Susan F. Slovin

PURPOSE: Metastatic androgen pathway modulation–sensitive (mAPMS) prostate cancer is generally immunologically cold. Emerging data suggest radiotherapy and androgen-deprivation therapy (ADT) augment the antitumor immune response to immune checkpoint blockade. We evaluated the efficacy and safety of atezolizumab combined with androgen receptor pathway inhibition (ARPI), ADT, and stereotactic body radiotherapy (SBRT) to the prostate in patients with de novo mAPMS prostate cancer. PATIENTS AND METHODS: SAABR was a multicenter phase II trial conducted at two academic centers. Patients with untreated de novo mAPMS prostate cancer received atezolizumab (1,200 mg intravenously every 3 weeks) followed by initiation of ADT and an ARPI, and SBRT to the prostate delivered in five fractions. Treatment continued for up to 2 years. The primary end point was freedom-from-failure at 2 years, defined as the absence of biochemical recurrence, radiographic progression, study withdrawal, or death. RESULTS: Twenty-eight patients were enrolled between July 2020 and April 2023 before the study closed early because of safety concerns. The median age was 65 years (IQR, 58-70); 82% had bone metastases and 50% had high-volume disease. At 2 years, 20 (71%) of 28 patients remained failure-free. Biochemical recurrence occurred in four patients (14%), radiographic progression in three (11%), and one patient (4%) discontinued study participation before 2 years. Treatment-related adverse events occurred in 96% of patients, with grade ≥3 events in 46%. Three serious treatment-related adverse events prompted study closure, including two grade 4 colonic perforations and one grade 5 hemophagocytic lymphohistiocytosis. CONCLUSION: Maximal hormonal blockade combined with atezolizumab + SBRT to the prostate is associated with significant toxicity and no clear clinical benefit compared with historic controls in de novo mAPMS prostate cancer.

Figure S1, S2, S3, S4, S5, S6, S7, S8, S9, Table S1

Purpose:Chimeric antigen receptor (CAR) T-cell therapies have shown potential in solid tumors. A higher proportion of stem cell–like memory T cells (TSCM) in CAR T-cell products could enhance engraftment, persistence, and prolong immune activity. This phase I trial (NCT04249947) evaluated the safety and efficacy of P-PSMA-101, an autologous TSCM-rich, bone-tropic CAR T-cell therapy targeting prostate-specific membrane antigen (PSMA), in patients with metastatic castrate-resistant prostate carcinoma (mCRPC). Secondary endpoints included objective response rate, prostate-specific antigen (PSA) response, and radiographic progression-free survival. Patients and Methods:The final P-PSMA-101 product was produced from leukapheresis using the piggyBac DNA transposon–based platform, which integrates a multicistronic transgene encoding an inducible caspase 9 (iCasp9) safety switch in addition to the CAR, generating TSCM-rich CAR T cells. Results:Among 33 treated patients, 18% (n = 6) had dose-limiting toxicities. Cytokine release syndrome (CRS) occurred in 61% (n = 20), with grade ≥3 CRS seen in 9% (n = 3). Activation of the iCasp9-based safety switch was required in 24% (n = 8) of cases, including one toxicity that was ultimately fatal and successful resolution of symptoms in the other seven. P-PSMA-101 demonstrated antitumor activity, with 21% (n = 7) of patients achieving a ≥50% PSA decline (PSA50 response). Among 13 RECIST-evaluable patients, one partial response was observed. Stable disease was observed in 61% (n = 20) of patients, with 21% (n = 7) maintaining disease stability for ≥3 months. Two patients experienced sustained remissions exceeding 12 months, characterized by PSA declines of more than 90%, corroborated by pharmacokinetic, biomarker, and PSMA-PET imaging data. Conclusions:Robust expansion of P-PSMA-101 CAR T cells resulted in toxicity but also durable responses in patients with mCRPC. Future trials of CAR T therapy may be informed by the results of this nonviral engineering, TSCM cell–enriched approach.See related commentary by Lee et al., p. 3417

