Neither trial was designed to clarify the timing of AA + P (ie, early at the androgen-sensitive status or later as primary treatment at the castrate-resistant stage). In both trials, first-line treatment at the castrate-resistant status was at investigators’ discretion (see Table 5). As with docetaxel, survival benefit with the addition of AA + P is clear for newly diagnosed metastatic patients. However, the most common presentation of patients with metastases is a relapse after some kind of local
Disease burden
The extent and burden of disease when selecting appropriate patients for combined treatment remains a matter of debate in regards the use of docetaxel in mHSPC [21], [22]. In the CHAARTED trial [3] only patients with high-volume disease benefited, according to an unplanned subgroup analysis. In that study, a high volume of disease was defined by either the location of metastases (any visceral deposit being considered as a high volume) or the location and number of bone metastases (at least one
Decision between the two options
The current key question for many patients and their treating physicians is the choice between six cycles of docetaxel and the long-term use of AA + P in newly diagnosed mHSPC. Once approved for the mHSPC setting, and apart from cost considerations and general patient preference, specific side effects will be a critical factor in decision making. Both modalities have distinct side effects, with the risk of febrile neutropenia from docetaxel being potentially the most severe and life threatening.
Treatment at progression
The last tricky question is about the treatment policy at disease progression. After docetaxel is given for mHSPC, it seems as if docetaxel retreatment at the castrate-resistant state might not be very effective. This assumption is based on exploratory data and small patient numbers [26]. After upfront AA + P for mHSPC, docetaxel was the most commonly used agent at progression in both trials, although only LATITUDE was blinded. Only a minority of patients received second-line enzalutamide. This
Conflicts of interest
N. Mottet has received grant funding from Takeda Pharmaceutical/Millenium, Astellas, Pierre Fabre, Sanofi, and Pasteur, and has received consultancy fees from Takeda Pharmaceutical/Millenium, Janssen, Astellas, BMS, Bayer, IPSEN, Ferring, Novartis, Nucle’tron, Pierre Fabre, Sanofi, and AstraZeneca. M. De Santis is a company consultant for GlaxoSmithKline, Janssen, Bayer, Novartis, Pierre Fabre, Astellas, Amgen, Eisai, ESSA, Merck, and Synthon; has received company speaker honoraria from Pfizer,
Addition of docetaxel to androgen deprivation therapy (ADT) for the treatment of metastatic hormone-sensitive prostate cancer (mHSPC) has been proved to be effective with an overall survival (OS) benefit in phase III clinical trials. The effectiveness of docetaxel with ADT in the general patient population remains unknown.
The purpose of this study is to report the clinical experience in mHSPC patients treated with 3rd-weekly docetaxel plus ADT in routine practice at two Danish institutions.
A two-center retrospective study including consecutive mHSPC patients treated with 3rd-weekly docetaxel plus ADT was conducted.
Outcomes of interest were OS, and biochemical and clinical progression-free survival.
A total of 173 consecutive patients with mHSPC who received docetaxel every 3rd week plus ADT between June 2015 and February 2018 were included. Most patients had high-volume disease (85%). All six planned docetaxel cycles were delivered in 149 cases (86%). Of the patients, 106 (61%) were alive at the last follow-up. At a median follow-up of 42 (37.8–58.6) mo, the median OS was 51.6 (41.5–56.3) mo. Castration-resistant prostate cancer (CRPC) developed in 46% within 1 yr, with a median time to CRPC of 15.6 (13.0–18.1) mo. Prostate-specific antigen nadir ≤0.2 ng/l was achieved in 15% of patients after 6 mo of ADT and in 19% after 12 mo.
The effect of docetaxel for mHSPC patients treated in routine practice appears comparable with the overall efficacy reported in the literature. Selection of patients will influence the results in clinical practice and clinical studies.
In this report, we looked at the clinical effectiveness of docetaxel combined with androgen deprivation therapy in men with metastatic hormone-sensitive prostate cancer (mHSPC) in a Danish population. We found the effect of docetaxel treatment for mHSPC in the general population to be comparable with the overall efficacy reported in published studies.
2020, Biochimica et Biophysica Acta - Reviews on Cancer
Citation Excerpt :
While ADT is the linchpin of systemic PCa treatment, it is often combined with other therapeutic agents for improved outcomes, particularly in patients with a high-volume disease or adverse-risk factors [35]. These include abiraterone acetate, which interferes with the adrenal production of testosterone precursors [36], and antiandrogens, which directly antagonize the androgen receptor at target cells. Various antiandrogens have been FDA-approved, including older drugs such as bicalutamide, nilutamide, and flutamide, as well as second-generation antiandrogens, among which are enzalutamide, darolutamide, and apalutamide [2,37–39].
