Survival of Patients with Metastatic Prostate Cancer After Disease Progression on an Androgen Receptor Axis–Targeted Therapy Given in the Metastatic Castration-Sensitive Versus Metastatic Castration-Resistant Prostate Cancer Setting

Sayegh, Nicolas; Tripathi, Nishita; Nussenzveig, Roberto; Thomas, Vinay Mathew; Tandar, Clara; Goel, Divyam; Nordblad, Blake; Sahu, Kamal Kant; Li, Haoran; Agarwal, Neeraj; Swami, Umang

doi:10.1016/j.euf.2022.06.015

Cited by 4 publications

(7 citation statements)

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“…15 In our study, the median OS of the whole study population that is, including patients with AR wt and AR + from the start of the first ARPI in the mCRPC setting was 37 months, similar to the previously reported OS in mCRPC patients across multiple studies, regardless of AR alteration status. 14,16,17 Similarly, the median OS across both cohorts after experiencing progression on the first-line ARPI was approximately 20 months. We have previously reported that the OS after progression on a first-line ARPI is similar regardless of whether the first ARPI is administered in the metastatic castrate-sensitive prostate cancer (mCSPC) or mCRPC setting.…”

Section: Discussionmentioning

confidence: 96%

“…We have previously reported that the OS after progression on a first-line ARPI is similar regardless of whether the first ARPI is administered in the metastatic castrate-sensitive prostate cancer (mCSPC) or mCRPC setting. 14 Overall, patients with AR alterations have been reported to have lower response rates to ARPIs and worse survival outcomes than those without AR alterations in the castration-resistant setting. 9,12,13 This finding was apparent in our analyses, which showed a clear OS benefit in patients without an AR alteration compared to those with one.…”

Section: Discussionmentioning

confidence: 99%

“…3,[8][9][10] mCRPC patients with AR amplification and the AR-V7 splice variant have been reported to have inferior survival outcomes on ARPIs. [11][12][13][14] The impact of AR alteration on survival outcomes after progression on an ARPI in patients with mCRPC has not been reported.…”

Section: Introductionmentioning

confidence: 99%

“…The AR alterations have also been implicated in resistance to ARPIs in metastatic castration‐resistant prostate cancer (mCRPC) 3,8–10 . mCRPC patients with AR amplification and the AR‐V7 splice variant have been reported to have inferior survival outcomes on ARPIs 11–14 . The impact of AR alteration on survival outcomes after progression on an ARPI in patients with mCRPC has not been reported.…”

Section: Introductionmentioning

confidence: 99%

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Impact of androgen receptor alterations on cell‐free DNA genomic profiling on survival outcomes in metastatic castration‐resistant prostate cancer

Tripathi,

Thomas,

Sayegh

et al. 2023

The Prostate

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BackgroundAndrogen receptor (AR) gene alterations, as detected by circulating tumor cell‐free DNA (cfDNA) genomic profiling, have been shown to emerge after a variable duration of androgen signaling inhibition. AR alterations were associated with inferior outcomes on treatment with androgen receptor pathway inhibitors (ARPI) in the first line metastatic castration‐resistant prostate cancer (mCRPC) setting in a phase 2 trial. Here in, we assessed the impact of these AR alterations on survival outcomes in a real‐world patient population of mCRPC experiencing disease progression on an ARPI.MethodsIn this IRB‐approved retrospective study, consecutively seen patients with a confirmed diagnosis of mCRPC, with disease progression on a treatment with ARPIs in the first line mCRPC setting, with no prior exposure to an ARPI in the castration sensitive setting, and with available cfDNA profiling from a CLIA certified laboratory were included. Patients were categorized based on AR status: wild‐type (ARwt) or alteration‐positive (AR+). The objective was to correlate overall survival (OS) after disease progression on the first‐line ARPI with the presence or absence of AR alterations. Kaplan–Meier and Cox Regression Tests were used as implemented in R‐Studio (v.4.2).ResultsA total of 137 mCRPC patients were eligible: 69 with ARwt versus 68 with AR+. The median OS posttreatment with the first ARPI was significantly higher for ARwt than AR+ patients (30.1 vs. 15.2 mos; p < 0.001). Of 108 patients who received a subsequent line of therapy, 63 received an alternate ARPI (AR+ 39 vs. 24 ARwt), while 20 received a taxane‐based therapy (11 AR+ vs. 9 ARwt). Among patients receiving an alternate ARPI, AR+ had numerically shorter OS (16.8 vs. 30.4 mos, p = 0.1). Among patients receiving taxane‐based regimens, the OS was not significantly different between AR+ and ARwt (14.5 vs. 10.1 mos, p = 0.18).ConclusionIn this real‐world study, mCRPC patients with AR alterations on cfDNA had inferior OS after disease progression on the first ARPI, compared to those who did not, and may impact outcomes on a subsequent ARPI but not on subsequent taxane‐based therapy received. By providing survival estimates for patients with or without AR alterations, our data may aid in patient counseling, prognostication, treatment decision, and for designing future clinical trials in this setting.

