Recent trends in the management of advanced prostate cancer

Advanced prostate cancer includes a wide spectrum of disease ranging from hormone naïve or hormone sensitive to castration resistant, both containing populations of men who have demonstrable metastatic and non-metastatic states. The mainstay of treatment for metastatic hormone-sensitive prostate cancer is androgen deprivation therapy (ADT). However, recent level 1 evidence demonstrates that the addition of chemotherapy or abiraterone acetate to ADT results in significant survival advantage as compared with ADT alone. Furthermore, in non-metastatic castration-resistant prostate cancer (M0 CRPC), two second-generation anti-androgens, apalutamide and enzalutamide, when used in combination with ADT, have demonstrated a significant benefit in metastasis-free survival. Here, we review the most recent studies leading to these significant changes in the treatment of advanced prostate cancer.


Introduction
There have been significant strides in the management of prostate cancer over the past decade. The majority of newly diagnosed cases (80%) are localized prostate cancer, and the remaining cases are advanced or metastatic disease 1 . Overall survival (OS) rates in localized disease are very high; however, this decreases dramatically for advanced and metastatic cases and ranges from 26% to 30% at 5 years 2 . Unique to prostate cancer is the fact that cancer cells are highly sensitive to the manipulation of the androgen pathway 3,4 . Testosterone and its metabolites have a stimulatory effect on prostate cancer cell growth, and hormonal manipulation and castration can induce prostate cancer cell death 5 . Therefore, the initial management of metastatic prostate cancer is based on androgen deprivation to achieve castrate levels (<50 ng/dL) of circulating testosterone, thereby depriving the cells of their primary fuel for growth.
For decades, androgen deprivation therapy (ADT), via medical or surgical castration, has been the primary treatment of metastatic prostate cancer. However, patients ultimately progress to castration resistance, wherein prostate cancer cells become resistant to ADT and develop mechanisms to proliferate despite castrate levels of testosterone. Patients who progress to castrationresistant prostate cancer (CRPC) progress rapidly and may die within 2 to 4 years 6,7 . However, prior to 2004, there were no US Food and Drug Administration (FDA)-approved therapies for CRPC until several landmark randomized controlled trials (RCTs) (TAX-327 and SWOG 9916) demonstrated that patients with metastatic CRPC (mCRPC) treated with docetaxel chemotherapy achieved a significant survival advantage compared with placebo 8,9 . Recently, two landmark studies (STAMPEDE and CHAARTED) examined the role of combined chemotherapy and ADT (chemohormonal therapy) as compared with ADT alone in hormone-sensitive disease 10,11 . Additionally, the LATI-TUDE trial and abiraterone arm of the STAMPEDE trial both demonstrated a survival benefit with abiraterone acetate plus prednisone when combined with ADT over ADT alone for hormone-sensitive prostate cancer 12,13 . All of these studies demonstrated a statistically significant benefit in OS and have changed the management paradigm in metastatic prostate cancer. In the castration-resistant setting, since 2010 and almost every year thereafter, several key RCTs have demonstrated survival benefit with new therapies before and after docetaxel-based chemotherapy. The culmination of these studies has led to the FDA approval of six new agents, which have varying mechanisms of action, in the management of metastatic and non-metastatic (M0) CRPC: sipuleucel-T, abiraterone acetate, enzalutamide, cabazitaxel, radium-223, and apalutamide 14-21 . Of particular significance is the recent approval of apalutamide and enzalutamide in the treatment of M0 CRPC, which was based upon two RCTs (SPARTAN and PROSPER) demonstrating significant improvement in metastasis-free survival (MFS) 21,22 . Prior to these trials, there were no approved agents for M0 CRPC.
The purpose of the present review is to provide an overview of the recent trends and advances in the management of metastatic castration-sensitive prostate cancer (CSPC) and M0 CRPC (Table 1). We will review the literature supporting the approval of upfront chemotherapy in metastatic CSPC as well as recent landmark studies supporting newer therapies for M0 CRPC.

Chemotherapy for metastatic castration-sensitive prostate cancer
Historically, following progression to CRPC, docetaxel chemotherapy was the first-line agent based on results of the TAX-327 and SWOG 9916 trials 8,9 . TAX-327 demonstrated that docetaxel every 3 weeks significantly decreased risk of death-hazard ratio (HR) 0.76, 95% confidence interval (CI) 0.62 to 0.94, p = 0.009-compared with mitoxantrone 8 . The median survival was 18.9 versus 16.4 months for docetaxel compared with mitoxantrone. In SWOG 9916, docetaxel plus estramustine was compared with mitoxantrone plus prednisone, and there was a 20% reduction in the risk of death with a median survival improvement of about 2 months, favoring docetaxel (p = 0.02) 9 . Therefore, docetaxel use was limited to the castrationresistant setting. The GETUG-AFU 15 trial was one of the first

