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Advances in mCRPC Management: Recent Approvals, Emerging Therapies, and Future Directions: A Letter from UroToday's mCRPC Center of Excellence Editor-in-Chief, A. Oliver Sartor, MD

I am delighted to serve as the new editor for UroToday’s Center of Excellence on mCRPC Treatment. We provide a multimedia, data-driven hub for information on regulatory approvals, clinical trials, diagnostics, guidelines, investigational treatments, and other aspects of this rapidly evolving field. In this editorial, I cover recent therapeutic approvals in mCRPC, clinical trials, and investigational therapies.

Prostate cancer is the second leading cancer and the most common cause of cancer-related mortality in men, resulting in approximately 397,000 deaths globally in 2022.1 Metastatic castration-resistant prostate cancer (mCRPC) is the final and most aggressive stage of disease, and its prevalence is rising.2,3 Currently, median survival after diagnosis of mCRPC is just over 2 years.4,5 Progressive, symptomatic mCRPC greatly diminishes patients’ functioning and quality of life, and its management consumes significant healthcare resources, making thoughtful clinical decision-making imperative.

When treating mCRPC, clinicians should consider not only individual patient and tumor characteristics, but which treatment(s) patients received in the hormone-sensitive setting. This is particularly important because androgen receptor pathway inhibitors (ARPIs), previously reserved for treating mCRPC, are now routinely included in ADT intensification regimens for patients with metastatic hormone-sensitive prostate cancer (mHSPC).6-12 Due to some degree of cross-resistance among ARPIs, prior ARPI exposure has direct implications for mCRPC treatment selection.13-16 Furthermore, as more patients with advanced prostate cancer appropriately receive an ARPI and (in some cases) docetaxel prior to their mCRPC diagnosis, there is an urgent need for novel mCRPC therapies.

Recently approved therapies

Lutetium-177 vipivotide tetraxetan

177Lu-PSMA-617 (177Lu-vipivotide tetraxetan) is the first PSMA-targeted isotope for treating prostate cancer and represents a major addition to our treatment armamentarium. This beta emitter received FDA approval in March 2022 for treating patients with PSMA-PET positive mCRPC who have previously received both an ARPI and taxane-based chemotherapy.17 In the phase 3 VISION trial, patients with PSMA-positive mCRPC based on PSMA-positive 68Ga-labeled PSMA-11 PET/CT scans were randomly assigned to receive either 177Lu-PSMA-617 (7.4 GBq every 6 weeks for 4-6 cycles) plus best supportive care or best supportive care alone.18 After a median follow-up of 20.9 months, 177Lu-PSMA-617 extended progression-free survival (PFS) by a median of 5.3 months (hazard ratio, 0.40; 99% CI, 0.29 to 0.57) and improved median overall survival (OS) by a median of 4 months (HR, 0.62; 95% CI, 0.52-0.74). 177Lu-PSMA-617 also significantly improved key secondary outcomes including objective responses, disease control, and time to symptomatic skeletal events.

177Lu PSMA-617 also has been evaluated for treating mCRPC in taxane-naïve patients. At ESMO 2023, we reported results from the phase 3 PSMAfore trial, in which patients with PSMA-positive mCRPC who had not received a taxane chemotherapy were randomly assigned to receive 177Lu PSMA-617 after an ARPI (abiraterone acetate/prednisone or enzalutamide) or a switch of ARPI. After a median follow-up of 7.3 months, the primary endpoint of radiographic PFS (rPFS) was significantly longer in the 177Lu PSMA-617 arm.19 177Lu-PSMA-617 also significantly improved secondary and exploratory endpoints, including PSA response, objective response rate, time to symptomatic skeletal events, and time to worsening of pain and health-related quality of life. However, the interpretation of OS was confounded by an 84% rate of crossover from the ARPI switch arm to the 177Lu PSMA-617 arm. In a subsequent preplanned analysis with 75% of deaths accrued, clinical outcomes consistently favored 177Lu-PSMA-617 over a change from one ARPI another, regardless of which ARPI patients received first.20 Based on these data, an expanded label is being sought for 177Lu PSMA-617 that would include an indication for treating mCRPC in the pre-taxane setting.

