Survival Outcomes From a Cumulative Analysis of Worldwide Observational Studies on Sequential Use of New Agents in Metastatic Castration-Resistant Prostate Cancer

Caffo, Orazio; Wissing, Michel D.; Bianchini, Diletta; Bergman, Andries M.; Thomsen, Frederik Birkebæk; Schmid, Sebastian; Yu, Evan Y.; Bournakis, Evangelos; Sella, Avishay; Zagonel, Vittorina; Giorgi, Ugo De; Tucci, Marco; Gelderblom, Hans; Galli, Luca; Pappagallo, Giovanni; Bria, Emilio; Sperduti, Isabella; Oudard, Stéphane; investigators, Castor study's

doi:10.1016/j.clgc.2019.09.010

Cited by 14 publications

(12 citation statements)

References 40 publications

(14 reference statements)

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“…This type of analysis clearly demonstrates that patients who moved more rapidly through multiple LOTs had a higher hazard of death at a given time point post-mCRPC diagnosis compared to those who had fewer LOTs at that time point. Prior studies have mainly focused of the impact of specific treatment sequences on OS among patients with mCRPC and were subject to several limitations [45][46][47][48]. First, they primarily focused on patients who had been treated with NHA and cabazitaxel in different sequences following progression on docetaxel, a treatment sequence that is no longer representative of current mCRPC treatment approaches [45][46][47][48][49].…”

Section: Discussionmentioning

confidence: 99%

Real-World Treatment Patterns and Overall Survival of Patients with Metastatic Castration-Resistant Prostate Cancer in the US Prior to PARP Inhibitors

et al. 2021

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Introduction: Therapeutic options for metastatic castration-resistant prostate cancer (mCRPC) patients are continuously advancing. We described mCRPC treatment patterns in the US from 2013 to 2019. Methods: Patients with a confirmed mCRPC diagnosis and adenocarcinoma histology were included in the US Flatiron Health Electronic Health Record-derived de-identified database. Treatment patterns [including treatment per lines of therapies (LOTs), LOT sequences, and time on treatment] and overall survival (OS) have been described in mCRPC settings. Results: Of 5213 patients (mean age: 72.6 years), 4374 (83.9%) were treated with C 1 LOT post-mCRPC diagnosis (among those with C 1 LOT, 55.3%, 29.5%, 14.7%, and 6.7% had C 2, 3, 4, and 5 LOTs, respectively). In first line (1L), the main treatment class was nextgeneration hormonal agents (NHA; 62.5% of patients with C 1 LOT), while the shortest and longest time on 1L were observed for chemotherapy (median 2.8 months) and NHA (median 5.1 months), respectively. The most common LOT sequences were NHA ? NHA (29.4% of patients with C 2 LOTs) and NHA ? NHA ? chemotherapy (16.7% of patients with C 3 LOTs). In Kaplan-Meier analyses, the median OS was 19.4, 14.6, and 11.1 months post-1L, 2L, and 3L start, respectively. Patients who moved rapidly through LOTs had an increased risk of death. Conclusions: NHA were widely used as 1L therapy in mCRPC patients from 2013 to 2019, but time on 1L NHA treatment was on aver-age\6 months. While NHA ? NHA was the most observed 1L ? 2L LOT sequence, a plethora of other LOT sequences were observed. OS was poor, highlighting an unmet need for lifeprolonging treatments.

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Section: Discussionmentioning

confidence: 99%

Real-World Treatment Patterns and Overall Survival of Patients with Metastatic Castration-Resistant Prostate Cancer in the US Prior to PARP Inhibitors

et al. 2021

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“…Given the availability of five agents capable of prolonging the survival of mCRPC patients in everyday clinical practice, [1][2][3][4][5][6][7] the main challenge facing clinicians is to optimize their sequential use to obtain the longest cumulative survival. Previously published studies of the sequential treatment of mCRPC have evaluated the use of DOC, CABA, AA, and ENZ in every possible order, 11 but none of them considered sequences including 223 Ra.…”

Section: Discussionmentioning

confidence: 99%

“…Although a number of retrospective studies have described the outcomes of the sequential use of LPAs, 11 none of them included mCRPC patients who received 223 Ra as part of their treatment. Therefore, it is not known whether including the use of 223 Ra in the therapeutic sequence has an impact on cumulative survival.…”

Section: Introductionmentioning

confidence: 99%

Sequencing Life-Prolonging Agents in Castration-Resistant Prostate Cancer Patients: Comparison of Sequences With and Without ²²³Ra

Caffo

Frantellizzi

Monari

et al. 2021

Cancer Biotherapy and Radiopharmaceuticals

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Background:The retrospective studies that have so far described the outcomes of the sequential use of lifeprolonging agents (LPAs) did not include metastatic castration-resistant prostate cancer (mCRPC) patients who received radium-223 ( 223 Ra) as part of their treatment. Consequently, it is not known whether including 223 Ra in the therapeutic sequence has an impact on cumulative survival. The aim of this study was to evaluate this impact by comparing the cumulative overall survival (OS) in two series of mCRPC patients sequentially treated with two or three LPAs after first-line docetaxel (DOC), including 223 Ra and not. Materials and Methods: The authors retrospectively reviewed the records of mCRPC patients with bone involvement alone who received two or three LPAs (including 223 Ra) after first-line DOC. The control group was a contemporary series of mCRPC patients with bone involvement alone treated with sequences of two or three LPAs other than 223 Ra after first-line DOC. Results: Median cumulative OS was 40.6 months in the 223 Ra group of 78 patients and 36.2 months in the non- 223 Ra group of 186 patients ( p = 0.08). OS outcomes were significantly influenced by the number of treatment lines, and baseline Eastern Cooperative Oncology Group performance status (PS) and prostate-specific antigen levels.