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Section: Discussionmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Impact of androgen receptor alterations on cell‐free DNA genomic profiling on survival outcomes in metastatic castration‐resistant prostate cancer

Tripathi,

Thomas,

Sayegh

et al. 2023

The Prostate

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“…Despite recent advances and the approval of multiple agents for the treatment of advanced prostate cancer, the disease remains lethal ( 10 , 11 ). After disease progression on an androgen receptor targeted therapy, the median overall survival of these patients is only two years ( 12 ). Therefore, it is critical to discover molecular pathways of disease progression and develop novel drugs targeting these pathways to improve outcomes.…”

Section: Discussionmentioning

confidence: 99%

Genomic landscape of advanced prostate cancer patients with BRCA1 versus BRCA2 mutations as detected by comprehensive genomic profiling of cell-free DNA

et al. 2022

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BRCA1-mutated prostate cancer has been shown to be less responsive to poly (ADP-ribose) polymerase (PARP) inhibitors as compared to BRCA2-mutated prostate cancer. The reason for this differential response is not clear. We hypothesized this differential sensitivity to PARP inhibitors may be explained by distinct genomic landscapes of BRCA1 versus BRCA2 co-segregating genes. In a large dataset of 7,707 men with advanced prostate cancer undergoing comprehensive genomic profiling (CGP) of cell-free DNA (cfDNA), 614 men harbored BRCA1 and/or BRCA2 alterations. Differences in the genomic landscape of co-segregating genes was investigated by Fisher's exact test and probabilistic graphical models (PGMs). Results demonstrated that BRCA1 was significantly associated with six other genes, while BRCA2 was not significantly associated with any gene. These findings suggest BRCA2 may be Frontiers in Oncology frontiersin.org 01

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Prognostic outcomes in Japanese patients with metastatic castration‐sensitive prostate cancer: Comparative assessments between conventional androgen deprivation therapy (ADT) and ADT with novel androgen receptor signal inhibitor

Watanabe,

Nakane,

Takahara

et al. 2024

Int J of Urology

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ObjectiveThe objective of this study was to compare the prognostic outcomes between metastatic castration‐sensitive prostate cancer (mCSPC) patients receiving conventional androgen deprivation therapy (ADT) and those receiving ADT plus a novel androgen‐receptor signaling inhibitor (ARSI) in routine clinical practice in Japan.MethodsThis was conducted as a retrospective multicenter study including 581 mCSPC patients, consisting of 305 receiving ADT alone or in combination with bicalutamide (group 1) and 276 receiving ADT plus one of the following ARSIs: abiraterone acetate, apalutamide, or enzalutamide (group 2). Prognostic outcomes between these 2 groups were comprehensively compared.ResultsIn the entire cohort, prostate‐specific antigen—progression‐free survival (PSA‐PFS) in group 2 was significantly longer than that in group 1, while no significant difference was noted in overall survival (OS) between the two groups. In patients corresponding to the LATITUDE high‐risk group, however, both PSA‐PFS and OS in group 2 were significantly longer than those in group 1. Of several factors examined, the following were identified as independent predictors of poor PSA‐PFS in the entire cohort as well as the LATITUDE high‐risk group: high C‐reactive protein, high lactate dehydrogenase, high alkaline phosphatase, high Gleason score, and group 1. Furthermore, it was possible to precisely classify both the entire cohort and LATITUDE high‐risk group into 3 risk groups regarding PSA‐PFS according to the positive numbers of independent factors: positive for ≤1 factor, favorable; 2 factors, intermediate; and ≥3 factors, poor.ConclusionCombined use of ARSIs with ADT could improve the prognostic outcomes of mCSPC patients, particularly those in the LATITUDE high‐risk group, in real‐world clinical practice in Japan.

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Survival of Patients with Metastatic Prostate Cancer After Disease Progression on an Androgen Receptor Axis–Targeted Therapy Given in the Metastatic Castration-Sensitive Versus Metastatic Castration-Resistant Prostate Cancer Setting

Cited by 4 publications

References 10 publications

Impact of androgen receptor alterations on cell‐free DNA genomic profiling on survival outcomes in metastatic castration‐resistant prostate cancer

Impact of androgen receptor alterations on cell‐free DNA genomic profiling on survival outcomes in metastatic castration‐resistant prostate cancer

Genomic landscape of advanced prostate cancer patients with BRCA1 versus BRCA2 mutations as detected by comprehensive genomic profiling of cell-free DNA

Prognostic outcomes in Japanese patients with metastatic castration‐sensitive prostate cancer: Comparative assessments between conventional androgen deprivation therapy (ADT) and ADT with novel androgen receptor signal inhibitor

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