Purpose:This study investigates a short-course, intensified regimen combining apalutamide, abiraterone acetate, and prednisone (AAP) and stereotactic body radiotherapy (SBRT) to reduce treatment burden and improve disease control in a very high-risk (VHR) population inadequately represented in prior trials.Patients and Methods:This multi-institutional, single-arm, phase 2 trial enrolled patients with VHR localized prostate cancer, defined according to the National Comprehensive Cancer Network as histologically confirmed adenocarcinoma with ≥2 high-risk features: Gleason score 8 to 10, prostate-specific antigen (PSA) ≥20, clinical or radiographic ≥T3, or >4 cores containing Gleason score 8 disease. Patients received 6 months of apalutamide, abiraterone acetate, and leuprolide plus prostate/seminal vesicle–directed ultra-fractionated SBRT. The primary endpoint was 3-year biochemical recurrence (BCR) rate by Phoenix criteria, with a prespecified superiority threshold of 150 ng/dL.Results:Between August 2016 and December 2022, 63 patients were treated. At 3 years, the Phoenix-defined BCR rate was 19%. BCR-free survival was 84.2% [95% confidence interval (CI), 75.6–93.7] with a median follow-up of 41 months (34–43). The 3-year MFS was 93.6% (95% CI, 87.8%–99.8%), with no deaths observed. The median time to testosterone recovery >150 ng/dL was 6 months (range, 3–24 months). No new safety signals emerged, and the only significant quality-of-life (QOL) decline was in the EPIC sexual subdomain at 12 months.Conclusions:Treatment intensification with apalutamide, AAP, androgen deprivation therapy, and SBRT was well-tolerated with limited impact on QOL. Although BCR rates exceed the superiority threshold, outcomes aligned with historic benchmarks, supporting further evaluation of the regimen in prospective trials.

Representativeness of Study Participants

Purpose: Chimeric antigen receptor (CAR) T-cell therapies have shown potential in solid tumors. A higher proportion of stem cell–like memory T cells (TSCM) in CAR T-cell products could enhance engraftment, persistence, and prolong immune activity. This phase I trial (NCT04249947) evaluated the safety and efficacy of P-PSMA-101, an autologous TSCM-rich, bone-tropic CAR T-cell therapy targeting prostate-specific membrane antigen (PSMA), in patients with metastatic castrate-resistant prostate carcinoma (mCRPC). Secondary endpoints included objective response rate, prostate-specific antigen (PSA) response, and radiographic progression-free survival. Patients and Methods: The final P-PSMA-101 product was produced from leukapheresis using the piggyBac DNA transposon–based platform, which integrates a multicistronic transgene encoding an inducible caspase 9 (iCasp9) safety switch in addition to the CAR, generating TSCM-rich CAR T cells. Results: Among 33 treated patients, 18% (n = 6) had dose-limiting toxicities. Cytokine release syndrome (CRS) occurred in 61% (n = 20), with grade ≥3 CRS seen in 9% (n = 3). Activation of the iCasp9-based safety switch was required in 24% (n = 8) of cases, including one toxicity that was ultimately fatal and successful resolution of symptoms in the other seven. P-PSMA-101 demonstrated antitumor activity, with 21% (n = 7) of patients achieving a ≥50% PSA decline (PSA50 response). Among 13 RECIST-evaluable patients, one partial response was observed. Stable disease was observed in 61% (n = 20) of patients, with 21% (n = 7) maintaining disease stability for ≥3 months. Two patients experienced sustained remissions exceeding 12 months, characterized by PSA declines of more than 90%, corroborated by pharmacokinetic, biomarker, and PSMA-PET imaging data. Conclusions: Robust expansion of P-PSMA-101 CAR T cells resulted in toxicity but also durable responses in patients with mCRPC. Future trials of CAR T therapy may be informed by the results of this nonviral engineering, TSCM cell–enriched approach.

