A New Therapeutic Era in Metastatic Castration-Resistant Prostate Cancer

Prostate cancer is the most common cancer diagnosed in men in the US, with more than 84,000 new cases estimated for 2026. Advancements in treatment options have greatly improved survival outcomes; for patients with localized prostate cancer, the 5-year survival rate is more than 90%.¹

However, prognoses worsen significantly for individuals with aggressive, advanced types of prostate cancer, such as metastatic castration-resistant prostate cancer (mCRPC). Approximately 10% to 20% of patients will develop mCRPC within 5 years of their initial diagnosis.¹ mCRPC is resistant to hormone therapies—the frontline treatment many patients receive—leaving many without adequate treatment options. The 5-year survival rate for mCRPC is approximately 38%, underscoring the critical need for more effective therapeutic options.²

Treatment of Prostate Cancer Across Time

In the 1990s, the introduction of biomarker-driven assessments, namely prostate-specific antigen (PSA) testing, led to a notable shift in earlier diagnosis. The use of PSA as a prognostic biomarker enabled earlier disease detection than conventional imaging tools such as CT or bone scans, leading to a 25% 8-year survival rate. PSA testing proved to be a key determinant of patient prognosis, with levels below 0.5 associated with better outcomes.³

Then came the mid-2000s—the era of docetaxel in hormone-sensitive settings. Patients experienced a clear benefit, with 8-year overall survival (OS) improving to approximately 35%, establishing that intensifying therapy earlier in the disease course could meaningfully extend survival. A decade later, the addition of androgen receptor pathway inhibitors (ARPIs) such as enzalutamide (Xtandi; Astellas Pharma US, Inc) or abiraterone acetate (Zytiga; Centocor Ortho Biotech Inc) in this setting raised 8-year OS rates to roughly 50%.³

These long-term survival gains appear closely linked to depth of response, as achieving a PSA level less than 0.2 is strongly associated with an approximate OS rate of 50%. Treatment intensification—by adding docetaxel or ARPIs—increases the proportion of patients who reach this favorable PSA threshold, helping to explain the observed improvements in long-term outcomes.³

“It’s now a much longer game—we’ve got patients alive beyond 10 years,” Christopher Sweeney, MBBS, a medical oncologist and director of the South Australian Immunogenomics Cancer Institute at Adelaide University in Australia, explained during a 2026 American Society of Clinical Oncology Genitourinary Cancers Symposium presentation.³ “Some of our treatments in hormone-sensitive [settings are associated] with long-term toxicities, and it is a real problem that we need to consider.”

Fast-forward another 10 years, and the standard of care for nearly all men with metastatic, hormone-sensitive disease is androgen deprivation therapy (ADT) plus an ARPI, unless contraindicated. Treatment is then tailored specifically by timing and volume of metastases (TABLE).³

“It’s somewhat simple: ADT plus ARPI for everyone,” Sweeney said.³ “Then work out whether your patient will benefit from additional therapy [docetaxel, radiation/stereotactic body radiotherapy] based on volume and timing of metastases.”

The Expanding ABCs of mCRPC Treatment

As the number and complexity of cancer therapies evolve, treatment has shifted from one-size-fits-all; modern care must integrate prior therapies, molecular profiling, imaging-defined resistance mechanisms, and toxicity considerations as well as clinical context and patient preferences. Although still evolving, the current pillars—or ABCs—of mCRPC treatment include ARPIs, biomarker-driven and bone-targeted therapies, chemotherapy, and an expanding fourth category of targeted approaches.³

“So it’s already complicated, and it’s about to get more complicated because now we have ABC plus D: druggable pathways,” explained Dana E. Rathkopf, MD, a genitourinary medical oncologist at Memorial Sloan Kettering Cancer Center in New York, New York, during the presentation.³

This next phase of therapeutic innovation reflects a shift away from single-mechanism sequencing toward biologically informed combinations and novel targets, with emerging strategies aimed at overcoming resistance, deepening responses, and extending benefit across increasingly defined patient subgroups. These include the following³:

1. AR pathway agents
   1. Degraders
   2. CYP11A1 inhibitors
   3. Regulated induced proximity targeting chimeras
2. Cell surface proteins
   1. T-cell engagers (TCEs)
   2. Antibody-drug conjugates (ADCs)
   3. Radioligand therapies
   4. Chimeric antigen receptor T-cell therapies
3. Homologous recombination repair
   1. PARP1-selective inhibitors

Together, these advances underscore how mCRPC management is moving beyond linear treatment algorithms toward a multidimensional framework—one that increasingly relies on molecular context, disease biology, and patient-specific factors to guide therapeutic decision-making.³

ADCs and B7-H3

B7-H3, a cell surface glycoprotein, represents a promising target in the treatment of mCRPC. When overexpressed, B7-H3 induces an immunosuppressive tumor microenvironment and promotes tumor growth. Research also reports it increases tumor survival, stemness, resistance to chemotherapy, and metastases through modulation of pathways such as JAK2/STAT3, MEK, and PI3K/AKT.^3,4

