Prostate cancer is the most commonly diagnosed cancer among men in developed countries and the second most commonly diagnosed cancer worldwide. Incidence rates are threefold higher in countries with a high human development index score than in those with a medium-to-low score (1–3). Prostate cancer accounted for approximately 6% of all cancer deaths in the United States (US) between 2012 and 2018 (4). Almost three-quarters of cases (73%) were diagnosed with localized (stage I–II) disease; 14% and 7% had regional spread (stage III) and distant metastases (stage IV) at diagnosis, respectively (4). In 2019, 29.2% of patients in England were diagnosed with stage I disease, with 12.9% having stage II, 21.2% having stage III, and 15.7% having stage IV (the stage was reported as “unknown” in 21%) (5). Despite being curable if diagnosed at an early, localized stage, metastatic prostate cancer is still incurable and will inevitably progress to become castration-resistant (6, 7).

Metastatic castration-resistant prostate cancer (mCRPC) is clinically challenging and lethal, with no curative treatment options (8, 9). The 5-year relative survival rate for distant metastatic prostate cancer in the US is currently 32.3% (4). In the United Kingdom (UK), the 5-year survival rate for stage IV prostate cancer is 49%, accounting for 14% of all cancer deaths in men (10). Beyond survival, health-related quality of life (HRQoL) and pain are highly relevant to patients with mCRPC (11). Up to 90% of patients have bone metastases, which are a clinically significant cause of morbidity that often result in severe bone pain, either directly due to metastatic disease or indirectly as a result of symptomatic skeletal events (SSEs) such as fracture and spinal-cord compression (2, 8).

Therapies for mCRPC have evolved greatly over the past decades. In addition to the introduction of androgen receptor pathway inhibitors (ARPIs) in both post-chemotherapy and chemotherapy-naïve settings, asymptomatic and minimally symptomatic patients can undergo treatment with the immunotherapy sipuleucel-T (US only) (12). While ARPIs have improved outcomes in mCRPC, primary or acquired resistance to these agents will ultimately develop in the majority of patients, limiting their effectiveness (7, 13). Docetaxel and cabazitaxel are options for chemotherapy, with a proven survival benefit in the mCRPC setting, and radium (Ra)-223 is a radiopharmaceutical approved for treatment of patients with symptomatic bone metastases and without visceral metastases (12, 14–17).

Recently, the poly (ADP-ribose) polymerase (PARP) inhibitors olaparib and rucaparib were approved as monotherapies in the US, and olaparib also in Europe for patients with mCRPC harboring germline or somatic mutations in DNA damage–repair (DDR) genes (18–21). Olaparib has also been approved by the FDA and EMA in combination with abiraterone for patients with prostate cancer and homologous recombination repair (HHR) mutations, especially BRCA2 (18, 20). In addition, the programmed death receptor 1 inhibitor pembrolizumab is approved in the US for patients with microsatellite instability-high tumors or genetic mutations consistent with Lynch syndrome (21, 22). These advances provide options for select groups of patients, and not all who are treated will benefit (23, 24). Established lines of evidence-based treatments beyond ARPIs and taxane chemotherapy in mCRPC are of limited clinical effectiveness. As such, recommendations in guidelines focus on first-line (1L) and second-line (2L) therapies, with few guidelines existing for treatments in the third-line (3L) setting and beyond (≥3L).

Combinations of ARPIs and PARP inhibitors include olaparib plus abiraterone (PROPEL) (25, 26), enzalutamide plus talazoparib (TALOPRO-2) (27, 28), niraparib plus abiraterone acetate (hereafter “abiraterone”; MAGNITUDE) (29), and enzalutamide with rucaparib (RAMP) (30). All combinations have shown associated benefits of median radiological progression-free survival (rPFS) in patients with mCRPC who harbor HHR mutations – the most frequently altered DDR genes in prostate cancer.

The purpose of this literature review was twofold: to reflect on the current treatment landscape for prostate cancer in the metastatic and castration-resistant setting, and to consider the economic burden of mCRPC. We aimed to identify the unmet needs for patients with late-stage mCRPC and explore the emerging treatment landscape.

Three separate structured literature reviews and one systematic literature review (one original and two updates) were conducted to identify publications relating to treatment guidelines, the treatment landscape, and the humanistic and economic burden of mCRPC.

