Managementul cancerului de prostată metastatic

Introduction

Prostate cancer remains the most frequently diagnosed malignancy among men worldwide, and represents a significant public health concern due to its high incidence and mortality rates. In 2025, it accounted for approximately 30% of all male cancers in the United States of America, making it the second leading cause of cancer-related death in men after lung cancer. The disease disproportionately affects individuals of African ancestry, with Afro-American men experiencing nearly double the mortality rate compared to Caucasian men, despite similar or lower incidence rates in some populations. These disparities underscore the importance of early detection strategies, including prostate-specific antigen (PSA) screening, which has contributed to improved survival outcomes over recent decades. Nevertheless, the rising trend in distant-stage diagnoses, particularly among younger men, signals a need for renewed focus on timely screening and equitable access to care⁽¹⁾.

Metastatic prostate cancer (mPCa) represents the most advanced and life-threatening stage of the disease, characterized by the spread of malignant cells beyond the prostate gland to distant organs – most commonly the bones, lymph nodes, liver and lungs. In Europe, approximately 10-20% of prostate cancer cases are diagnosed at the metastatic stage, with a rising trend in younger patients and in regions with limited access to early screening programs. Despite therapeutic advances, mPCa remains incurable, and its management centers on prolonging survival and maintaining quality of life⁽²⁾.

Androgen deprivation therapy (ADT) has been for a prolonged period of time the standard in the therapeutical management of advanced prostate cancer. Both localized and metastatic forms of prostate cancer are distin­ctly reliant on androgens, which stimulate tumor growth through the androgen receptor signaling pathway. As a result, ADT is a fundamental component of all systemic treatment protocols for metastatic prostate cancer, most commonly achieved through medical castration using gonadotropin-releasing hormone (GnRH) agonists such as leuprolide, goserelin, triptorelin or antagonists among which degarelix or relugolix. These agents work by suppressing testicular androgen production, aiming to keep serum testosterone levels below 50 ng/dL⁽³⁾.

Systemic treatment in metastatic
hormone-sensitive prostate cancer (mHSPC)

Androgen receptor pathway inhibition: ARPI-based systemic therapy

The combination of androgen deprivation therapy with androgen receptor pathway inhibitors (ARPIs) has emerged as the current standard of care for patients with metastatic hormone-sensitive prostate cancer (mHSPC). This paradigm shift is supported by multiple landmark clinical trials demonstrating superior overall survival and disease control compared to ADT alone. Agents such as abiraterone acetate, enzalutamide, apalutamide and darolutamide – when added to ADT – have shown consistent benefits across diverse patient populations, including those with high- and low-volume disease. Both European and American guidelines, including those from the European Association of Urology (EAU), European Society for Medical Oncology (ESMO) and National Comprehensive Cancer Network (NCCN), now recommend ADT plus ARPI as first-line systemic therapy in mHSPC, reflecting a growing consensus on the need for intensified treatment strategies early in the disease course. This approach not only delays progression to castration-resistant prostate cancer (CRPC) but also improves the quality-adjusted survival outcomes^(4,5).

The LATITUDE trial focused on newly diagnosed, high-risk mHSPC patients treated with abiraterone ace­tate plus prednisone and ADT versus ADT alone. The study demonstrated significant improvements in both OS (HR 0.62; 95% CI; 0.51-0.76; p<0.001) and rPFS (HR 0.47; 95% CI; 0.39-0.55; p<0.001). Median overall survivor (OS) was 53.3 months in the abiraterone group versus 36.5 months in the control arm, while median radiographic progression-free survival (rPFS) was 33 months versus 14.8 months. Subgroup analysis showed the greatest overall survival benefit in patients with synchronous, high-volume disease, with modest effects in metachronous high-volume and synchronous low-volume subgroups. No OS benefit was observed in metachronous low-volume disease. The safety profile was acceptable, with hypertension and hypokalemia being the most frequent adverse events. These results position abiraterone plus ADT as a foundational therapy in high-risk, high-volume mHSPC⁽⁶⁾.

