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Evolving Treatment Strategies in Metastatic Castration-Resistant Prostate Cancer

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Released: September 01, 2026

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In this commentary, expert faculty reviews the evolving treatment landscape for metastatic castration-resistant prostate cancer (mCRPC), with emphasis on biomarker-driven therapy, combination strategies, radiopharmaceuticals, and emerging approaches for overcoming resistance. The faculty also examines real-world gaps in germline and somatic testing; phase III data supporting PARP inhibitor/ARPI combinations, PSMA-targeted radioligand therapy, and radium-223 plus enzalutamide; and the role of PTEN-directed AKT inhibition in advanced prostate cancer. Investigational approaches targeting EZH2, CYP11A1, mutant or persistent androgen receptor signaling, and tumor-associated cell-surface targets are also highlighted. Together, these data underscore the importance of early comprehensive biomarker testing, appropriate sequencing of established therapies, toxicity and supportive care considerations, and clinical trial participation when standard options are limited.

Neal D. Shore
Neal D. Shore, MD, FACS
Evolving Treatments in mCRPC

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Key Takeaways
  • Real-world data suggest that HRR testing is inconsistent, with only 59.2% of newly diagnosed, actively treated patients with mCRPC across 500 US sites having been tested.
  • For patients with bone-predominant mCRPC without visceral metastases treated with radium-223 plus enzalutamide, bone-protecting therapy with zoledronic acid or denosumab should be considered and discussed through shared decision-making, given the evidence for reducing fracture risk.
  • Capivasertib with abiraterone and prednisone is now FDA approved for patients with PTEN-deficient metastatic androgen pathway modulation-naive or -sensitive prostate cancer as determined with an approved companion assay.

The treatment landscape for advanced prostate cancer is becoming increasingly complex. For many years, treatment of metastatic castration-resistant prostate cancer (mCRPC), recently reframed by the Prostate Cancer Working Group 4 as androgen pathway modulation–resistant (APMR) disease, largely involved sequential use of androgen receptor (AR)–directed therapy, chemotherapy, and selected radiopharmaceuticals. That framework is expanding to a broader model built around combination therapy, biomarker-based treatment selection, and therapies directed against targets beyond conventional AR signaling.

PARP inhibitors can now be paired with androgen receptor pathway inhibitors (ARPIs) in molecularly selected patients; PSMA-targeted radioligand therapy has moved earlier in the treatment sequence; and radium-223 can be combined with AR-directed therapy in selected patients with bone-metastatic disease. Inhibition of the PI3K/AKT pathway has created a new treatment option for PTEN-deficient disease. At the same time, a growing group of investigational therapies is being evaluated to overcome persistent AR dependence or to bypass the AR pathway altogether.

Biomarker Testing as the Entry Point
Although biomarker testing is increasingly important to treatment selection, real-world data suggest that testing is inconsistent. In a chart review of 996 patients with newly diagnosed, actively treated mCRPC across 500 US sites, only 59.2% underwent homologous recombination repair (HRR) testing. Among those who were tested, testing often occurred late, with 64% evaluated only after mCRPC treatment had already begun. Of the 187 patients found to have an HRR alteration, approximately one third did not receive a PARP inhibitor. Care was delivered predominantly in the community, more often by oncologists (93%) than urologists (6%) or academic centers (1%), which makes the findings particularly relevant to routine practice. They also illustrate a growing mismatch between the availability of targeted treatments and how often patients are characterized well enough to identify those available options.

HRR testing is only one part of the picture. Germline findings such as BRCA2 may have implications for relatives and for treatment selection, and somatic testing can identify actionable tumor alterations. PTEN immunohistochemistry (IHC), ideally assessed early in the metastatic course, can identify patients who may be eligible for capivasertib-based therapy. HER2 IHC testing may identify rare patients with HER2-positive (IHC 3+) tumors who could be eligible for the tumor-agnostic trastuzumab deruxtecan indication. As the number of biomarker-defined options expands, molecular and target-based characterization is becoming an increasingly important component of treatment planning across the advanced prostate cancer continuum.