PARPi-based combinations

Defects in DNA damage response and repair (DDR) genes, particularly the homologous recombination repair (HRR) gene BRCA2, are associated with increased risk of prostate cancer and with more aggressive disease.21 It is estimated that 25% to 30% of patients with mCRPC harbor germline or somatic HRR alterations.22 Certain DDR gene aberrations confer sensitivity to poly-(ADP ribose) polymerase (PARP) inhibition, making PARP inhibitors of considerable interest for treating advanced prostate cancer. The initial FDA approval was for rucaparib in patients with BRCA1 and BRCA2 mutations and the next FDA approval was for olaparib in patients with HRR mutations. Because preclinical data suggested the presence of synergy between androgen receptor inhibition and PARP inhibitors,23 additional studies were performed in patients without HRR alterations. In the randomized phase 3 PROPEL trial, the combination of olaparib plus abiraterone/prednisone significantly prolonged imaging-based PFS compared with abiraterone plus placebo as first-line therapy for patients with mCRPC, irrespective of HRR status.24 After a median follow-up of 36.6 months, olaparib plus abiraterone also was associated with a trend toward improved OS, although the difference did not reach statistical significance (median OS, 42.1 months with olaparib plus abiraterone vs. 34.7 months with placebo plus abiraterone; HR, 0.81, 95% CI, 0.67-1.00). Anemia was the most common grade 3-4 adverse event, with an incidence of 16% with olaparib plus abiraterone and 3% with abiraterone plus placebo. In May 2023, the FDA approved olaparib in combination with abiraterone and prednisone or prednisolone for the treatment of adults with deleterious or suspected deleterious BRCA-mutated mCRPC.25 Also of note, in the phase 2 BRCAAway trial of patients with mCRPC and BRCA1/2 alterations, the combination of olaparib plus abiraterone was well tolerated and resulted in significantly longer PFS compared with either agent given alone or sequentially.26

In June 2023, the FDA also approved the doublet of talazoparib plus enzalutamide for treating patients with HRR-mutated mCRPC.27 This approval was based on positive results from the randomized phase 3 TALAPRO-2 trial, in which talazoparib plus enzalutamide significantly improved rPFS compared with placebo plus enzalutamide in patients with mCRPC who had relevant HRR alterations and were receiving ongoing ADT.28 Grade 3-4 anemia occurred in 46% of talazoparib recipients but usually improved after dose reductions, leading to treatment discontinuation in 8% of patients. (Note that indirect comparisons and network meta-analyses have suggested that talazoparib is associated with a greater risk for anemia compared with olaparib).29,30 No talazoparib-related deaths were reported. In the most recent report from this trial, OS data were immature but showed a trend toward favoring talazoparib (HR for death, 0.69; 95% CI, 0.46-1.03; p=0.07).31 The ongoing TALAPRO-3 trial also is comparing talazoparib plus enzalutamide with placebo plus enzalutamide in patients with mHSPC harboring DDR/HRR alterations.32

Finally, in August 2023, the FDA approved the combination of niraparib plus abiraterone for treating patients with BRCA-mutated mCRPC.33 In the randomized phase 3 MAGNITUDE trial, first-line treatment with this doublet significantly improved rPFS, time to symptomatic progression, and time to initiation of cytotoxic chemotherapy compared with abiraterone plus placebo in patients with BRCA 1/2-mutated mCRPC.34 Overall survival also was significantly longer in the niraparib/abiraterone arm after a prespecified analysis was performed to account for imbalances between arms with regard to subsequent treatment with PARPis and other life-prolonging therapies.

It is worth noting that these ARPI-PARPi combinations may be of limited use for treating mCRPC in settings where the majority of patients with mCRPC are ARPI-exposed. However, relatively slow uptake of mHSPC treatment intensification in some areas means that PARPi-ARPI combinations are still relevant for some patients with mCRPC.6,35

Considerations for patients with MMR deficiency/MSI instability

Unselected patients with mCRPC have shown poor responses to anti-PD-1 therapies both compared to, and combined with, standard treatments such as chemotherapy, ARPIs, and PARPis.36,37 However, studies have identified favorable responses to PD pathway inhibition in patients whose tumors harbor inactivating alterations in mismatch repair genes (MMR deficiency; dMMR) or have high levels of microsatellite instability (MSI-high).38 The reported prevalence of these alterations in patients with prostate cancer varies greatly, probably due to differences among assays and study populations. Prevalence tends to be lower (approximately 1%) in localized prostate cancer and higher (typically 3-5%) in patients with mCRPC.39 For the latter patients, PD-1 pathway inhibition represents a valid treatment consideration.