The development of Castration-Resistant Prostate Cancer (CRPC) remains a major challenge in the treatment of this disease. While Androgen Deprivation Therapy (ADT) can result in tumor shrinkage, a primary response of Prostate Cancer (PCa) cells to ADT is a senescent growth arrest. As a response to cancer therapies, senescence has often been considered as a beneficial outcome due to its association with stable growth abrogation, as well as the potential for immune system activation via the Senescence-Associated Secretory Phenotype (SASP). However, there is increasing evidence that not only can senescent cells regain proliferative capacity, but that senescence contributes to deleterious effects of cancer chemotherapy, including disease recurrence. Notably, the preponderance of work investigating the consequences of therapy-induced senescence on tumor progression has been performed in non-PCa models. Here, we summarize the evidence that ADT promotes a senescent response in PCa and postulate mechanisms by which senescence may contribute to the development of castration-resistance. Primarily, we suggest that ADT-induced senescence may support CRPC development via escape from senescence, by cell autonomous-reprogramming, and by the formation of a pro-tumorigenic SASP. However, due to the scarcity of direct evidence from PCa models, the consequences of ADT-induced senescence outlined here remain speculative until the relationship between senescence and CRPC can be experimentally defined.
PTOV1 is a transcription and translation regulator and a promoter of cancer progression. Its overexpression in prostate cancer induces transcription of drug resistance and self-renewal genes, and docetaxel resistance. Here we studied PTOV1 ability to directly activate the transcription of ALDH1A1 and CCNG2 by binding to specific promoter sequences. Chromatin immunoprecipitation and electrophoretic mobility shift assays identified a DNA-binding motif inside the PTOV-A domain with similarities to known AT-hooks that specifically interacts with ALDH1A1 and CCNG2 promoters. Mutation of this AT-hook-like sequence significantly decreased the expression of ALDH1A1 and CCNG2 promoted by PTOV1. Immunohistochemistry revealed the association of PTOV1 with mitotic chromosomes in high grade prostate, colon, bladder, and breast carcinomas. Overexpression of PTOV1, ALDH1A1, and CCNG2 significantly correlated with poor prognosis in prostate carcinomas and with shorter relapse-free survival in colon carcinoma. The previously described interaction with translation complexes and its direct binding to ALDH1A1 and CCNG2 promoters found here reveal the PTOV1 capacity to modulate the expression of critical genes at multiple levels in aggressive cancers. Remarkably, the AT-hook motifs in PTOV1 open possibilities for selective targeting its nuclear and/or cytoplasmic activities.
Whether or not the benefit of docetaxel in men with mCSPC is restricted to men with a high burden of metastases is debated.9–11 However, patient-specific comorbidities, including patients at high risk of myelosuppression, patient preferences, patient age, and toxicity profile might limit the use of docetaxel in patients with mCSPC.12,13 Evidence before this study
In the interim analyses of the LATITUDE study, the addition of abiraterone acetate plus prednisone to androgen deprivation therapy (ADT) led to a significant improvement in overall survival and radiographic progression-free survival compared with placebos plus ADT in men with newly diagnosed high-risk metastatic castration-sensitive prostate cancer (mCSPC). Here, we present long-term survival outcomes and safety of abiraterone acetate plus prednisone and ADT from the final analysis of the LATITUDE study.
This is a multicentre, randomised, double-blind, phase 3 trial done at 235 sites in 34 countries. Eligible patients (men aged ≥18 years) had newly diagnosed, histologically or cytologically confirmed prostate cancer with metastases, Eastern Cooperative Oncology Group (ECOG) performance status of 0–2, and at least two of the three high-risk prognostic factors (Gleason score of ≥8, presence of three or more lesions on bone scan, or presence of measurable visceral metastasis except lymph node metastasis). Patients were randomly assigned (1:1) to receive abiraterone acetate (1000 mg) once daily orally plus prednisone (5 mg) once daily orally and ADT (abiraterone acetate plus prednisone group) or matching placebos plus ADT (placebo group); each treatment cycle was 28 days. Randomisation was done by a centralised interactive web response system in a country-by-country scheme using permuted block randomisation, stratified by presence of visceral disease and ECOG performance status. The coprimary endpoint of overall survival was assessed in the intention-to-treat population. This study is registered at ClinicalTrials.gov, number NCT01715285 and is complete.