The searches and screens for each systematic review detailed in Supplemental Figure S2 yielded the following:

Interventional (efficacy) systematic literature review ( Supplemental Figure S3 )

HRQoL systematic literature review ( Supplemental Figure S4 )

Economic systematic literature review ( Supplemental Figure S5 )

The findings of these structured and systematic literature reviews demonstrate the challenges associated with the limited alternatives available for the treatment of mCRPC in the ≥2L setting. The data establish the existence of both a humanistic and economic burden in ≥2L mCRPC; patients are heavily affected in terms of HRQoL, side effects, and survival, as well as incurring substantial healthcare costs. That said, this burden is not limited to the ≥2L setting. Many patients do not receive treatment beyond 1L, and published data collected in the 2010s show that most patients with ≥2L mCRPC will receive only palliative care (77–80), contrasting starkly against the number of therapies being studied in phase 3 trials. There is a lack of data informing decisions around optimal treatment sequencing, including how clinicians and patients make these decisions while taking into account cost-effectiveness. Thus, there is a clear unmet need in patients with mCRPC who have been treated with at least one ARPI and at least one taxane. International collaboration is needed to standardize treatment sequencing to provide superior outcomes for these patients.

The information collected in this review regarding treatment patterns in mCRPC in the recent epoch before the introduction of PARP inhibitors in 2020 is generally confirmed by recently published real-world studies from the US, Australia, Europe, and Japan (9, 81–83). The ARPIs enzalutamide and abiraterone were the most common 1L systemic options for patients with mCRPC; the next most frequently used 1L systemic option was chemotherapy (primarily docetaxel), and then sipuleucel-T (9, 81, 83). Of note, one study reported at congress (thus not included in the review) noted undertreatment of patients in the US, with 38% of patients not receiving any 1L therapy (78). Similar findings regarding treatment patterns were reported in Canada and Australia (also congress reports), with the exception of sipuleucel-T; the most commonly used 1L options were ARPIs (26%–94%) and docetaxel (26%–30%) (84–86). In Spain, 64.2% of patients who had mCRPC with DDR gene mutations were treated in the 1L setting with abiraterone plus prednisone/enzalutamide (87).

The preferred 2L systemic option was chemotherapy in all countries except Japan, where either enzalutamide (83) or LHRH agonists/antagonists (44) were the more common options, and Spain, where ARPIs and chemotherapy were used equally often (83). In one study in Spain that was reported in a congress abstract, the most frequent choice of 2L therapy was abiraterone/enzalutamide (31.4%) or docetaxel (30.6%); however, 24.8% received no 2L therapy (87). Docetaxel is reportedly more commonly used as a 2L option in Canada (57%) compared with the US (6%–22%). Overall, these findings are consistent with National Comprehensive Cancer Network (NCCN) guidelines (12). Combination therapy with olaparib and abiraterone is currently being studied as a 1L option in the phase 3 PROpel trial, with recently published data demonstrating significantly improved rPFS over abiraterone alone in patients with mCRPC (25.0 vs. 16.4 months; HR 0.67; 95% CI 0.56–0.81), regardless of whether or not they harbored HRR gene mutations. OS data were immature in the planned interim analysis (40%); however, a trend toward improved OS with olaparib plus abiraterone versus abiraterone alone was reported (HR 0.83; 95% CI 0.66–1.03) (88). The HRs for time to first subsequent therapy or death and time to second progression or death (0.74 and 0.69, respectively), reported in an earlier primary analysis of PROpel, supported efficacy beyond first imaging-based progression (26). In August 2023, niraparib (not yet approved for prostate cancer) was approved in combination with abiraterone for the treatment of patients with deleterious or suspected deleterious BRCA1- or BRCA2-mutated mCRPC, based on the findings of the MAGNITUDE trial (NCT03748641) (89). This combination is also under investigation for the treatment of patients with deleterious HRR gene-mutated metastatic castration-sensitive prostate cancer (AMPLITUDE; NCT04497844) (89). It is also being studied in combination with cetrelimab (anti-programmed death 1 antibody) in patients with mCRPC, including the subpopulation with DDR gene defects (QUEST; NCT03431350) (90, 91), regardless of prior treatment history (except for prior PARP inhibition in AMPLITUDE).

