SM-88 Safe, Active in Nonmetastatic CRPC

Benjamin A. Gartrell, MD

Updated phase II data showed that SM-88 may be an effective option either before or as an additive to current prostate cancer therapies where normal testosterone may be preferred, as the agent may not worsen quality-of-life (QoL) parameters related to testosterone level, said Benjamin A. Gartrell, MD.

Results from the small prospective trial, which were presented at the 2019 Genitourinary Cancers Symposium, showed that 82% of patients treated with SM-88 experienced an improvement in prostate-specific antigen (PSA) doubling time. In addition, 67% of the patients who received SM-88 demonstrated a decline in circulating tumor cells (CTCs) of >30%. The overall median PSA doubling time at enrollment was 5.3 months and improved to 6.5 months after therapy (P = .02).

“One thing we are very interested in doing is taking a population of patients who are currently receiving androgen deprivation therapy (ADT) or hormonal therapy and figuring out if it is possible to delay the time until the patient needs hormonal therapy—that is what we are trying to do with SM-88,” said Gartrell, lead study author.

The drug compound also appeared to be well tolerated, with few associated adverse events (AEs) observed that are commonly reported with hormone therapy. In the study, 96% of patients reported no cases of hot flashes, 83% said they did not lose their sex drive, and 61% said that they did not see their sexual performance affected by treatment. In a post-therapy questionnaire, 74% reported their QoL as “excellent.”

OncLive: Please provide some background to SM-88.

What were the findings presented from this study?

What was the toxicity profile of the drug?

What are the next steps for this research?

What other prostate cancer studies recently presented at the 2019 Genitourinary Cancers Symposium were you excited about?

In an interview with OncLive, Gartrell, an assistant professor of urology at Albert Einstein College of Medicine and a medical oncologist at Montefiore Medical Center, discussed the promise of SM-88 in this patient population, as well as other therapeutic options that are emerging for various prostate cancer subtypes.Gartrell: SM-88 is a novel, oral, nonhormonal medicine that is being evaluated [as a treatment of patients with] prostate cancer. It is based on a novel derivative of the amino acid tyrosine. SM-88 is given in combination with 3 additional medicines that are all approved by the FDA, but they are given for noncancer indications. The hope is that SM-88 targets cancer metabolism, and we believe that it will have a negative effect on cancer cells but no impact on normal cells. We also expect it to have a great toxicity profile. This was a phase II trial of patients with nonmetastatic prostate cancer who had a rising PSA. Patients were given SM-88, and what we found was that there was a significant decrease in CTC. There was also a significant slowing of PSA rise, or you could call it a prolongation of PSA doubling time. The [profile] was excellent. We believe that patients would like to avoid ADT, which is a hormonal medicine, for as long as possible. When men receive ADT, it means their testosterone is made to go very low. Therefore, typical AEs that we see are hot flashes, sexual side effects, weight gain, and loss of muscle and bone. There is certainly a decrease in QoL as well. SM-88 is a nonhormonal therapy and is not associated with any of these AEs. In this clinical trial, we did not see any of the typical hormone-associated AEs or any deterioration of QoL. We expect that we will develop SM-88 in patients with nonmetastatic prostate cancer, specifically in those who have undergone local therapy for their disease and have a rising PSA. The current standard of care for these patients would be to initiate hormone therapy to lower testosterone, but we expect to develop a clinical trial where we will offer men [who are] in this situation SM-88 versus placebo. This is a space that is becoming pretty crowded. We now have the approval of apalutamide (Erleada) for patients with nonmetastatic CRPC. We also have enzalutamide (Xtandi) [for the same indication].

In addition to that, the ARAMIS trial is now showing us good evidence for darolutamide. [This agent is being evaluated in] patients with nonmetastatic CRPC who have a rising PSA; these patients have a castrate level of testosterone, so by definition, their disease is castration-resistant. Darolutamide is a novel antiandrogen agent, and when added to ADT in ARAMIS, it was shown to have a significant benefit in prolonging metastases-free survival in these patients. The outcomes look very similar to what we saw with enzalutamide and apalutamide in the same population. The toxicity profile looks reassuring; darolutamide is generally a well-tolerated drug.

What does this say about how prostate cancer treatment has evolved?

What can be accomplished in this space within the next 5 years?

We also saw data from the ARCHES trial, which was a study looking at the addition of enzalutamide in a patient population known as metastatic hormone-naïve prostate cancer. For many years, we would just give these patients ADT. We have had made developments in recent years with docetaxel, and, even more recently, abiraterone acetate (Zytiga). Now, we have data with enzalutamide. What we have seen in ARCHES is that enzalutamide plus ADT has a significant benefit in terms of radiographic progression-free survival versus ADT alone. Overall survival was a secondary endpoint, but there are not sufficient enough data yet to comment on that endpoint. It is pretty clear that as time has gone on, the outcomes for patients have gotten much better. If we think several years back, we saw significant advances made in [the development of new] options for [patients with] metastatic CRPC. More recently, we are seeing advances in metastatic hormone-naïve disease. We have also made progress in nonmetastatic CRPC. All of this is essentially escalating the intensity of hormonal medicines.In the next 5 years, I expect to see continued advances made in what we have spoken about. One very important area that has not become a standard of care in prostate cancer is immunotherapy, with the exception of sipuleucel-T (Provenge). I do hope that some of the checkpoint inhibitors will find a role in prostate cancer.

The other exciting therapy that is on the rise is the use of PARP inhibition in patients who have a biomarker, suggesting benefit from that drug. Right now, we are seeing them used in patients with certain mutations in their germline or somatic mutations within their cancer. These patients seem to have the highest probability of benefitting from PARP inhibitors. We have significant evidence of benefit in small single-arm clinical trials. We are waiting for larger trials to confirm this benefit and we hope to see this in the near future.

Gartrell BA, Del Priore G, Retter AS, et al. Evaluating non-hormonal therapy in a phase II trial of SM-88 for rising PSA prostate cancer. J Clin Oncol. 2019;37 (suppl 7S; abstr 83).