The ARCHES trial evaluated enzalutamide plus ADT versus ADT alone in men with mHSPC, including both high- and low-volume disease. The study met its primary endpoint, with enzalutamide significantly improving rPFS (HR 0.39; 95% CI; 0.30-0.50; p<0.001). Final OS analysis showed a survival benefit (HR 0.66; 95% CI; 0.53-0.81; p<0.0001), with median follow-up of 44.6 months. PSA responses were robust, with 68.1% of patients in the enzalutamide arm achieving undetectable PSA levels versus 17.6% in the control group. Subgroup analysis revealed consistent overall survival benefit in both high-volume (HR 0.70) and low-volume (HR 0.71) disease. The safety profile was consistent with prior enzalutamide studies, with fatigue and hypertension among the most common adverse events. These findings reinforce enzalutamide plus ADT as a potent option for delaying progression and improving survival in mHSPC⁽⁷⁾.

The TITAN trial, a multinational phase III study, investigated apalutamide plus ADT versus ADT alone in men with mHSPC, regardless of disease volume or prior docetaxel use. The trial demonstrated a significant improvement in overall survival (HR 0.65; 95% CI; 0.53-0.79; p<0.001) and radiographic progression-free survival (HR 0.48; 95% CI; 0.39-0.60; p<0.001). At 24 months, overall survival was 82.4% in the apalutamide group versus 73.5% in the placebo group. After a median follow-up of 44 months, the estimated median OS was 71.8 months with apalutamide. Subgroup analysis showed consistent benefit across both high-volume and low-volume disease, with overall survival reaching 113.7 months in the low-volume subgroup. The safety profile was manageable, with rash and fatigue being the most common adverse events. These results confirm apalutamide plus ADT as a versatile and effective first-line treatment for mHSPC across disease volumes⁽⁸⁾.

The ARANOTE trial, a phase III randomized, double-blind study, evaluated darolutamide plus ADT versus ADT alone in men with mHSPC. The trial met its primary endpoint, showing a significant improvement in radiographic progression-free survival with darolutamide (HR 0.54; 95% CI; 0.41-0.71; p<0.0001). At 24 months, rPFS was 70% in the darolutamide arm versus 52% in the placebo group. Subgroup analysis revealed a particularly strong effect in patients with low-volume disease (HR 0.30; 95% CI; 0.15-0.60), with median rPFS not reached. However, overall survival did not reach statistical significance (HR 0.74; 95% CI; 0.53-1.03). Notably, 95% of patients had synchronous metastases, and the safety profile was favorable, with fewer discontinuations due to adverse events in the darolutamide group (6.1% versus 9%). These findings support darolutamide plus ADT as an effective and well-tolerated option for delaying progression in mHSPC, especially in low-volume synchronous disease⁽⁹⁾.

Chemotherapy in metastatic hormone-sensitive prostate cancer (mHSPC)

Extensive research has shown that certain patients with metastatic prostate cancer derive additional benefit from therapies beyond ADT. Chemotherapy, defined as the use of cytotoxic agents that disrupt rapid cell division and induce cell death, has played a recognized role in this setting since the 1990s. Over the past decade, treatment paradigms for hormone-sensitive metastatic prostate cancer have evolved significantly, with clinical trials supporting the intensification of therapy by combining ADT with next-generation antiandrogens – with or without chemotherapy. Currently, chemotherapy is approved by both the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for use in metastatic castration-sensitive (mCSPC) and castration-resistant prostate cancer (mCRPC). Commonly employed chemotherapeutic agents include taxane-based drugs such as docetaxel and cabazitaxel, which bind reversibly to tubulin, inhibit microtubule depolymerization, and thereby block cell division and induce apoptosis⁽¹⁰⁾.

In 2004, TAX327 and SWOG9916 clinical trials indicated significant improvement in overall survival in male patients with mCRPC treated with ADT and doce­taxel/prednisone (or docetaxel and estramustine in SWOG9916), compared to ADT plus mitoxantrone/prednisone, which meant an immediate change of mCRPC treatment paradigm. The association between hormonal therapy and cytotoxic therapy has reflected a paramount scientific rational, as clonal populations in advanced and resistant prostate cancer are heterogeneous – both within and between metastatic sites – and may be differentially driven by androgen receptor (AR)-dependent and AR-independent mechanisms. This has led to the earlier integration of chemotherapy into the therapeutic sequence, even in the setting of metastatic disease that remains sensitive to hormonal therapy. This approach is particularly considered for patients with high tumor burden, including those with visceral metastases and significant symptoms^(11,12).