PARP Inhibitor Plus ARPI Combinations
The PROpel, TALAPRO-2, and MAGNITUDE clinical trials established the activity of combining PARP inhibition with AR pathway blockade in mCRPC, and also showed that the magnitude of benefit varies by tumor biology. In the HRR-unselected, all-comers population of TALAPRO-2, adding talazoparib to enzalutamide in first-line mCRPC extended median overall survival (OS) to 45.8 months vs 37.0 months (HR: 0.80). Across these trials, the largest and most consistent benefit has been seen in patients with HRR alterations, particularly BRCA1/2 alterations and especially BRCA2.

These trials led to FDA approvals of olaparib plus abiraterone for BRCA-mutated mCRPC, talazoparib plus enzalutamide for HRR gene–mutated mCRPC, and niraparib plus abiraterone for BRCA-mutated mCRPC.  In December 2025, the niraparib and abiraterone combination was also approved for BRCA2-mutated metastatic castration-sensitive disease based on the AMPLITUDE trial, in which adding niraparib reduced the risk of radiographic progression or death by approximately half in BRCA2-mutated patients (HR: 0.46), extending PARP-based combinations into the hormone-sensitive setting. The phase III TALAPRO-3 trial has since shown that talazoparib plus enzalutamide significantly improves radiographic progression-free survival (PFS) in HRR-altered metastatic castration-sensitive disease. That combination is under FDA priority review, with a decision expected in late 2026.

The clinical significance is therefore less about identifying a universal PARP-based doublet than about matching the regimen to the appropriate disease setting. The potential for added toxicity with these PARP inhibitor combination regimens, including myelosuppression and gastrointestinal effects, also remains part of that balance. In patients without HRR alterations, the incremental benefit is generally less compelling, which further reinforces the importance of molecular selection.

PSMA-Targeted Radioligand Therapy and Actinium
PSMA-directed therapy represents a different form of precision treatment, one based on cell-surface expression rather than a genomic alteration. The VISION trial established 177Lu-PSMA-617 as a survival-prolonging option for PSMA-positive mCRPC after prior ARPI and taxane therapy, improving median OS to 15.3 months vs 11.3 months (HR: 0.62). The PSMAfore trial subsequently showed that treatment could be moved earlier in the disease course, improving radiographic PFS compared with a switch to another ARPI in taxane-naive patients whose disease had progressed on an ARPI. Those data supported the 2025 expansion of the FDA indication of 177Lu-PSMA-617 to patients previously treated with an ARPI who are considered appropriate to delay taxane chemotherapy. More recently, in July 2026, the FDA approved ¹⁷⁷Lu-PSMA-617 in combination with an ARPI for PSMA-positive metastatic hormone-sensitive prostate cancer based on the PSMAddition trial.

The movement of radioligand therapy earlier in mCRPC has broadened the role of PSMA-targeted treatment and raised new questions about sequencing. These decisions are best navigated through shared decision-making and a multidisciplinary team spanning medical oncology, urology, radiation oncology, and nuclear medicine. It has also increased interest in alpha-emitting radiopharmaceuticals. Actinium-225–based radioligands targeting PSMA and ACP3 (acid phosphatase 3/prostatic acid phosphatase) are also being investigated in patients with mCRPC.

Radium-223 and Bone-Metastatic Disease
Radium-223 remains another important alpha-emitting radiopharmaceutical, particularly in bone-predominant mCRPC. The PEACE-3 trial evaluated radium-223 plus enzalutamide in patients with bone-metastatic mCRPC without visceral disease and demonstrated improvements in radiographic PFS and, at the final analysis, OS, which reached a median of 38.2 months vs 32.6 months (HR: 0.76), compared with enzalutamide alone.

The trial also reinforced the importance of bone protection. After fracture concerns emerged from ERA-223, use of a bone-protective agent such as denosumab or zoledronic acid became mandatory during PEACE-3 enrollment, and fracture rates fell substantially, from 53.6% to 17.9% in the combination arm and from 20.3% to 12.1% with enzalutamide alone. These phase III results support consideration of radium-223 plus enzalutamide in appropriately selected patients with bone-metastatic mCRPC and no visceral disease, while also illustrating the importance of bone-protecting therapy. Because PEACE-3 enrolled patients from androgen deprivation therapy alone, a practical real-world question is how to sequence for patients who progress on an ARPI doublet, a decision that also depends on regional drug accessibility.

