Data from the first 13 evaluable patients enrolled in a phase II study of SM-88 showed a reduction in circulating tumor cells, a slowing of prostate-specific antigen increase, and delayed radiographic progression of disease in nonmetastatic prostate cancer.
Mack Roach III, MD
A novel nonhormonal nontoxic combination consisting of an amino acid analogue, a CYP3a4 inducer, an mTOR inhibitor, and an oxidative stress catalyst (SM-88) may delay or obviate the need for chemical castration to control nonmetastatic prostate cancer. In an ongoing open-label phase II study of SM-88, data from the first 13 evaluable patients enrolled showed a reduction in circulating tumor cells (CTCs), a slowing of prostate-specific antigen (PSA) increase, and delayed radiographic progression of disease compared with prediction models.
As reported by Mack Roach III, MD, at the 2018 Genitourinary Cancers Symposium, therapy was well-tolerated with no treatment-related serious adverse events. Notably absent were toxicities typically associated with androgen deprivation therapy (ADT).
“This study is really a proof of principle that a relatively nontoxic compound can be developed, which has the promise to slow the progression compared to no treatment, and potentially be competitive to other treatments,” said Roach, a radiation oncologist and professor of radiation oncology and urology at the University of California, San Francisco.
The potential effectiveness in cancer of SM-88 relies on the recognition that the glycolytic pathway is different in cancer than in normal cells (based on the Warburg effect). SM-88 selectively targets tumors through oxidative stress, changing the tumor’s preferred metabolites. The pivotal component of the compound is a dysfunctional tyrosine derivative that interferes with cancer cells’ protein synthesis process.
“This compound was empirically found to impact the glycolytic pathway in a way that is detrimental to cancer cells and not detrimental to normal, and therefore the toxicity is quite low,” Roach said. The attractiveness to me as an investigator is that we have a relatively nontoxic compound that has anticancer activity manifested by a reduction in CTCs and has the potential to be used earlier in the course of the disease so men don’t have to take forms of castration or take cytotoxic chemotherapy.”
The phase II study is an ongoing, open-label, multicenter, single-arm trial in which 19 patients have been enrolled so far, with 13 having received the medication 230 mg twice daily, and 12 having completed at least 1 cycle. A total of 34 are planned for recruitment.
The 13 patients had a mean age of 71 years, 45% underwent curative intent surgery and 55% radiation therapy previously, and 91% had previous ADT. The time since initial therapy was a mean of 8.8 years and the mean time since their last ADT was 5.5 years. The PSA at baseline was 5.7 ng/mL. Their Eastern Cooperative Oncology Group performance status at baseline was 1.
Overall, 57% of patients had a >50% reduction in CTCs following treatment with SM-88. Approximately 36% had <5 cells/7.5 mL of blood and 36% had at least 1 measure that was undetectable, with the median time to an undetectable level being 20 weeks (range, 3-28 weeks).
Twelve of the 13 patients had at least 1 cycle with an improvement in PSA levels, defined as at least 1 decrease in PSA level. CTCs may be a better prognostic marker than PSA levels, said Roach, especially in early recurrent prostate cancer in which PSA levels may be affected by multiple noncancerous conditions. “These were people who had recurred after treatment, and the PSAs were relatively high when they recurred, so potentially if you move treatment earlier, it will have greater activity, and you may want to combine it with other kinds of treatment,” he said. “In general, in people who have rising PSAs, their PSA is going to keep rising.” The expected rate of radiographic progression for the study sample from the time of biochemical recurrence to a median of 12 months was about 18% by the Memorial Sloan Kettering Cancer Center prostate cancer prediction nomogram. The observed result with SM-88 treatment was about 7%.
The intimacy domain on the EORTC QLQ-PR25 and the mental domain on the Q20-28 questionnaires remained stable. Sixty two percent reported no or resolved hot flashes, 100% indicated an improved or stable interest in sex or being sexually active, 54% reported excellent or nearly excellent overall health, and 54% indicated excellent or nearly excellent quality of life.
Testosterone levels increased from an average of 292.8 ng/mL at baseline to an average of 337.8 ng/mL on treatment. There were no statistically significant changes in weight, glucose levels, hematocrit levels, or QTC interval. The main toxicity appeared to be an increase in blood pressure, but with no placebo group and a number of confounders, the importance of this finding is uncertain, said Roach. In the 3 normotensive patients, mean arterial pressure increased from an average of 89.9 mm Hg at baseline to 104.8 mm Hg on treatment. In the 10 patients with hypertension at baseline, these averages were 98.6 and 114.7 mm Hg, respectively.
Roach M, Gostout Z, Zawisny P, et al. Phase II trial of SM 88 in non-metastatic biochemical recurrent prostate cancer. Presented at: 2018 Genitourinary Cancers Symposium; February 8-10, 2018; San Francisco, Calif. Abstract 175.