The intensification of upfront treatment with ADT plus docetaxel in the initial management of mHSPC was tested by three key phase III studies. In the GETUG-AFU 15 trial, 385 patients were randomized to receive either ADT associated with docetaxel administered every three weeks (up to nine cycles, without prednisone) or ADT alone. At a median follow-up of 50 months, overall survival was not significantly different between groups (hazard ratio [HR] 1.01; CI 95%; 0.75-1.36). Nonetheless, the post hoc analysis based on metastatic disease volume revealed a trend toward benefit in the subgroup with high tumor burden (HR 0.78; 95% CI; 0.56-1.09); however, this did not reach statistical significance⁽¹³⁾. CHAARTED trial was the first study to report significant improvement of the associated therapy between ADT and docetaxel for mHSPC. The study enrolled 790 patients randomized 1:1 to receive ADT in monotherapy or ADT plus docetaxel (for six cycles). The trial also had numerous prespecified stratification factors, including tumor volume, where high-volume disease was defined as the presence of any visceral metastases or four or more bone lesions, with at least one located beyond the vertebral bodies and pelvis. After a median follow-up of 28.9 months, the combo therapy was associated with a significant prolonged overall survivor (57.6 months versus 44 months; HR 0.61; 95% CI; 0,47-0.80; p<0.001), as well as with a benefit on the secondary endpoints of the trial, respectively time to castration resistance prostate cancer and PSA undetectable ((14). The STAMPEDE trial, conducted across multiple arms and phases, also demonstrated a significant benefit of adding docetaxel to ADT. Arm E of the study (ADT plus docetaxel plus zoledronic acid) showed an improvement in overall survival compared to ADT monotherapy (HR 0.78; 95% CI; 0.66-0.93). Subgroup analysis clearly revealed this effect in patients with metastatic disease. However, a subsequent subgroup analysis after a median follow-up of 78.2 months failed to demonstrate a survival benefit from docetaxel when retrospectively evaluating tumor volume according to the CHAARTED definition. Notably, 95% of patients in the STAMPEDE-M1 cohort had synchronous disease, which may indicate the presence of aggressive disease biology⁽¹⁵⁾. The latter differs clearly from the samples of CHAARTED and GETUG-15 trials, which had different rates of patients with metachronous disease and low-vo­lume disease (aproximately 17%). A later meta-analysis, which followed GETUG-AFU15, CHAARTED and STAMPEDE by the STOPCAP group, demonstrated a benefit on overall survival through the addition of docetaxel to ADT, with an extensive effect in the synchronous group with high-volume disease. A modest effect was observed in the metachronous subgroup, with high-volume disease, and synchronous subgroup, with low-volume disease. There was no effect in the metachronous disease, low-volume, which is associated with a more favorable outcome. Also, it is noteworthy to mention the fact that not all patients are eligible for docetaxel, usually due to comorbidities. Radiotherapy of the prostate has also been beneficial for overall survival, with a more favorable safety profile compared to docetaxel for men with mHSPC with synchronous and low-volume disease⁽¹⁶⁾.

Triple therapy in metastatic hormone-sensitive prostate cancer

Two randomized controlled trials have recently revealed a global benefit on survival rate with triple therapy (next-generation androgen receptor-targeted agents [ARTA] + docetaxel + ADT) compared to double therapy (docetaxel + ADT) in metastatic hormone-sensitive prostate cancer, which led to novel treatment options. In our previous systematic review and network meta-analysis regarding the role of triple therapy versus double therapy, the studies focused on ARTA + ADT, as this is the standard treatment based on the current guidelines. Based on the aforementioned findings, ADT alone is not a viable treatment option anymore for mHSPC. Similar considerations apply to double therapy docetaxel + ADT⁽¹⁷⁾. For low-volume mHSPC, in comparison to ADT, the benefit of combo therapies, other than ARTA + ADT, was not substantial. For high-volume mHSPC, the association between darolutamide + docetaxel + ADT and the association between abiraterone + docetaxel + ADT showed a significant benefit on radiographic progression-free survival, as well as on median survival. In high-volume mHSPC, a significant improvement on overall survival (HR 0.76; CI 95%; 0.59-0.97) was highlighted only by the darolutamide + docetaxel + ADT association, compared to ARTA + ADT, reemphasizing the importance of triple therapy in high-volume mHSPC⁽¹⁸⁾. It is important to mention that PEACE-1 trial did not include a comparator arm of ARTA + ADT. PEACE-1 demonstrated a benefit in rPFS with triplet therapy for both high-burden and low-burden disease. However, the improvement in median overall survival was specifically pointed out in the high-burden population with synchronous metastatic disease⁽¹⁹⁾. Following PEACE-1 and ARASENS trials, a paramount prognostic subgroup is highlighted, namely the category of patients with synchronous disease since diagnosis^(19,20).

