Non-metastatic Recurrent Prostate Cancer Research Articles

Replicating the timing of androgen deprivation therapy randomized trial (TROG 03.06 and VCOG PR 01-03 [TOAD]) for recurrent prostate cancer using real-world observational data.

e17090 Background: The landmark TOAD trial (Lancet Oncol 2016) demonstrated an overall survival benefit for immediate compared to delayed androgen deprivation therapy (ADT) for patients with recurrent prostate cancer or unsuitable for curative treatment. However, the extent to which TOAD trial results can be replicated in real-world population-based observational data is unknown. For these reasons, we used TOAD trial data and criteria to define a similar retrospective cohort of men with rising PSA after definitive treatment of localized prostate cancer to compare immediate versus delayed ADT for recurrent non-metastatic disease. Methods: We used two data sources to conduct this study: 1) TOAD trial data, and 2) national electronic health record, cancer registry, administrative, pharmacy, and laboratory data for men treated with radical prostatectomy or radiotherapy for localized prostate cancer and laboratory confirmed biochemical recurrence (BCR) between 2005- 2015 in the Veterans Health Administration. We defined BCR according to guidelines and used National Death Index data through 2019 for survival outcomes. We designated randomization to the ‘immediate’ and ‘delayed’ arms for men receiving ADT within (immediate) or after (delayed) 2 years of BCR in the observational data. We used Cox proportional hazards regression models adjusting for age, PSA at BCR, comorbidities, and Gleason score, stratified by prior ADT exposure, to compare survival outcomes for immediate versus delayed ADT. Results: We identified 9,866 men with BCR after radical prostatectomy, 3,431 after radiotherapy alone, and 2,703 after radiotherapy and adjuvant ADT. The mean age at randomization for the TOAD cohort was older (74.8 vs. 75.9 years, delayed vs. immediate) compared to our observational cohort (68.1 vs. 67.0 years, delayed vs. immediate). In unadjusted survival analyses, we found both overall and prostate cancer-specific survival were higher among patients with delayed ADT (log-rank p-value < 0.001 for both). Our multivariable survival models among men with and without prior ADT exposure also demonstrated survival benefit associated with delayed ADT (prior ADT exposure, adjusted hazard ratio (aHR) 2.3, 95% confidence interval (CI) 1.7, 3.0, no prior ADT exposure 2.6, 95% CI 2.4, 2.8). Conclusions: The benefit of immediate ADT administration compared to delayed as reported within the TOAD study was not found in a comparable observational cohort of men with non-metastatic recurrent prostate cancer. Even after multivariable adjustment, we found clear association of delayed ADT administration with improved survival outcomes suggesting selection bias and unobserved confounding, or that delayed ADT may be warranted for selected patient populations necessitating further investigation. Source of Funding: NCI R01 CA242559.

Phase II trial of SM 88 in non-metastatic biochemical recurrent prostate cancer.

175 Background: Despite toxicity and no clear survival benefit, non-metastatic recurrent prostate cancer (nmPC) is typically treated with androgen deprivation therapy (ADT). SM88 is a relatively non-toxic novel combination therapy (amino acid analogue, CYP3a4 inducer, mTOR inhibitor and catalyst) based on the Warburg effect, with activity in a variety of cancers including prostate (JCO 2017 35, e16567). Phase I and II results demonstrated stable or rising testosterone levels while achieving a reduction of CTCs (circulating tumor cells) and no radiographic progression events (Annal Oncol 2017, 28(5):274-5). We now report results for toxicities typically seen with ADT. Methods: Prospective ongoing Phase Ib/II of SM88 (230mg po bid) in recurrent nmPC with rising PSA (PCWG3 definition), detectable CTCs, and no radiographically identified metastases at baseline. Results: Since Sept 2016, there have been 17 consented (of 34 planned) with 10 evaluable (completed > 1 cycle) (median 7, range 1-13). Mean age was 71.2 (53-84); all had prior ADT after curative intent RT (50%) or surgery (50%); with no patient currently on ADT. Mean testosterone level was 307.6 ng/dL before SM88 and 349.2 after (p = 0.07, one-tail T test), rising in (5/10) or remained stable except for one patient who entered the trial castrate ( < 2.5). Overall 70% had some grade 1-2 adverse event (AE) but no drug related serious AE. EORTC-QLQ-C30 relating to mental function domain (Q20-28) and QLQ-PR25 intimacy domains (Q44-50) remained stable, including 9 (90%) reporting no or resolved hot flashes; 7 (70%) reporting an improved or stable “interest in sex”; and 6 (60%) having “excellent” “overall health” and “QOL”. Weight and osteoporosis (measured by Urinary NTX) did not worsen; mean EKG QTc (422 ms); mean arterial pressure (95.1 mmHg); glucose (115.2 mg/dl) and hematocrit (41.5%) were not affected. Conclusions: Toxicities typically associated with ADT were not seen with SM88, a novel non-hormonal anti-neoplastic. Despite the limited follow-up, these data suggest that ADT may be avoided or delayed without progression in selected patients with nmPC. A phase III RCT of SM88 vs patient choice of hormonal or active surveillance is planned for confirmation of these results. Clinical trial information: NCT02796898.