There appears to be more variation regarding treatment sequencing, the importance of which has been emphasized in the updated Prostate Cancer Working Group recommendations (92, 93). There is currently no evidence-based guidance or consensus on the optimal sequence beyond 2L, and a lack of randomized trials to clarify the issue. According to a recent PubMed-based literature review of clinical studies on treatment sequencing and combinations in mCRPC, abiraterone followed by enzalutamide was the best sequential treatment in docetaxel-naïve patients, whereas enzalutamide was the most effective subsequent choice of treatment for patients who had previously failed on docetaxel (94). The findings of a phase 2 crossover study with HRQoL as an outcome measure support the use of abiraterone as a first subsequent therapy in patients with treatment-naïve mCRPC (95). In the CARD study, patients with mCRPC who had failed on docetaxel and either abiraterone or enzalutamide (before or after docetaxel), and then treated with 3L cabazitaxel experienced longer rPFS and OS than their counterparts who were treated in 3L with the other ARPI (i.e., abiraterone in those who had previously received enzalutamide, and vice versa) (47). The most common 1L-to-2L sequence identified in the present literature review was ARPI-to-chemotherapy, with other sequences being chemotherapy-to-ARPI, ARPI-to-ARPI, and chemotherapy-to-chemotherapy. Several trials are ongoing with ARPI plus androgen deprivation therapy (ADT) in combination with a third agent (“triplet therapies”) to treat metastatic hormone-sensitive prostate cancer (mHSPC), such as ENZAMET, ARASENS, and PEACE-1. Findings to date provide equivocal evidence that (at least for patients with high-volume mHSPC) OS, PFS, and various measures of PROs are improved by the addition of agents such as docetaxel, darolutamide, enzalutamide, and abiraterone to ADT (96–100). These findings may lead to changes in mCRPC sequencing. However, it should be noted that the timing of administration of the docetaxel-related regimen differed between the three trials (i.e., delivered before, during, or just after ARPI) (97, 98, 100). Furthermore, trials are underway to identify molecular biomarkers that predict response or primary resistance to particular treatments, which may be invaluable in the treatment decision-making process to optimize the patient’s therapeutic journey (101, 102). Biomarkers currently under study include: circulating androgen receptor gene status (assessed using liquid biopsy); alterations in phosphatase and tensin homolog protein and its pathway; immune biomarkers (e.g., programmed death ligand 1, sex-determining region Y-box 2; and DDR gene mutations (103–105). The multicenter, outcome-adaptive, biomarker-driven ProBio study is currently using a biomarker-driven platform to inform treatment decisions in men with mCRPC (102).

Geographic differences in the preferred treatment sequence were noted; for example, chemotherapy-to-ARPI was a more common 1L-to-2L sequence than ARPI-to-ARPI and chemotherapy-to-chemotherapy in Germany, Italy, and the UK, while chemotherapy-to-ARPI and ARPI-to-ARPI was administered to a similar degree in France and Spain (83). The most frequent 1L-to-2L treatment sequence in a large retrospective study in the US was abiraterone-to-enzalutamide, followed by enzalutamide-to-abiraterone (82), while in Ontario, Canada, the preference was to provide a subsequent (2L) treatment with a different mechanism of action (abiraterone or enzalutamide followed by docetaxel, with Ra-223 being the most common 3L treatment) (80). A retrospective, multicenter analysis of real-world data performed in Australia found that the most frequent subsequent systemic therapy was a carboplatin-based regimen, and that some patients also received rechallenge with an ARPI or docetaxel (106). However, it was also reported that choice of subsequent treatment did not impact survival outcomes; median OS did not differ according to subsequent systematic therapy (106). In contrast, in a single-center study, docetaxel rechallenge has shown meaningful anti-tumor activity in pretreated patients with mCRPC in the salvage setting (107).