The ENZAMET trial enrolled a statistically undersized sample among patients benefiting from docetaxel. Thus, no statistical significance was attained. The study demonstrated a benefit in patients with high tumor volume, but no benefit in those with visceral metastases was shown. Therefore, in patients with visceral involvement, tumor cells may rely less on the androgen receptor signaling pathway and more on alternative signaling mechanisms⁽²¹⁾.

In addition, PEACE-1 trial included a molecular analysis of tumors based on the enrolled sample of patients; these tumors were analyzed through immunohistochemistry and through next-generation sequencing (NGS). Worth mentioning is that the molecular type did not impact rPFS and overall survival, and thus it was concluded that the molecular hierarchization does not contribute as a predictive factor, but only as a prognostic factor. The response to abiraterone added to the standard of care (SOC) remained constant in PEACE-1 study, regardless of the molecular subgroup. Molecular classification has an important role as a prognostic factor, so that patients with luminal tumors have a better outcome than the other subgroups, and patients with neuroendocrine differentiation have the worst prognosis. Another important finding revealed by the molecular analysis in the PEACE-1 study is that genetic alterations in tumor suppressor genes represent a highly unfavorable prognostic factor. The presence of inactive tumor suppressor genes (p53, PTEN, RB) is associated with increased disease aggressiveness and a more rapid progression toward castration-resistant prostate cancer⁽¹⁹⁾.

Currently, in mHSPC, especially in synchronous and high-volume disease scenarios, the chemotherapeutical guidance is suggested for the patients eligible for docetaxel, taking into consideration the fact that docetaxel should be added to the combination of ADT and a new next-generation androgen receptor-targeted agent (ARTA) for a rapid control of the disease, for a prolonged interval until disease progression, and for better survival⁽¹⁷⁾.

Systemic treatment in metastatic castration resistant prostate cancer (mCRPC)

The therapeutic landscape for mCRPC has expanded significantly with the approval of several agents demonstrating survival benefits in phase III trials. These include abiraterone, enzalutamide, docetaxel, cabazitaxel, sipuleucel-T, radium-223, 177Lu-PSMA-617 and olaparib⁽¹⁰⁾. Additionally, osteoclast inhibitors such as denosumab and zoledronic acid are routinely used to reduce skeletal-related events in patients with bone metastases⁽²²⁾.

Recent shifts in treatment sequencing – particularly the earlier use of ARSIs and docetaxel in mHSPC – have introduced new challenges in the mCRPC management. Triplet therapy (ADT + ARSI + docetaxel) has replaced the prior standard of ADT plus docetaxel, but this intensification raises concerns about cross-resistance. Sequential use of abiraterone and enzalutamide shows limited efficacy, whereas cabazitaxel remains effective in patients progressing after docetaxel and ARSI therapy⁽²³⁾.

Radioligand therapy with 177Lu-PSMA-617 offers a novel and effective option for patients with PSMA-positive mCRPC, showing promising results in terms of survival and disease control⁽²⁴⁾. Similarly, PARP inhibitors such as olaparib are beneficial in patients harboring homologous recombination repair gene mutations, including BRCA1 and BRCA2⁽²⁵⁾.

Chemotherapy in mCRPC

Chemotherapy remains a cornerstone of systemic therapy in metastatic castration-resistant prostate cancer, particularly in patients with aggressive disease bio­logy or progression following androgen receptor pathway inhibitor (ARPI) therapy. Taxane-based regimens are the foundation of chemotherapeutic management. Since 2004, docetaxel (DOC) has been approved by the FDA as first-line treatment for mCRPC, demonstrating a modest improvement in median overall survival by approximately 2-3 months. Despite this survival benefit, the objective response rate (ORR) was limited – only 12% of patients responded to DOC, compared to 7% in the mitoxantrone (MIT) arm⁽²⁶⁾.

Cabazitaxel (CAB), a next-generation taxane, was introduced as second-line therapy for patients progressing after docetaxel. In the phase III TROPIC trial, cabazitaxel prolonged the overall survivor by a similar margin (2-3 months) and achieved a higher response rate of 14.4% compared to MIT. Its efficacy in the post-docetaxel setting has positioned cabazitaxel as a preferred option in patients with ARPI-refractory disease⁽²⁶⁾.