Phase Ib pharmacokinetics of non-hormonal SM88 in patients with non-metastatic recurrent prostate cancer.

e14061 Background: SM88 is a combination of tyrosine isomers ( TI) and repurposed drugs (modulators of CYP3A4, mTOR, and oxidative stress). This regimen has previously reported non-toxic activity in cancers including prostate (PC) ( J Clin Oncol 2013 31: e22095). We present summary data from a completed Ib trial of non-metastatic recurrent PC (nmPC), an ideal candidate for a well-tolerated, non-androgen based treatment. Methods: This was an open-label safety and PK trial of SM88 in patients with nmPC. Cohort 1 received 230 and cohort 2 - 460 mg/day of TI, along with the lowest available doses of the other 3 agents. Multiple samples were drawn at pre-dose and up to 48 h post dosing from 4 patients after a single TI dose; after a single dose of all 4 components; and after 2 weeks of steady state daily combined dosing (SS). Only cohort 2 results are presented. Results: See table below. Each of the 3 approved drugs had expected PK results that will be provided. There was no evidence that the combination altered the expected PKs at SS. There were no serious drug related adverse events. Favorable biomarker activity was documented at both TI dose levels. Conclusions: Single dose and SS TI results from this completed phase Ib trial are consistent with preclinical predictions (ESMO 2016. Ann Oncol (2016) 27 (suppl_6): 1605P). TI PK results changed transiently with the additional components but returned to desirable levels at SS including a higher Cmax, AUC, and more rapid Tmax, indicating rapid absorption. The PK results (not shown) are consistent with the published data for the approved agents, despite the use of lower than typical label doses. Based on these results, the higher TI dose was chosen for the ongoing phase II expansion cohort in nmPC patients. SM-88 appears to have predictable PK as an effective metabolomic regimen for the treatment of advanced prostate cancer devoid of significant toxicities. [Table: see text]

Pharmacodynamic study of disulfiram in men with non-metastatic recurrent prostate cancer

BackgroundPreclinical drug screens identified disulfiram as a potent in vitro inhibitor of prostate cancer cell growth. Although many mechanisms for its anticancer activity have been proposed, tumor suppressor gene re-expression through promoter demethylation emerged as one of the more plausible.MethodsWe conducted an open-label, dose escalation trial of disulfiram in men with non-metastatic recurrent prostate cancer after local therapy. Dose escalation occurred if a demethylating “response” [i.e. ≥10% decrease in peripheral blood mononuclear cell (PBMC) global 5meC content] was observed in <3 patients in cohort 1. Cohort 1 and 2 received disulfiram 250 mg and 500 mg daily respectively. The primary endpoint was the proportion of subjects with a demethylation response. Secondary endpoints included rate of PSA progression at 6 months, changes in PSA doubling time and safety/tolerability.ResultsChanges in global 5meC content were observed in 2 of 9 patients (22.2%) in cohort 1 and 3 of 10 (30.0%) in cohort 2. Only 5 subjects were on trial for ≥6 months, all were in cohort 1 and all had PSA progression by 6 months. No changes in PSA kinetics were observed in either cohort. Disulfiram was poorly tolerated with 6 patients experiencing grade 3 AEs (3 per cohort). Three of the responders displayed pre-treatment instability in their 5meC content.ConclusionsA minority of patients had transient global PBMC demethylation changes. Instability in 5meC may limit the reproducibility of these findings, limiting our ability to confirm our hypothesis. Given the toxicities and no clinical benefits, further development of disulfiram should not be pursued in this population.

A prostate cancer clinical trials consortium trial of disulfiram (D) in men with nonmetastatic recurrent prostate cancer (PCa).

219 Background: Epigenetic silencing of tumor suppressor genes (TSG) by promoter methylation contributes to carcinogenesis and progression. Targeting these epigenetic changes in PCa has been hindered by a paucity of available agents. D potently inhibits PCa growth in vitro and can cause demethylation and re-expression of known TSGs in PCa cells lines. Methods: To determine if D leads to demethylation changes [i.e. decreased global 5meC DNA content from peripheral blood mononuclear cells (PBMC)] we conducted an open-label, dose escalation trial of D in men with non-metastatic recurrent PCa after local therapy. Dose escalation occurred if a demethylating “response” (i.e. &gt;10% decrease in global 5meC content) in &lt;3 patients was observed in cohort 1. Cohort 1 and 2 received D 250 mg and 500 mg daily respectively; 1 cycle equaled 4 weeks. The primary endpoint was the proportion of subjects with a demethylation response. Secondary endpoints included rate of PSA progression at 6 months (i.e. confirmed &gt;50% rise over baseline and &gt;2 ng/mL above nadir), changes in PSA doubling time (PSADT) and safety/tolerability. Results: Two patients out of 9 (22.2%) in cohort 1 met our primary endpoint. Cohort 2 accrued a total of 10 patients, 3 (30.0%) of which had &gt;10% decrease in global 5meC content. Only 5 subjects were on trial for ≥6 months, all were in cohort 1 and all had PSA progression by 6 months. Median PSADT change post-treatment was not significantly different between responders and non-responders (266.9 vs -7.8 days, P=0.18) or between cohorts 1 and 2 (22.5 vs -39.7 days, P=0.54). While there were no grade (G) 4 adverse events (AE), the drug was poorly tolerated with 6 patients experiencing G3 AE (3 per cohort). There was a trend toward fewer median number of completed cycles in cohort 2 vs cohort 1 (5 vs 9 cycles, P=0.12). Common AE included: fatigue, GI toxicity, ataxia/dizziness, and constitutional symptoms. Conclusions: A minority of patients had global PBMC demethylation changes, consistent with D acting as a probable demethylating agent in those individuals. Given the toxicities associated with D and no significant clinical benefits, further development of this agent should not be pursued in this population. Clinical trial information: NCT01118741.