SPECTRA study: A phase II trial of supraphysiological androgen to enhance treatment activity with DNA-damaging agents in men with metastatic castration resistant prostate cancer (mCPRC).

TPS279 Background: Prostate cancer models exhibit paradoxical growth suppression following exposure to supraphysiological androgen levels. Translated clinically, this therapeutic approach is termed bipolar androgen therapy (BAT), which induces fluctuations of testosterone (T) levels between supraphysiological and castrate ranges, via cyclical parenteral T administration. Prior studies of BAT show PSA50 response (i.e. >50% decline in PSA from baseline) rate of 25% and median progression-free survival (PFS) of ~6 months in patients with mCRPC. Induction of dsDNA damage may mediate anti-tumor effects of BAT, with prior studies showing that PARP inhibitors and ionizing radiation have the potential to augment such effects - likely as a consequence of BAT suppressing genes involved in homologous recombination repair (HRR) and non-homologous end joining. To develop more active BAT regimens, we are conducting a trial testing the hypothesis that BAT combined with other DNA-damaging agents including cytotoxic chemotherapy or 177Lutetium-PSMA-617 (LuPSMA) will be more effective than historically observed with BAT alone. Methods: This open-label, single center phase II trial is investigating the effects of BAT plus carboplatin AUC 5 IV (Cohort 1), etoposide 100 mg PO daily (Cohort 2), or LuPSMA 7.4 GBq IV (Cohort 3). Men with asymptomatic mCRPC treated with ≥1 prior androgen receptor pathway inhibitor are eligible for any cohort based on their preference and in consultation with the treating provider. All patients continue ADT and receive T cypionate 400 mg IM on Day 1 of an every 28 day cycle (Cohorts 1; 2) or Day 1 of an every 6 week cycle (Cohort 3). Each cohort is divided into subcohorts where cycle 1 consists of either BAT monotherapy, carboplatin/etoposide/LuPSMA monotherapy, or combination therapy. Metastatic tissue biopsies are obtained on Cycle 1, Day 8 to assess differences in DNA damage (e.g. γH2ax IHC) between subcohorts. After Cycle 1, all patients receive combination therapy until radiographic progression. The primary endpoint is to determine PSA50 response following 12 weeks combination therapy. Enrollment of 21 patients per cohort (n=63 total) provides 86% power to detect PSA50 of ≥50% for each cohort vs a null hypothesis of PSA50 of 25% at a 1-sided α=0.1. Secondary endpoints: radiographic response rate, radiographic PFS, PSA PFS, overall survival. Correlative work will assess differences in outcomes based on HRR mutation status and evaluate other genomic and transcriptomic features associated with treatment response/resistance. Cohorts 1 and 2 are open to accrual with 23/63 patients enrolled as of October 2025 (NCT06039371). Clinical trial information: NCT06039371 .