The Lank Center for Genitourinary Oncology at Dana-Farber Cancer Institute presents a succinct summary of all the prostate cancer clinical updates you need to know from AACR 2026.
Good evening, everyone, and uh thank you for joining uh our Dana-Farber GUACR 2026 highlights. So, I'm uh fortunate to be joined by our outstanding panelists, uh, uh, which include Doctor Cherry, Doctor McGregor, and Doctor Adesh Chaudhury. So, tonight, I'll be focused more on like a GU related abstracts, um, that kind of spanning from prostate cancer, ADC synthetic lethality. And possible bladder cancer implication, uh, in, from the AC ACR. So, uh, ASia this year, every year was kind of quite enormous with more than 7400 abstracts and nearly 250,000 clinical trial abstracts. So it is kind of quite broad uh conference, which goes from like a bench to bedside, and many trials are presented. So, for the sake of the simplicity, I kind of organize um this talk into three sections. The first, the prostate cancer with mainly PSMA radiotherranostic and epigenetic DDR synthetic lethality, and in the bladder space, uh, potential role for ADC and synthetic lethality therapies and, and in uh RCC immune modulation and new target, emerging new targets in renal cell carcinoma. With further, uh, without further delay, I'd like to move on to like prostate cancer where our discussant is Doctor Atti Choudhury. And we have to abstract to discuss. The first one is a phase one dose escalation, uh, expansion study of fractionated, uh, uh, dose and multiple cycle with NTPSMA targeted alpha emitter actinium J591. So the main clinical rationale for the study, 225 actinium J591 aims to deliver potent alpha emitteror therapy to PSMA expressing prostate cancer with antibody-based targeting, and fractionation in this trial is intended to preserve the activity while mitigating the peak toxicity from the higher dose exposure. And also those dense dosing may improve the cumulative toxer dose and decrease the response and like resistant in the disease. And especially this is relevant in a patient who progressed after ERPI and the toxins. This was previously, like in some published data with 32 patients. This is phase one dose escalation type uh uh trial. Mostly metastatic castration resistant prostate cancer post ERPI and chemo, and PSMA PET was not used for eligibility. In this trial, uh, the safety of two regimens at differing level of administration of the radioactive PSMA targeted alpha radionuclettide with 2225. Acinium J59 was evaluated. The trial basically, three cohorts were designed. One was vaccinated dose dense cohort. The other one was multiple cycle. And the third cohort they created was prior luteium PSMA treated cohort. The primary endpoint for the study was dose limiting toxicities, recommended phase 2 dose. Uh, secondary endpoints include PSA response, radiological response, and adverse events, quality of life, and overall survival. The dose limiting toxicity were mainly hematological, they defined as a grade 4, or any grade toxicity that delayed the next administration of the treatment in both fractionated and multiple cycle cohort. In total, uh, trial enrolled 60 patients, uh, 42 patients in fractionated cohort, 8 patients had a prior lutetium therapy, and 18 patients were enrolled in a multiple cycle cohort. Uh, in overall cohort, the median age was 73. Uh, all patients were high risk based on the CALBG risk group, and the performance status was reasonable, ECOG-1 in most of the patients. Most of the patients had bone metastasis, close to 90%. And uh in terms of the systemic therapy, uh most of the patients received more than 50% received more than one ARPI and chemotherapy were heavily treated in most of the cohort. So, uh, in fractionated cohort with 34 patients, those limiting toxicities were observed in 43 patients, all thrombocytopenia, and there were no clinically significant bleeding, and there was some delay in day 15 administration in 1 patient. Moving on to like dose limiting toxicity in prior luteium PSMA treated patients, only 2 patients had grade 4 thrombocytopenia without any clinical uh uh clinical bleeding. In multiple cohort, 3 patients developed, uh, uh, dose-limiting toxicities, and all 3 patients required, uh, delay in cycle 3 treatment. Um. So, main treatment emergent adverse events were neutropenia, thrombocytopenia, anemia, which we are aware, and other toxicities include fatigue, xerostomia, and nausea. As we can see in this waterfall plot, the PSA response was highest, uh, around around 60% in both fractionated and the prior lutetium PSMA, whereas in the multiple cohort, uh, the multiple dosing cycle, it was 28%. Uh, this is racist response per patient and cohort, and more than 70% patients had response in this cohort as well. In terms of progression-free survival, although this trial was not designed to compare between the cohorts, but numerically higher progression-free survival with 5.2 months in fraction needed and 3.8 months in a prior luteian group, and the multiple cycles just had 3 months of progression-free survival. Similarly, there were no, uh, statistically difference um in the overall survival, but numerically higher survival uh months of survival in a fractionated as compared to the multiple cycles, 16.4 