Current treatment guidelines from ASCO, AUA, NCCN®, ESMO and EAU emphasize the importance of tailoring chemotherapy decisions to individual clinical and prognostic factors. The metastatic pattern is particularly relevant: hepatic metastases are associated with poorer outcomes and reduced efficacy of both ARPI and chemotherapy, whereas pulmonary metastases tend to confer a more favorable prognosis. In patients with liver involvement, microtubule inhibitors – docetaxel (if not previously administered) or cabazitaxel – are generally preferred due to their cytotoxic potency. Supporting this approach, a phase II study (NCT02254785) demonstrated that cabazitaxel yielded a higher clinical benefit rate than enzalutamide or abiraterone in poor-prognosis mCRPC patients, including those with liver metastases⁽²⁷⁾.

ARPI-based therapy in mCRPC

The androgen receptor (AR) axis plays a central role in the pathogenesis and progression of metastatic castration-resistant prostate cancer (mCRPC). As a result, targeting the AR pathway remains a foundational strategy in first-line systemic therapy. Androgen receptor signaling inhibitors (ARSIs) are key agents in this approach, either by directly antagonizing AR function or by inhibiting androgen biosynthesis to achieve maximal androgen blockade⁽²⁸⁾.

Abiraterone acetate is a selective inhibitor of cytochrome P450 17A1 (CYP17), a critical enzyme in androgen synthesis. When combined with prednisone (AAP), abiraterone has demonstrated clinical benefit in both pre- and post-docetaxel settings. Improvements have been observed after the initiation of cytotoxic therapy, regarding opioid use for cancer-related pain, PSA progression, performance status decline, progression-free survival (PFS) and overall survival. However, objective response rates remain modest: 6.6% in chemotherapy-naive patients and 14.8% in those previously treated with docetaxel⁽²⁹⁾.

Enzalutamide is a potent AR antagonist that inhibits multiple steps in the AR signaling cascade. Compared to first-generation agents such as bicalutamide, nilutamide and flutamide, enzalutamide exhibits higher AR affinity and broader efficacy. In a phase III, double-blind, placebo-controlled trial, enzalutamide improved the overall survival by approximately five months in mCRPC patients who had failed prior docetaxel therapy. The ORR reached 29%, while the quality-of-life response rate was 43%⁽³⁰⁾. Notably, cross-resistance between abiraterone and enzalutamide has been observed. Fewer than 10% of patients respond to abiraterone after enzalutamide, whereas enzalutamide following abiraterone yields response rates between 15% and 30%^(31,32).

Apalutamide is another next-generation AR inhibitor, binding to the receptor with fivefold greater affinity than bicalutamide. In mCRPC patients, clinical benefit was observed in 80% of AAP-naive individuals and in 43% of post-AAP patients who continued apalutamide for six months or longer. The ORR was 50% in the AAP-naive group, while no objective responses were reported in the post-AAP cohort⁽³³⁾.

Darolutamide, a structurally distinct AR antagonist, demonstrates superior potency and a favorable safety profile compared to enzalutamide and apalutamide. In early-phase ARADES trials, darolutamide achieved one complete response and two partial responses, yielding an ORR of 50% in mCRPC patients^(34-36).

PARP inhibitors in mCRPC

Homologous recombination repair (HRR) gene mutations are present in approximately 20-30% of metastatic prostate cancers, with BRCA2 being the most frequently altered. These defects create vulnerabilities that can be exploited by poly (ADP-ribose) polymerase (PARP) inhibitors through synthetic lethality⁽³⁷⁾.

The phase III PROfound trial compared olaparib (300 mg BID) with enzalutamide or abiraterone in mCRPC patients harboring HRR mutations and progressing after prior ARPI therapy. In patients with BRCA1/2 or ATM mutations, olaparib significantly improved radiographic progression-free survival (rPFS) and overall survival, with median OS reaching 19.1 months versus 14.7 months in the control arm. Olaparib also delayed disease progression and preserved the quality of life, with an acceptable safety profile⁽³⁸⁾.

Genetic testing – germline or somatic – is essential to identify HRR mutations and guide PARP inhibitor use. Currently, olaparib and rucaparib are approved as monotherapy for mCRPC with HRR deficiency. Olaparib is indicated after ARPI therapy, either before or after doce­taxel, while rucaparib is approved for BRCA-mutated mCRPC following both ARPI and taxane chemotherapy. In the TRITON-3 trial, rucaparib showed superior rPFS compared to docetaxel in BRCA-mutated patients (11.2 versus 6.4 months; p<0.001), supporting its use before or after chemotherapy⁽³⁹⁾.