Abiraterone for metastatic castration-sensitive prostate cancer
The implications of the STAMPEDE and CHAARTED trials are significant because chemohormonal therapy has now become a widely considered first-line therapy in high-volume metastatic HSPC. However, the recent LATITUDE trial, which examined the role of abiraterone acetate plus prednisone in combination with ADT in the hormone-sensitive metastatic prostate cancer setting, has also demonstrated a survival advantage compared with ADT plus placebo 12 . Fizazi et al. randomly assigned 1,199 patients with metastatic HSPC to abiraterone acetate plus prednisone combined with ADT versus ADT plus placebo and demonstrated a significant benefit in survival in the abiraterone arm (HR 0.62, 95% CI 0.51 to 0.76, p <0.001) 12 . Furthermore, there was a significant benefit with abiraterone with respect to time to initiation of chemotherapy as second-line therapy following disease progression, although fewer patients received secondline chemotherapy than expected 12 . James et al. studied the abiraterone arm of the STAMPEDE trial, in which 1,917 men were randomly assigned to abiraterone plus ADT compared with ADT alone 13 . There was a significant 3-year survival advantage for men in the abiraterone arm of 83% versus 76% in the ADT-alone group (HR 0.63, 95% CI 0.52 to 0.76, p <0.001) 13 . Importantly, owing to the multi-arm, multi-stage trial design, the patient population differed slightly from that of the LATITUDE group in that some men had node-positive only disease as well as node-negative, non-metastatic disease. Both trials demonstrated a survival benefit, and, as a result, abiraterone acetate as well as chemotherapy may also be considered in metastatic CSPC. A recent analysis of data from the STAMPEDE trial compared abiraterone with docetaxel in the castration-sensitive state and found no difference in overall and prostate cancer-specific survival 24 . Therefore, the approval and utilization of these therapies in combination with ADT in the hormone-sensitive state represent a major advance and paradigm shift in the management of metastatic prostate cancer.

Treatment of non-metastatic castration-resistant prostate cancer
Progression from the hormone-sensitive to the castrationresistant state is defined as a rising prostate-specific antigen (PSA) with T levels below 50 ng/mL. In the clinical trial setting, the Prostate Cancer Clinical Trials Working Group 3 definition of PSA progression is an at least 25% increase, and an absolute increase of at least 2 ng/mL from the nadir PSA, confirmed at least 3 weeks later 25 . Despite progression to castration resistance, a subset of patients may not harbor detectable metastasis by the traditional imaging techniques used in the trials and therefore are categorized as having M0 CRPC. Patients with M0 CRPC are at high risk for progression to metastatic disease. In fact, within 2 years, about 15% to 33% can develop metastasis, implying that castration resistance may lead to rapid progression and potentially a high risk of mortality in this population 26,27 . Until 2018, there were no approved agents for first-line treatment of asymptomatic M0 CRPC. Prior to the current year, guideline recommendations supported continued ADT in M0 CRPC, with close surveillance, because the androgen receptor remains functionally active in this disease state 28 . There were no level 1 data showing a significant therapeutic advantage with any particular therapy in M0 CRPC. Therefore, this disease state represented a challenging clinical conundrum because although castration resistance is a harbinger of metastatic disease and mortality, there were no efficacious options for treatment. If the patient or treating physician wished to pursue treatment, the first-generation anti-androgens (flutamide, bicalutamide, and nilutamide) and first-generation androgen synthesis inhibitors (ketoconazole with steroid) were occasionally used with variable and limited efficacy 28,29 .
In 2016, the STRIVE study demonstrated potential therapeutic benefit with enzalutamide in M0 CRPC. Penson et al. randomly assigned 396 men on ADT, with M0 (n = 139) or metastatic (n = 257) CRPC, to enzalutamide (160 mg/day) or bicalutamide (50 mg/day) 30 . Enzalutamide reduced the risk of progression or death by 76% compared with bicalutamide (HR 0.24, 95% CI 0.18 to 0.32, p <0.001) and the median progression-free survival was 13.7 months longer for men in the enzalutamide arm 30 . Although these findings were noteworthy, they were not sufficient to lead to FDA approval in M0 CRPC.
Recently, apalutamide, a novel non-steroidal anti-androgen which acts as an androgen receptor inhibitor, was studied in patients with M0 CRPC 21 . The SPARTAN trial randomly assigned  31 . Enzalutamide was subsequently FDA-approved for use in M0 CRPC. The importance of patient selection cannot be underestimated. Patients in both of these landmark trials of M0 CRPC were selected on the basis of high risk for metastases as indicated by a rapid PSA doubling time. Furthermore, the newer positron emission tomography imaging-based tracers were not used in these studies and it is possible that a subset of these men had metastases that were not detectable by the limits of conventional computed tomography imaging and nuclear bone scan. In patients with a slow doubling time, observation may be an appropriate management strategy.

Emerging treatments
Poly (

Conclusions
There have been significant recent strides in the management of advanced prostate cancer. Major changes in the treatment of hormone-sensitive disease have occurred on the basis of level 1 evidence to support upfront use of docetaxel plus ADT and in addition the use of androgen annihilation with abiraterone acetate plus prednisone in combination with ADT. Also, in the M0 CRPC state, there are now two randomized trials demonstrating improved MFS with the addition of apalutamide or enzalutamide in combination with ADT for patients at high risk for metastases. PARP inhibitors and immunotherapeutic agents such as CTLA-4 inhibitors are also being studied and may become a part of the treatment armamentarium in the near future.

Grant information
The author(s) declared that no grants were involved in supporting this work.

Open Peer Review Current Referee Status:
Editorial Note on the Review Process are commissioned from members of the prestigious and are edited as a F1000 Faculty Reviews F1000 Faculty service to readers. In order to make these reviews as comprehensive and accessible as possible, the referees provide input before publication and only the final, revised version is published. The referees who approved the final version are listed with their names and affiliations but without their reports on earlier versions (any comments will already have been addressed in the published version).
The referees who approved this article are:

Version 1
The benefits of publishing with F1000Research: Your article is published within days, with no editorial bias You can publish traditional articles, null/negative results, case reports, data notes and more The peer review process is transparent and collaborative Your article is indexed in PubMed after passing peer review Dedicated customer support at every stage For pre-submission enquiries, contact research@f1000.com Klinik für Urologie, Uro-Onkologie, Roboter-assistierte und Spezielle Urologische Axel Heidenreich Chirurgie, Universitätsklinikum Köln, Köln, Germany No competing interests were disclosed. Competing Interests: 1