months in a fractionated group. So my key takeaways from this trial is that uh actinium 225J591 represents a rational PSMA targeted alpha strategy, and dose dense regimen demonstrated favor favorable safety profile and encouraging preliminary efficacy in patients with advanced prostate cancer with or without prior lutetium radioligand therapy. This dosing was not feasible in patient population who are getting every 6 weeks. The core question remains whether the patient who received alpha radioligand therapy, is the response going to be there, although authors didn't specifically describe about that, and what will be the outcome in a patient who just have bone only versus bone plus visceral or visceral-only meds. Now, moving on to the pre-clinical or uh uh in which there's a good biologic mechanistic in the prostate cancer, which was presented in this abstract, CBPP 300 and PARP inhibitor combination treatment synergy, uh, potentially enhance the anti-tumor efficacy in the models of advanced prostate cancer. So, CBPP 300 act as a key um AR co-activators and promote HR mediated DNA repair in the prostate cancer. Its amplification and expression is associated with poor outcomes, and this is also associated to uh promote the survival in the prostate cancer patients. Previously, some studies tried blocking those bromoomin domain, uh, inhibiting that domain was not very useful in tumor suppression. So authors basically suggested that there's a PARP is responsible for detecting single stranded DNA breaks and initiating cellular repair cascade, and with CBPP300, which is homologous histone acetyl transferase, act as an essential transcripts coactivator. In prostate cancer, the CBPP-300 aggressively drives the oncogenic ER signaling and expression of the DNA repair genes. So independent blockade of either target causes cellular stress, but simultaneous inhibition is hypothesized to create a biological crisis and tumor suppression. So, inhibiting CVPP 300 impact the tumor HR repair mechanism, and that kind of create a BRCAS um and chemical vulnerability. So, an author demonstrated that uh in vitro, uh synergy there's a synergy of CBP P 300 inhibition with PARP inhibitor in in vitro, and they further demonstrated efficacy in X vivo patient derived eggplants. So this, uh, uh, translational research suggests that, uh, in the, the metabolic or genetic environment of the advanced prostate cancer is particularly susceptible to simultaneous inhibition of the CBP P300 and PARP. Uh, so, that gives it headway to do some early clinical trial that potentially will be helpful in a biomarker-driven early phase clinical trial in MCRPC. Um, and if they, they, they are like part knife versus plots, part exposed, that need to define the safety and activity in the coming trials. With that, I'll hand over to Doctor Atish Choudhury to comment more on these abstracts. Yes, so the actinium drug, the actinium 225J591, is the, an agent that we're testing here at Dana-Farber in a um trial sponsored by Converge, and J591 is an antibody that targets PSMA. This is a Opposed to the Novartis agent, which is the AAA 817, which is a small molecule that targets uh PSMA and uh as an antibody, it has different properties in terms of the distribution and in terms of the half-life. And because of the differences in distribution, the toxicities are quite different. Um, in that the, uh, actinium J591 seems to cause much less xerostomia compared to the AAA 817, whereas it causes, um, a lot more myelosuppression, and that myelosuppression can be quite long standing and dose limiting as was indicated, um, by Doctor Thapa. So definitely we need to know how best. To dose these agents to balance the safety and uh and toxicity, because, um, certainly these alpha emitting radio ligands, the alpha particles are much more potent, um, but shorter traveling than beta particles, um, so probably can get more cell kill in the immediate vicinity, but we've definitely seen a fair amount. of toxicity to these agents. So, um, if these, uh, studies are basically guiding the converge on how the convergent therapeutics, um, on how best to dose these agents for their, um, phase 2 and phase 3 expansions, that will hopefully, hopefully be, um, very helpful to us and our patients. Um, as far as the second study, um, certainly we have interest in epigenetic modifiers in prostate cancer. Um, we have EZH2, um, inhibitor studies that are moving into phase 3 with the Pfizer drug, and we also had a phase one study of a dual bet P300 inhibitor in prostate cancer. Um, similarly to these, um, Radioligands, these drugs are associated with toxicities as well, including myelosuppression, um, and, you know, as far as conferring BRCAS, nothing seems to confer BRCAs quite as well as an actual bona fide BRCA2 mutation, whether germline or inherited. So, um, all of these. Effects when inpatients seem to be rather modest. So, um, you know, we're very interested in knowing how, um, these epigenetic modifiers might synergize with a variety of different drugs that we use for prostate cancer, but I think in terms of what's really promising and what's going to really, um, lead to patient benefits with PARP inhibitors outside of the BA BRCA context is really yet to be defined. Great presentations, Vicky.