Targeting the PI3K/AKT Pathway
PTEN loss provides another example of how biomarker selection is changing prostate cancer treatment. PTEN deficiency, present in roughly 1 in 4 patients, activates the PI3K/AKT pathway and is associated with more aggressive disease biology. CAPItello-281 evaluated the AKT inhibitor capivasertib added to abiraterone and androgen deprivation therapy in patients with PTEN-deficient metastatic hormone-sensitive prostate cancer and demonstrated a significant improvement in radiographic PFS, extending the median to 33.2 months vs 25.7 months (HR: 0.81).

In June 2026, the FDA approved capivasertib with abiraterone and prednisone for patients with PTEN-deficient metastatic androgen pathway modulation–naive or –sensitive prostate cancer as determined with an approved companion PTEN IHC assay. Although this development occurred outside the castration-resistant setting, it illustrates how biomarker-directed combination therapy is moving earlier in disease and further diversifying the treatment landscape, where multiple approved doublets and triplets now make biomarker- and setting-based selection increasingly important. Of note, diarrhea, hyperglycemia, and rash are key toxicities associated with AKT inhibition. They are important to be aware of and will need to be well managed to help patients remain on therapy.

Emerging Therapy Beyond Conventional AR Blockade
Despite the expanding role of radiopharmaceuticals, PARP inhibitors, and other targeted combinations, many cases of mCRPC remain biologically dependent on AR signaling after progression on an ARPI. Several investigational strategies are attempting to exploit that dependence in different ways.

Mevrometostat inhibits EZH2, an epigenetic regulator implicated in prostate cancer progression and lineage plasticity. In early randomized data, biomarker-unselected patients with mCRPC previously treated with abiraterone, mevrometostat plus enzalutamide extended median radiographic PFS to 14.3 months vs 6.2 months (HR: 0.51) with enzalutamide alone. The combination has advanced to phase III development (MEVPRO-1 and MEVPRO-2), one of several EZH2-directed programs now in prostate cancer development. Opevesostat, a CYP11A1 inhibitor, suppresses steroidogenesis upstream of CYP17A1. In the phase II CYPIDES study in heavily pretreated mCRPC, PSA50 responses were more frequent in patients with AR ligand-binding domain (AR-LBD) mutations than in those with AR-LBD wild-type disease (53.0% vs 14.7%, respectively). These approaches illustrate how resistant disease may remain AR driven even when conventional AR blockade is no longer effective.

AR degradation represents another strategy. BMS-986365 was designed both to degrade the AR and antagonize residual receptor activity, and promising activity in an early-phase trial led to evaluation in the phase III rechARge study. However, recently it was reported online that an analysis of the dose-finding portion of the rechARge study suggested it was unlikely to meet its efficacy endpoint; these data have yet to be reported. A separate AR ligand-directed degrader, BMS-986460, remains under evaluation in a recruiting phase I trial in mCRPC. Another oral AR degrader, luxdegalutamide (ARV-766), has shown early prostate-specific antigen responses in patients with AR-LBD mutations.

Beyond AR-dependent mechanisms, the field is also exploring therapies directed against cell-surface and immune targets. STEAP1- and DLL3-directed T-cell engagers, CAR T-cell approaches, and strategies targeting B7-H3 and TROP2 through antibody–drug conjugates, radioligands, or other platforms all represent efforts to attack prostate cancer through mechanisms that are less dependent on androgen signaling. These approaches remain investigational, but they broaden the therapeutic horizon considerably.

A More Individualized Treatment Landscape
The most important change in advanced prostate cancer may therefore be the transition away from a largely linear sequence of therapies. Treatment is increasingly shaped by HRR status, PTEN expression, PSMA expression, site of disease, prior treatment, and emerging resistance biology. Combination regimens and targeted therapies are creating more opportunities, but they also make patient selection more consequential.

The real-world HRR testing data show that this transformation is not simply a question of drug availability. The ability to identify the relevant biomarker can determine whether a targeted treatment ever becomes an option. As therapies directed at DNA repair defects, PSMA, PI3K/AKT signaling, persistent AR biology, and new cell-surface targets continue to evolve, biomarker characterization is becoming one of the central organizing features of advanced prostate cancer care.

Your Thoughts
In your own practice, what are your biggest accessibility and implementation challenges to ensuring that patients with metastatic prostate cancer are being adequately tested for actionable biomarkers? What questions related to the topics discussed in this commentary would you like to ask the experts?

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In your current practice, at what point do you order germline and somatic HRR testing for patients with mCRPC?

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