In the phase III TALAPRO-2 study (NCT03395197), the combination of talazoparib and enzalutamide significantly improved radiographic progression-free survival compared to enzalutamide plus placebo across the entire study population, including both HRR mutation carriers and non-carriers. However, overall survival data remain immature in this trial⁽⁴⁰⁾. In contrast, the phase III MAGNITUDE study (NCT03748641) demonstrated a significant rPFS benefit in the HRR-mutated (HRRm) cohort treated with niraparib plus abiraterone versus placebo plus abiraterone as first-line therapy for mCRPC (median: 16.5 versus 13.7 months; HR 0.70; 95% CI; 0.56-0.96; p=0.022). No benefit was observed in the non-HRRm cohort (HR 1.09; 95% CI; 0.75-1.57; p=0.66). Final overall survival analysis in patients with BRCA-mutated mCRPC showed improved survival with niraparib plus abiraterone (HR 0.66; 95% CI; 0.46-0.95; p=0.02)⁽⁴¹⁾. In the phase III PROpel study (NCT03732820), first-line treatment with abiraterone plus olaparib led to improved PFS compared to abiraterone plus placebo (median: 24.8 versus 16.6 months; HR 0.66; 95% CI; 0.54-0.81), regardless of HRR mutation status. A post hoc exploratory analysis revealed that the rPFS benefit of olaparib plus abiraterone was most pronounced in HRRm subgroups (HR 0.50; 95% CI; 0.34-0.73) and especially in BRCA-mutated subgroups (HR 0.23; 95% CI; 0.12-0.43), sparking considerable debate. Final OS analysis from PROpel showed a trend toward improved survival, with a median overall survival of 42.1 months in the abiraterone plus olaparib group versus 34.7 months in the abiraterone plus placebo group (HR 0.81; 95% CI; 0.67-1; p=0.05)⁽⁴²⁾.

Regulatory approvals differ by region. In the U.S., olaparib or niraparib combined with abiraterone are approved for BRCA-mutated mCRPC, while talazoparib plus enzalutamide are approved for selected HRR mutations (including BRCA1, BRCA2, MLH1, MRE11A, NBN, PALB2 and RAD51C)⁽⁴³⁾. EMA indications are broader, allowing use in patients for whom chemotherapy is not clinically indicated, regardless of HRR status. When selecting therapy, clinicians must consider mutation type, toxicity profiles, maturity of survival data (PROpel being the only trial with overall survival benefit), and patient access. Notably, patients with ARPI-resistant mCRPC were not included in PROpel, MAGNITUDE or TALAPRO-2, leaving uncertainty about efficacy in this subgroup^(40-42).

Metastasis-directed therapy in oligoprogressive mCRPC

In select patients with oligoprogression during systemic therapy, metastasis-directed approaches such as stereotactic body radiotherapy (SBRT) may offer clinical benefit. The phase II ARTO trial demonstrated that adding SBRT to abiraterone significantly improved PSA response and progression-free survival (PFS), with a 65% reduction in risk of progression or death (HR 0.35; p<0.001)⁽⁴⁴⁾. Similarly, the TRAP study reported a median PFS of 6.4 months (95% CI; 5.9-12.8) in oligoprogressive mCRPC patients treated with SBRT, with over 40% remaining progression-free at 12 months and no significant impact on quality of life. Retrospective analyses further support the use of local therapy to delay systemic treatment escalation in patients with limited metastatic burden⁽⁴⁵⁾.

Radiopharmaceuticals in mCRPC

Radiopharmaceuticals have become an integral part of the treatment landscape for metastatic castration-resistant prostate cancer (mCRPC), particularly in patients with bone-predominant disease. Radium-223 dichloride, an alpha-emitting agent, selectively targets areas of increased bone turnover, being indicated for patients with symptomatic bone metastases without visceral involvement. However, its combination with abiraterone has been associated with increased fracture risk unless bone-protective agents such as denosumab or zoledronic acid are used concurrently⁽⁴⁶⁾.