Between Feb 12, 2013, and Dec 11, 2014, 1209 patients were screened, of whom ten were ineligible because of study site violations. 1199 patients were randomly assigned to either the abiraterone acetate plus prednisone group (n=597) or placebo group (n=602). After the results of the first interim analysis (cutoff date Oct 31, 2016), the study was unmasked to patients and investigators, and patients in the placebo group were allowed to cross over to receive abiraterone acetate and prednisone plus ADT treatment as per a protocol amendment (Feb 15, 2017) in an open-label extension phase of the study (up to 18 months from the protocol amendment). This final analysis (data cutoff Aug 15, 2018) was done after a median follow-up of 51·8 months (IQR 47·2–57·0) and 618 deaths (275 [46%] of 597 in the abiraterone acetate plus prednisone group and 343 [57%] of 602 in the placebo group). Overall survival was significantly longer in the abiraterone acetate plus prednisone group (median 53·3 months [95% CI 48·2–not reached]) than in the placebo group (36·5 months [33·5–40·0]), with a hazard ratio of 0·66 (95% CI 0·56–0·78; p<0·0001). The most common grade 3–4 adverse events were hypertension (125 [21%] in the abiraterone acetate plus prednisone group vs 60 [10%] in the placebo group vs three [4%] in the 72 patients who crossed over from placebo to abiraterone acetate plus prednisone) and hypokalaemia (70 [12%] vs ten [2%] vs two [3%]). Serious adverse events of any grade occurred in 192 (32%) of 597 patients in the abiraterone acetate plus prednisone group, 151 (25%) of 602 in the placebo group, and four (6%) of 72 in the crossover group. The most common treatment-related serious adverse event was hypokalaemia (four [1%] patients in the abiraterone acetate plus prednisone group and none in the other groups). Treatment-related deaths occurred in three (<1%) patients each in the abiraterone acetate plus prednisone group (gastric ulcer perforation, sudden death, and cerebrovascular accident) and the placebo group (sudden death, cerebrovascular accident, and pneumonia), with none in the crossover group.
The combination of abiraterone acetate plus prednisone with ADT was associated with significantly longer overall survival than placebos plus ADT in men with newly diagnosed high-risk mCSPC and had a manageable safety profile. These findings support the use of abiraterone acetate plus prednisone as a standard of care in patients with high-risk mCSPC.
The current standard of care for metastatic prostate cancer (PCa) is androgen deprivation therapy (ADT) plus either docetaxel or abiraterone. Growing evidence suggests that metastasis-directed therapy (MDT) and/or local therapy targeted to the primary tumour (ie, prostate) may be of benefit in the setting of oligometastatic disease. Several prospective studies are underway; however, until robust evidence is available to guide treatment decisions, physicians are challenged with how best to manage patients with oligometastases.
This comprehensive review aims to collate the available evidence to date for a role of MDT and/or prostate-targeted therapy in the setting of oligometastatic PCa, as well as discuss ongoing trials in this setting.
We searched PubMed for the combination of “prostate cancer” and “oligometastatic”, “oligometastases”, “oligometastasis”, “solitary metastases”, “stereotactic body radiotherapy”, “SBRT”, “stereotactic ablative radiotherapy”, “SABR”, “salvage lymphadenectomy”, or “metastasectomy” in publications over the last 20 yr. We also searched ClinicalTrials.gov to identify relevant ongoing trials.
The studies were divided according to the timing of metastasis into synchronous (ie, detected at the time of primary PCa diagnosis) and metachronous (ie, detected after treatment of the primary tumour), and according to treatment modality into MDT (including salvage lymph node dissection [sLND]) and prostate-targeted treatment. For MDT of synchronous/metachronous metastases, we included 16 completed studies and 11 ongoing prospective studies. In the case of sLND for nodal-only recurrence after primary treatment with curative intent, we included 11 completed studies. Finally, for prostate-targeted treatment of synchronous metastatic PCa, we included 25 completed studies and 11 ongoing prospective studies. In selected patients with oligorecurrent disease, early detection and aggressive treatment of metastatic lesions (surgery or radiotherapy) appears to be a feasible strategy and may delay the use of systemic therapies. MDT is a promising option in oligometastatic PCa patients, but more robust data are needed. In the setting of synchronous oligometastatic disease, aggressive cytoreductive treatment needs further data to confirm the benefits.
In this review, we provide a comprehensive overview of the current literature on the treatment of patients with oligometastatic PCa. The data suggest that although ADT plus either docetaxel or abiraterone remains the mainstay of treatment for mPCa, in oligometastatic PCa, improved outcomes may be achieved with metastasis- and prostate-targeted therapies. The studies included in this review are mainly retrospective in nature, limiting the strength of the evidence they provide. Prospective studies are ongoing, and their results are eagerly awaited.
We reviewed the treatment of patients with prostate cancer that has spread to five sites or fewer. We conclude that while androgen deprivation plus either docetaxel or abiraterone should remain the standard of care, there is evidence that treatment targeted at the metastases and the primary tumour may improve the outcome for the patient and potentially delay the use of systemic treatment.
Patient summary: Metastatic prostate cancer remains a lethal disease, irrespective of improved treatment options for patients. Two large randomised clinical trials recently reported on a combination of androgen deprivation therapy (ADT) with added abiraterone acetate (1000 mg/d) plus prednisone (AA + ) for metastatic hormone-sensitive (mHSPC) PCa. Both trials show a significant longer overall survival for patients that receive the combination of ADT and AA +, as compared to ADT alone.