Ifinatamab deruxtecan (I-DXd; Merck) is a B7-H3–targeting ADC being evaluated in the phase 1B/2 pan-tumor, open-label IDeate-PanTumor02 trial (NCT06330064)⁵ in patients with recurrent or metastatic solid tumors who received 1 or more systemic therapies for the selected tumor indication. All patients across cancer types will receive I-DXd at a dosage of 12 mg/kg intravenously.³

Early data show promising results, with an overall response rate—the trial’s primary end point—of approximately 25% in patients with mCRPC and approximately 33% in the heavily pretreated population of patients with liver metastases.³

The most common adverse event (AE) was nausea, which is now routinely pretreated with antiemetics. Anemia was the most common grade 5 or higher treatment-emergent AE and likely related to off-tumor effects.³

TCEs

Prostate cancer has historically been considered an “immunologically cold” tumor (ie, does not trigger a strong immune response), characterized by limited baseline immune infiltration and poor responsiveness to conventional immunotherapy approaches. TCEs represent a strategy to overcome these limitations by directly recruiting and activating T cells within the tumor microenvironment. These agents simultaneously bind a tumor-associated antigen and CD3 on T cells, physically bringing T cells into close proximity with tumor cells, promoting immune synapse formation and amplification of T-cell–mediated cytotoxicity.³

STEAP1

STEAP1 is another overexpressed cell surface protein that drives progression in patients with prostate cancer, with the highest prevalence seen in mCRPC. Due to limited expression in normal tissues, STEAP1 is a promising target for a treatment with reduced off-tumor effects.³

Xaluritamig (Amgen) is a STEAP1-targeting TCE that was evaluated in a phase 1 expansion cohort (NCT07140900)⁶ involving step-up dosing to 1.5 mg administered intravenously every 2 weeks. In a heavily pretreated mCRPC population, the agent demonstrated encouraging activity, with a PSA decline of at least 50% (PSA50) observed in approximately 53% of patients and a PSA90 response in 34%. The objective response rate was 28%. Cytokine release syndrome (CRS) occurred predominantly during the first treatment cycle and became more manageable with clinical experience and step-up dosing; musculoskeletal toxicity ultimately influenced dose selection.³

KLK2

A second TCE approach targets KLK2, selected for its prostate epithelium expression, high homology/coexpression with PSA, and regulation by AR signaling.³

In a phase 1 study (NCT04898634),⁷ pasritamig (Johnson & Johnson), an investigational KLK2-targeting TCE, demonstrated a favorable safety profile, with very low rates of CRS limited to grade 1 events. The phase 1 dose was 300 mg administered intravenously every 6 weeks, using a short step-up strategy. In a heavily pretreated population—many of whom had received prior taxane chemotherapy and radioligand therapy—the median radiographic progression-free survival (PFS) was approximately 7.9 months and PSA50 responses were observed in roughly 42% of patients.³

Notably, the extended dosing interval may have mechanistic implications, potentially allowing longer dosing intervals to reduce T-cell exhaustion and activation-induced cell death, thereby preserving more durable antitumor immune responses.³

EZH2 Inhibitors

EZH2 is a member of the Polycomb-group family that promotes progression in mCRPC by remodeling chromatin, enhancing AR activity, and supporting neuroendocrine transformation. Mevrometostat (Pfizer Oncology) is an investigational EZH2 inhibitor that encourages tumor suppression and reduces AR signaling. Early research data suggest it may revert cells from a neuroendocrine‑like phenotype back toward an AR‑sensitive phenotype.³

Mevrometostat is being evaluated in combination with enzalutamide in a phase 1 study (NCT03460977) comparing the combination regimen with enzalutamide monotherapy in patients with mCRPC.⁸ Based on the open-label, randomized, dose-expansion part of this study, the combination demonstrated encouraging clinical activity, with a median radiographic PFS of approximately 14.3 months. Biochemical responses were also observed, with PSA50 responses achieved in 34.1% of patients and an objective response rate of 26.7%.³

Dose optimization played an important role in improving tolerability. The initial dosing regimen of mevrometostat (1250 mg twice daily under fasting conditions) was associated with increased gastrointestinal toxicity. An optimized regimen of 875 mg twice daily administered with food maintained similar efficacy while offering a more favorable tolerability profile.³

AR Degraders

BMS-986365 (Bristol Myers Squibb) represents a next-generation AR-targeting strategy that combines receptor antagonism with targeted protein degradation. The agent binds the AR as a potent antagonist while also engaging cereblon, functioning in a proteolysis-targeting chimera–like manner to promote AR degradation.³

In phase 1 evaluation (NCT04428788),⁹ the safety profile for BMS-986365 was notable for correct QT interval (QTc) prolongation as the most frequently observed AE. QTc prolongation occurred in 47% of patients at any grade and in 9% at grade 3; however, all events were asymptomatic. These events were manageable with dose modifications, and no treatment discontinuations were attributed to treatment-related AEs.³