Geographic differences in treatment sequencing preference may be attributable to a variety of country-, patient-, and physician-based factors, such as whether or not ARPI rechallenge is allowed, reimbursement rules, patient preference for oral versus intravenous agents, access and cost of newer agents, and the specialism of the treating physician (83, 108–110). Patients may live in regions without access to newer agents or where screening is not common and they are diagnosed at a later stage, rendering them ineligible for certain therapies (44, 108). Rechallenge with ARPIs is discouraged in ESMO and European Association of Urology (EAU) guidelines due to the potential for cross-resistance (101, 111, 112), but in the local guidelines for Germany, Italy, and Japan it is a suggested treatment option (83). Moreover, local reimbursement criteria may preclude rechallenge with a different ARPI – this is the case in Canada, with exceptions in the case of intolerance with the first ARPI or (in some provinces) if chemotherapy was used in between (“sandwich therapy”) (80, 113). According to one US study that compared therapy choice between oncologists and urologists, a significantly greater proportion of patients treated by oncologists were prescribed hormone therapy, chemotherapy, and radiation therapy; nonchemotherapy options were significantly more commonly prescribed by urologists than by oncologists (114). Another study from the US reported that in the 2L setting, oncologists were most likely to prescribe hormone therapy and chemotherapy, while for urologists the most commonly prescribed treatments were sipuleucel-T and hormone therapy (115). Other work from the US reported that urologists were increasingly prescribing oral therapies such as abiraterone and enzalutamide (116). Treatment options for mCRPC continue to evolve, and particularly in the 2L setting with the recent approval of several novel therapies such as PARP inhibitors (olaparib, rucaparib), immunotherapies (pembrolizumab), and ¹⁷⁷Lu-PSMA-617. Although all of these new agents are now included in one or more of the recently updated NCCN, ESMO, EAU, and American Urological Association prostate cancer treatment guidelines, there is little real-world evidence regarding their use (12, 110, 111, 117). Olaparib and rucaparib are both approved in one or more countries (including the US) for the treatment of patients with HRR gene-mutated mCRPC who have progressed on ARPIs (olaparib) or in patients with mutations in BRCA1 or BRCA2 who have progressed on an ARPI and a taxane-based chemotherapy (rucaparib). Of note, NCCN guidelines do not recommend use of olaparib for patients harboring PPP2R2A mutations due to preliminary evidence of reduced efficacy in these patients (12). For both of these PARP inhibitors, gene mutations are confirmed using US Food and Drug Administration-approved companion diagnostics (18, 19). Among patients with mCRPC, only 11%–33% harbor germline mutations in DDR genes, including HRR genes such as BRCA1/BRCA2 (118, 119); therefore, the majority of patients are not eligible to receive them. Moreover, in a recent network analysis of the PROfound and CARD studies, it was noted that certain patient subgroups achieved reduced or no benefit with olaparib, including those harboring mutations in genes other than BRCA1 or BRCA2, compared with active standard-of-care agents (e.g., cabazitaxel) (120). Pembrolizumab is also approved in the US for the treatment of patients with mismatch-repair-deficient or microsatellite-instability-high solid tumors who have no satisfactory alternative (21), and ¹⁷⁷Lu-PSMA-617 is approved for patients with PSMA-positive (determined using a PSMA imaging agent) mCRPC who have progressed on an ARPI and taxane-based therapy (121). It remains to be seen how these new agents will be incorporated into the treatment landscape in the real-world setting. Access to all therapy options has been shown to result in longer survival in patients with prostate cancer (122).

Most pivotal phase 3 trials for currently approved treatments for mCRPC were published prior to 2017 ( Supplemental Table 15 ), and thus data for only two trials were included in this review: PROfound (olaparib vs. enzalutamide plus abiraterone) (45, 46) and CARD (cabazitaxel vs. enzalutamide or abiraterone plus prednisone) (47). Despite differences in the patient populations, both studies demonstrated improved survival with the study drug over abiraterone or enzalutamide. In PROfound, OS varied (according to the particular cohort) from 14.1 to 19.1 months with olaparib and from 11.5 to 15.1 months with an ARPI; rPFS was 5.8 versus 3.5 months (45, 46). In CARD, OS was 13.6 months with cabazitaxel versus 11.0 months with an ARPI, and PFS was 4.4 and 2.7 months, respectively (47). Based on these clinical trials, newer agents have been approved and brought into clinical practice (12, 112). Survival data for other approved treatments that were outside the scope of this review are provided in Supplemental Table S15 .