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“…To treat mCRPC, ADT is combined with the chemotherapeutic agent docetaxel, and failing this the patient may be referred to the taxane cabazitaxel [ 49 ] or radiation therapy with radium 223 to target bone metastases [ 50 ]. Despite the availability of these new agents and the improved overall survival with sequential use, there is no consensus on proper sequencing and the median overall survival remains poor, ranging from 21 to 29 months [ 51 ]. This is at least partially due to the development of resistance and cross-resistance mechanisms; for example, it has been demonstrated that acquired resistance to docetaxel induces cross-resistance to cabazitaxel, and that resistance to enzalutamide induces cross resistance to abiraterone [ 52 ].…”

Section: Prostate Cancer Backgroundmentioning

confidence: 99%

Novel Combinatorial Approaches to Tackle the Immunosuppressive Microenvironment of Prostate Cancer

Shackleton

Ali

Khan

et al. 2021

Cancers

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Prostate cancer (PCa) is the second-most common cancer in men worldwide and treatment options for patients with advanced or aggressive prostate cancer or recurrent disease continue to be of limited success and are rarely curative. Despite immune checkpoint blockade (ICB) efficacy in some melanoma, lung, kidney and breast cancers, immunotherapy efforts have been remarkably unsuccessful in PCa. One hypothesis behind this lack of efficacy is the generation of a distinctly immunosuppressive prostate tumor microenvironment (TME) by regulatory T cells, MDSCs, and type 2 macrophages which have been implicated in a variety of pathological conditions including solid cancers. In PCa, Tregs and MDSCs are attracted to TME by low-grade chronic inflammatory signals, while tissue-resident type 2 macrophages are induced by cytokines such as IL4, IL10, IL13, transforming growth factor beta (TGFβ) or prostaglandin E2 (PGE2) produced by Th2 cells. These then drive tumor progression, therapy resistance and the generation of castration resistance, ultimately conferring a poor prognosis. The biology of MDSC and Treg is highly complex and the development, proliferation, maturation or function can each be pharmacologically mediated to counteract the immunosuppressive effects of these cells. Herein, we present a critical review of Treg, MDSC and M2 involvement in PCa progression but also investigate a newly recognized type of immune suppression induced by the chronic stimulation of the sympathetic adrenergic signaling pathway and propose targeted strategies to be used in a combinatorial modality with immunotherapy interventions such as ICB, Sipuleucel-T or antitumor vaccines for an enhanced anti-PCa tumor immune response. We conclude that a strategic sequence of therapeutic interventions in combination with additional holistic measures will be necessary to achieve maximum benefit for PCa patients.

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Survival Outcomes From a Cumulative Analysis of Worldwide Observational Studies on Sequential Use of New Agents in Metastatic Castration-Resistant Prostate Cancer

Cited by 14 publications

References 40 publications

Real-World Treatment Patterns and Overall Survival of Patients with Metastatic Castration-Resistant Prostate Cancer in the US Prior to PARP Inhibitors

Real-World Treatment Patterns and Overall Survival of Patients with Metastatic Castration-Resistant Prostate Cancer in the US Prior to PARP Inhibitors

Sequencing Life-Prolonging Agents in Castration-Resistant Prostate Cancer Patients: Comparison of Sequences With and Without ²²³Ra

Novel Combinatorial Approaches to Tackle the Immunosuppressive Microenvironment of Prostate Cancer

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Survival Outcomes From a Cumulative Analysis of Worldwide Observational Studies on Sequential Use of New Agents in Metastatic Castration-Resistant Prostate Cancer

Cited by 14 publications

References 40 publications

Real-World Treatment Patterns and Overall Survival of Patients with Metastatic Castration-Resistant Prostate Cancer in the US Prior to PARP Inhibitors

Real-World Treatment Patterns and Overall Survival of Patients with Metastatic Castration-Resistant Prostate Cancer in the US Prior to PARP Inhibitors

Sequencing Life-Prolonging Agents in Castration-Resistant Prostate Cancer Patients: Comparison of Sequences With and Without 223Ra

Novel Combinatorial Approaches to Tackle the Immunosuppressive Microenvironment of Prostate Cancer

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Sequencing Life-Prolonging Agents in Castration-Resistant Prostate Cancer Patients: Comparison of Sequences With and Without ²²³Ra