See MDPI, Basel, Switzerland. This article is an open access short article distributed under the terms and conditions with the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ four.0/).Cancers 2021, 13, 4522. https://doi.org/10.3390/cancershttps://www.mdpi.com/journal/cancersCancers 2021, 13,2 ofKeywords: metastatic castrationresistant prostate cancer; metastatic hormonesensitive prostate cancer; metastatic hormonena e prostate cancer; nonmetastatic castrationresistant prostate cancer; chemotherapy; androgenreceptor signaling inhibitors; LuPSMA; PARP inhibitors; ipatasertib1. Introduction The therapy landscape of advanced prostate cancer has entirely changed in current years. Various treatment selections have demonstrated the ability to enhance the overall survival (OS) of patients with metastatic hormonesensitive prostate cancer (mHSPC) and metastatic castration resistant prostate cancer (mCRPC) when added to the androgendeprivation therapy (ADT). These remedies incorporate chemotherapy with docetaxel and cabazitaxel, androgenreceptor signaling inhibitors (ARSi), radium223, and radiotherapy to key tumor. Phase 3 trials have also shown that the addition of ARSi to ADT improves the outcomes of patients with nonmetastatic castration resistant prostate cancer (nmCRPC). Nevertheless, no standardized strategy to properly sequence all of these treatment solutions continues to be defined. Couple of randomized trials have compared these diverse methods, plus the majority of facts is offered by retrospective series and secondary analyses. This extensive critique aims at delivering one of the most convincing proof on the finest sequencing of agents in unique settings of advanced prostate cancer and to go over existing information that support the usage of particular biomarkers during the remedy selection. 2. Optimal Sequencing in mHSPC, nmCRPC and mCRPC two.1. Collection of FirstLine Treatment 2.1.1. FirstLine mHSPC Longterm ADT has been the remedy of L-Norvaline Autophagy decision within the mHSPC setting for decades, with an estimated median OS of about three.5 years in contemporary series [1,2]. In current years, however, the addition of chemotherapy, ARSi, and radiotherapy to major tumor to ADT have been shown to supply a important survival benefit in sufferers with mHSPC [3]. The addition of docetaxel to ADT demonstrated an OS get ranging from ten.4 to 16 months in the CHAARTED and STAMPEDE trials, respectively [1,2]. The OS advantage of adding abiraterone acetate to ADT was 16.8 months (53.3 vs. 36.5 months) within the LATITUDE trial [4] and 33.six months (79.two vs. 45.six months) within the STAMPEDE trial [5]. Enzalutamide and apalutamide also supplied a considerable OS benefit in sufferers with mHSPC enrolled in the ENZAMET (HR 0.67, 95 CI 0.52.86) and TITAN trials (HR 0.67, 95 CI 0.51.89) [6,7]. Radiotherapy towards the primary tumor prolonged OS in patients with lowvolume mHSPC [8]. All round, the significant survival benefit observed in these trials, together with the significant improvement of several secondary endpoints, strongly support the clinical use of those approaches through the firstline therapy of mHSPC (Table 1). Although these trials have introduced new active selections for the treatment of mHSPC, no direct headtohead comparisons are currently accessible. Crosstrials comparisons appear to become inappropriate given that the median OS observed within the manage arms varies from 36.5 months of the LATITUDE trial to 52.2 months from the TITAN trial. In addition, the majority o.