The humanistic burden associated with mCRPC was high across the included studies, demonstrating that mCRPC is associated with poor HRQoL and imposing a significant burden on patients. This burden was worse for patients with SSEs, skeletal-related events, or bone metastases (2, 62). Although treatment was often associated with a delayed deterioration in HRQoL, no trends for one regimen over another emerged. Two studies (not identified in the current review) determined that patients treated with abiraterone reported less fatigue and cognitive impairment and had more favorable PROs compared with enzalutamide in both real-world and clinical trial settings (95, 123). However, a propensity score-matching study found that whilst there was no significant difference in the development of new comorbidities between the two agents, OS was better with enzalutamide; moreover, the overall Charlson Comorbidity Index score (and not its items) was a significant predictor of OS (124). There is increasing awareness that HRQoL is an important endpoint of value to both patients and healthcare providers. While the impact of treatments on many aspects of HRQoL in patients with localized disease is well established, there is less information on patients with advanced disease who are more likely to have poor performance status, are more frequently affected by pain due to bone metastases, and for whom the balance between longevity and quality of life is perhaps more important (125, 126). A recent systematic review of patient values, preferences, and expectations found that, while cancer progression or survival, pain, and fatigue were key considerations regarding treatment decisions, alleviation of pain was valued at the expense of survival benefits among symptomatic patients (127). PRO endpoints are included in clinical registration trials, as well as product labels of the latest interventions, and form an important part of disease management in patients with mCRPC (128, 129). However, the tools used to measure HRQoL in patients with mCRPC may not fully capture patients’ lived experiences of the burden of advanced prostate cancer (130–132). Some HRQoL instruments (e.g., EORTC QLQ-C30) are generic and have not been optimized to measure the specific burden of mCRPC; prostate cancer-specific tools (e.g., FACT-P) may capture a more accurate picture. It is therefore encouraging that a recent systematic review of trials on advanced prostate cancer conducted between 2011 and 2019 found that FACT-P was the most frequently adopted HRQoL tool (11/14 trials), followed by EQ-5D (6/14 trials) and EORTC QLQ-C30 (3/14 trials) (129). The evidence from that review demonstrated that in phase 3 trials, currently available systemic treatments (including ARPIs, Ra-223, and docetaxel) had a positive impact on HRQoL in patients with advanced cancer compared with standard ADT. Data for newer agents such as olaparib were available only for phase 2 trials, but nonetheless were also found to be beneficial (129). Moreover, some instruments are more meaningful at particular stages of the disease. Holmstrom et al. describe a conceptual model that characterizes patient experiences of living with mCRPC, indicating symptoms and impacts, such as fatigue, pain, urinary frequency, interference with daily activities, and frustration, that are not adequately assessed with currently available PRO instruments (133).

Further studies are required to determine the cost-effectiveness of the recently approved therapies, the optimal treatment sequence in patients who have progressed, and models that use data from real-world studies, not clinical trials. The economic burden to healthcare systems of patients with mCRPC is ongoing as patients are still progressing on currently available treatments.

There is a lack of overall consensus on genetic testing. US and European guidelines now recommend genetic testing (somatic and/or germline), especially in patients with advanced prostate cancer, and earlier genetic testing in patients who are high risk (including those with a relevant family history) (134, 135). In contrast, a post-meeting survey from the Asia-Pacific Advanced Prostate Cancer Consensus Conference revealed that biomarker testing is limited to patients who have progressed on multiple lines of therapy (136).

In summary, the lack of available data to inform the delivery of appropriate treatments beyond 2L to patients with mCRPC means that the optimal sequence remains undefined (85, 106, 137). The data have shown that options with alternative mechanisms of action may be preferred to avoid cross-resistance between ARPIs (80, 101). The treatment options for mHSPC are increasing, and future real-world studies assessing the impact of mHSPC treatment algorithms on subsequent mCRPC treatment alternatives are needed. In addition, there is a need for innovative treatment options in post-taxane and post-ARPI mCRPC that improve survival and HRQoL, as well as having a tolerable safety profile. Aligning and then switching from 1L to 2L mCRPC therapies in a timely manner will help to ensure patients receive the most benefit from a clinically efficacious agent. New treatment options for the ≥2L setting may help not only treatment sequencing optimization, but may also result in improvements to the humanistic and economic burden.

OM and RG designed this study. GK contributed to the literature search, review, and data extraction. DL, SC, AM, OM, and RG contributed to manuscript drafting and manuscript revision. All authors have reviewed and approved the final version of this manuscript.