Radioligand therapy has emerged as a promising treatment modality in later lines of care. Most mCRPC tumors exhibit high prostate-specific membrane antigen (PSMA) expression, making them suitable targets for PSMA-directed therapies. 177Lu-PSMA-617 delivers beta-particle radiation directly to PSMA-positive cells and their surrounding microenvironment. In the randomized phase II TheraP trial, patients with mCRPC who had progressed after docetaxel were randomized to receive either cabazitaxel or 177Lu-PSMA-617. A ≥50% reduction in PSA levels was achieved in 66% of patients treated with 177Lu-PSMA-617 versus 37% in the cabazitaxel group. Moreover, grade 3-4 adverse events were less frequent in the radioligand arm (33% versus 53%), suggesting a more favorable safety profile⁽⁴⁷⁾.

Further evidence was provided by the phase III VISION trial, which enrolled men with PSMA-positive mCRPC previously treated with at least one AR pathway inhibitor and one or two taxane regimens. Patients were randomized to receive either up to six cycles of 177Lu-PSMA-617 (vipivotide tetraxetan) plus standard of care (SoC), or SoC alone. Treatment with 177Lu-PSMA-617 resulted in a median overall survival of 15.3 months versus 11.3 months in the control arm, corresponding to a 38% reduction in risk of death (HR 0.62; 95% CI; 0.52-1; p<0.07). Radiographic progression-free survival (rPFS) was extended by 5.3 months (8.7 versus 3.4 months), with a 60% reduction in risk of progression (HR 0.40; 99.2% CI; 0.29-0.57; p<0.001). Additionally, time to first symptomatic skeletal event (SSE) or death was prolonged by 4.7 months, with a 50% reduction in risk (HR 0.50; 95% CI; 0.40-0.62; p<0.001)⁽⁴⁸⁾.

These findings have positioned radioligand therapy as a viable and increasingly earlier option in the treatment sequence for mCRPC, particularly in patients with PSMA-positive disease and prior exposure to ARPIs and taxanes^(47,48).

Immunotherapy and biomarker-driven treatment in mCRPC

Although immunotherapy has historically played a limited role in prostate cancer, emerging biomarker-driven strategies have introduced new therapeutic opportunities in metastatic castration-resistant prostate cancer (mCRPC). Among these, microsatellite instability (MSI) and mismatch repair deficiency (dMMR) are key genomic alterations that warrant evaluation. While MSI-high (MSI-H) and dMMR are relatively rare in prostate cancer – occurring in fewer than 9% of cases –, their presence carries significant therapeutic implications⁽⁴⁹⁾.

Sipuleucel-T, an autologous cellular immunotherapy, remains an option for asymptomatic or minimally symptomatic patients without visceral metastases, offering modest survival benefit in select cases⁽⁵⁰⁾.

Pembrolizumab, a monoclonal antibody targeting the programmed death-1 (PD-1) receptor, has received the FDA approval for the treatment of advanced solid tumors, including prostate cancer, that exhibit MSI-H, dMMR or high tumor mutational burden (TMB-H ≥10 mutations per megabase)⁽⁴⁹⁾.

In mCRPC patients with these biomarkers, pembrolizumab may be considered as a treatment option prior to initiating chemotherapy with docetaxel, typically following progression on an androgen receptor pathway inhibitor (ARPI). This sequencing reflects the potential for durable responses in biomarker-selected populations, despite the overall immunologically “cold” nature of prostate cancer⁽⁴⁹⁾.

Dostarlimab, another anti-PD-1 monoclonal antibody, is also FDA-approved for dMMR tumors in a histology-agnostic context. However, clinical data specific to prostate cancer remain limited, and its role in mCRPC is still under investigation. As genomic profiling becomes more integrated into routine practice, identifying patients with actionable biomarkers such as MSI-H, dMMR or TMB-H will be essential for optimizing treatment selection and for expanding the use of immunotherapy in this traditionally resistant disease⁽⁴⁹⁾.

A major ongoing challenge in the management of mCRPC is the absence of a unified treatment sequencing strategy, driven in part by cross-resistance within the androgen receptor signaling pathway. The therapeutic landscape continues to evolve with the approval of novel agents and intensification strategies, offering new opportunities but also increasing complexity. To optimize outcomes, enhanced patient profiling – incorporating genomic, molecular and clinical predictive and prognostic factors – is essential for guiding the sequential use of available therapies and for personalizing treatment decisions.  

Corresponding author: Andreea Lăzescu E-mail: andreea.lazescu@gmail.com

Conflict of interest: none declared.

Financial support: none declared.

This work is permanently accessible online free of charge and published under the CC-BY licence.