Purpose: This study investigates a short-course, intensified regimen combining apalutamide, abiraterone acetate, and prednisone (AAP) and stereotactic body radiotherapy (SBRT) to reduce treatment burden and improve disease control in a very high-risk (VHR) population inadequately represented in prior trials. Patients and Methods: This multi-institutional, single-arm, phase 2 trial enrolled patients with VHR localized prostate cancer, defined according to the National Comprehensive Cancer Network as histologically confirmed adenocarcinoma with ≥2 high-risk features: Gleason score 8 to 10, prostate-specific antigen (PSA) ≥20, clinical or radiographic ≥T3, or >4 cores containing Gleason score 8 disease. Patients received 6 months of apalutamide, abiraterone acetate, and leuprolide plus prostate/seminal vesicle–directed ultra-fractionated SBRT. The primary endpoint was 3-year biochemical recurrence (BCR) rate by Phoenix criteria, with a prespecified superiority threshold of 150 ng/dL. Results: Between August 2016 and December 2022, 63 patients were treated. At 3 years, the Phoenix-defined BCR rate was 19%. BCR-free survival was 84.2% [95% confidence interval (CI), 75.6–93.7] with a median follow-up of 41 months (34–43). The 3-year MFS was 93.6% (95% CI, 87.8%–99.8%), with no deaths observed. The median time to testosterone recovery >150 ng/dL was 6 months (range, 3–24 months). No new safety signals emerged, and the only significant quality-of-life (QOL) decline was in the EPIC sexual subdomain at 12 months. Conclusions: Treatment intensification with apalutamide, AAP, androgen deprivation therapy, and SBRT was well-tolerated with limited impact on QOL. Although BCR rates exceed the superiority threshold, outcomes aligned with historic benchmarks, supporting further evaluation of the regimen in prospective trials.

PURPOSE: Poly(ADP-ribose) polymerase inhibitors (PARPis) are effective for the treatment of metastatic castration-resistant prostate cancer (mCRPC) harboring homologous recombination repair (HRR) gene alterations, but predictive biomarkers beyond individual gene alterations remain poorly defined. We aimed to identify genomic features associated with response to PARP inhibition in real-world data. MATERIALS AND METHODS: This is a single-center retrospective study of patients with mCRPC who received PARPi therapy. All patients underwent tumor genomic profiling using a single panel sequencing assay. Responses were defined as prostate-specific antigen (PSA50) (≥50% PSA decline from baseline) and objective radiographic response by RECIST 1.1. We explored the association of genomic features with response to therapy. RESULTS: Among 120 patients with mCRPC who received a PARPi, 54% had BRCA2 / 1 alterations and 16% had no HRR gene alterations. Other alterations include ATM (10%), CDK12 (10%), BARD1 (2%), CHEK2 (7%), and PALB2 (2%). Overall, 37% had PSA50 responses (95% CI, 27 to 47) and 43% had RECIST responses (95% CI, 27 to 61). Patients with BRCA2 alterations had the highest response rates (52% PSA50, 72% RECIST), and biallelic BRCA2 loss was associated with better outcomes. Panel-based mutational signatures (SigMA, SBS3 from DeepSig) were associated with BRCA -mutated status and overall response to PARPi. Six patients without known HRR gene alterations had responses; one was later found to harbor BRCA2 loss. Limitations include the small study size, retrospective design, and use of panel-based sequencing. CONCLUSION: Most PARPi responders had alterations in HRR genes, particularly BRCA2 , although some responders lacked known biomarkers associated with PARPi response. Our findings in this real-world data set support HRR gene testing for PARPi use in mCRPC and highlight the need for novel genome-wide biomarkers for patient selection.

Figure S4. Biodistribution Study

Figure S3. Scatter plot of gene expression for genes shown in Figure 3D isolated from matched anti-EPCAM vs anti-TROP-2 captured CTCs at the same timepoint.