis between the two study arms, and thus this study is unable to provide data to suggest which dose may be more efficacious in terms of PSA parameters.
In conclusion, ATN-224 therapy was associated with significant post-treatment changes in PSA parameters compared to pre-treatment values in men with PSA-recurrent non-metastatic prostate cancer when used at a dose of 30 mg/day but not at the higher dose. Further analyses (perhaps using pooled data from several comparable studies) are required to determine whether changes in PSA kinetics (PSA doubling time, slope, velocity) correlate with clinically-relevant endpoints in this patient population. In addition, placebo-controlled trials may aid the interpretation of future trials evaluating non-hormonal investigational drugs in this patient population.