Clinical activity was observed across molecular subgroups, with responses documented in both ligand-binding domain (LBD) wild-type and LBD-mutant tumors. In a post hoc analysis, patients treated in the prechemotherapy setting achieved a median radiographic PFS of 16.5 months.³

Opevesostat (Merck) is an AR degrader-adjacent agent that targets steroidogenesis upstream of CYP17, the enzymatic target of abiraterone, by inhibiting CYP11A1. Unlike other AR degraders, opevesostat shuts down the production of ligands that drive the AR receptor, rather than degrading the protein itself. This mechanism blocks the production of all adrenal steroid hormones and their precursors, potentially suppressing signaling driven by a broad range of AR ligand-binding domain mutations and alternative ligands.³

Early development was characterized by marked adrenal suppression at higher initial doses. Subsequent optimization strategies included dose titration and the addition of dexamethasone and fludrocortisone for hormonal replacement. In phase 2 expansion cohorts of the CYPIDES trial (NCT03436485),¹⁰ the incidence of serious adrenal insufficiency–related AEs was approximately 3%, and these events were generally well managed with supportive care.³

Encouraging efficacy signals were observed, including PSA responses and tumor shrinkage in both LBD-mutant and LBD wild-type disease. Although activity appeared greater in LBD-mutant tumors, meaningful responses were seen across both molecular subgroups. Ongoing phase 3 studies are expected to clarify the extent of differential benefit based on AR mutation status.³

Advancing mCRPC Care

Collectively, these emerging approaches highlight how the treatment landscape for mCRPC is rapidly shifting from incremental advances within established classes to a broader, more nuanced therapeutic ecosystem. As these novel agents move closer to clinical practice, the challenge will be determining the best way to sequence, combine, and individualize them across the disease continuum.

“The key takeaway points for today are that there are many, all caps, MANY promising new therapeutic targets and drug classes in late-stage development for mCRPC,” said Rathkopf.³ “This means that treatment selection will increasingly require integration of prior therapies, molecular profiling, and imaging characterization of resistance mechanisms, toxicity, and clinical context. Future directions are already here with combination strategies using these drugs earlier in the disease states, models, and refinement of therapeutic delivery and sequencing.”

REFERENCES

1. Prostate cancer—patient version. National Cancer Institute. Accessed February 26, 2026. https://www.cancer.gov/types/prostate

2. Metastatic castration-resistant prostate cancer (mCRPC). Mayo Clinic. December 24, 2025. Accessed February 27, 2026. https://www.mayoclinic.org/diseases-conditions/metastatic-castration-resistant-prostate-cancer/survival-rates/gnc-20593193

3. Dorff T, Ong M, Sweeney C. Treatment selection, response assessment and monitoring access across the spectrum of advanced prostate cancer. Panel presented at: 2026 American Society of Clinical Oncology Genitourinary Cancers Symposium; February 26-28, 2026; San Francisco, CA.

4. Guo C, Figueiredo I, Gurel B, et al. B7-H3 as a therapeutic target in advanced prostate cancer. Eur Urol. 2023;83(3):224-238. doi:10.1016/j.eururo.2022.09.004

5. A study to evaluate the efficacy and safety of ifinatamab deruxtecan (I-DXd) in subjects with recurrent or metastatic solid tumors (IDeate-PanTumor02). ClinicalTrials.gov. Updated February 12, 2026. Accessed February 27, 2026. https://clinicaltrials.gov/study/NCT06330064#study-plan

6. Study evaluating the safety, tolerability, and efficacy of xaluritamig in combination with androgen receptor pathway inhibitors in participants with metastatic hormone-sensitive prostate cancer. ClinicalTrials.gov. Updated February 13, 2026. Accessed March 4, 2026. https://clinicaltrials.gov/study/NCT07140900

7. A study of JNJ-78278343, a T-cell-redirecting agent targeting human kallikrein 2 (KLK2), for advanced prostate cancer. ClinicalTrials.gov. Updated February 13, 2026. Accessed February 27, 2026. https://clinicaltrials.gov/study/NCT04898634

8. A study of mevrometostat for treatment of relapsed/​refractory SCLC, castration resistant prostate cancer, and follicular lymphoma. ClinicalTrials.gov. Updated February 3, 2026. Accessed February 27, 2026. https://clinicaltrials.gov/study/NCT03460977

9. Study to evaluate the safety and tolerability of CC-94676 in participants with metastatic castration-resistant prostate cancer. ClinicalTrials.gov. Updated December 22, 2025. Accessed March 4, 2026. https://clinicaltrials.gov/study/NCT06764485

10. Safety and pharmacokinetics of ODM-208 in patients with metastatic castration-resistant prostate cancer (CYPIDES). ClinicalTrials.gov. Updated July 22, 2025. Accessed February 27, 2026. https://clinicaltrials.gov/study/NCT03436485