Pembrolizumab, a PD-1 inhibitor, was the first therapy specifically approved for broadly treating dMMR/MSI-high solid tumors, including prostate cancer. Eligible patients have MSI-high or dMMR solid tumors that have progressed following prior treatment and have no satisfactory alternative treatment options.40 The accelerated FDA approval (in 2017) and the regular approval (in 2023) of this indication were based on positive findings from the multicohort, non-randomized, open-label KEYNOTE trials—KEYNOTE-158 included patients with advanced prostate cancer (n=8).37 It is important to note that PD-L1 positivity does not itself predict treatment response to pembrolizumab—patients should have MSI-high/dMMR alterations confirmed by an FDA-approved assay.

Dostarlimab, a PD-1 receptor inhibitor, was also FDA-approved in July 2023 as a tumor-agnostic therapy for patients with recurrent or advanced MMR-deficient solid tumors.41 In a randomized, multicenter, double-blind, placebo-controlled basket trial, patients with advanced/recurrent solid tumors received intravenous dostarlimab or placebo, plus carboplatin and paclitaxel, followed by a maintenance regimen of dostarlimab or placebo for up to 3 years.42 Strikingly, among 118 patients with dMMR/MSI-high tumors, 24-month estimated PFS was 61.4% in the dostarlimab arm and 15.7% in the control arm (HR, 0.28; 95% CI, 0.16-0.50). In keeping with other studies of PD-1 pathway inhibitors, dostarlimab was of much less benefit in the overall (unselected) study population. A phase 2 study of dostarlimab is now recruiting (NCT04165772).

Oligoprogressive prostate cancer

The term oligoprogression describes patients whose cancer is generally controlled with systemic treatment but has detectable metastatic progression at a small number of sites in the body (usually 3-5 or less). For these patients, metastases-directed therapy (MDT) may overcome the few sub-clones that have developed resistance, thereby prolonging the length of time that patients can stay on a systemic treatment that is otherwise still working. Stereotactic body radiotherapy (SBRT) is the most common method of providing MDT, including in patients with oligoprogressive prostate cancer. This is a form of marked hypofractionation in which a high, targeted dose radioablative treatment is delivered over a greatly reduced number of fractions. In a recent systematic review and meta-analysis of 20 prospective studies of MDT for treating metastatic prostate cancer, SBRT was well tolerated and provided excellent local disease control.43

Limited but compelling prospective clinical trial data suggest that SBRT can improve clinical outcomes in patients with oligoprogressive mCRPC. In the randomized phase 2 ARTO trial, 157 patients with oligometastatic mCRPC (<3 nonvisceral metastatic lesions) were randomly assigned on a 1:1 basis to receive abiraterone/prednisone either alone or together with concomitant SBRT to all disease sites.44 Six months after the start of treatment, the primary endpoint of rate of biochemical response (>50% PSA decrease from baseline) occurred in 79.6% of patients who received SBRT plus abiraterone compared with 68.3% of patients who received abiraterone only; the resulting OR of 5.34 (95% CI, 2.05-13.88; p=0.001) significantly favored the experimental arm. In this study, PSA levels decreased to <0.2 ng/mL in 38.8% of patients in the SBRT-abiraterone arm versus 23.2% of patients in the control arm (p<.001). Six-month PFS also was significantly prolonged in the SBRT-abiraterone arm compared with abiraterone only (HR for progression, 0.35; 95% CI, 0.21-0.57). In a smaller, single-arm, phase 2 trial (MEDCARE) of 20 patients with oligoprogressive mCRPC, MDT (physician’s choice of SBRT or metastasectomy) to 38 total lesions delayed the need for next-line systemic treatment by a median of 17 months, and 2-year prostate cancer-specific survival and OS were 80% and 70%, respectively, with no early or late grade <3 toxicities identified.45

Investigational agents of interest

Several novel investigational agents for the treatment of mCRPC are currently being evaluated in clinical trials. The radiopharmaceutical 225Ac-J591 consists of an anti-PSMA monoclonal antibody (J591) attached to the alpha emitter actinium-225 (225Ac). Unlike beta emitters such as 177Lu)–PSMA-617, alpha emitters deliver intense, localized radiation, leading to potent tumor cell destruction while minimizing damage to surrounding tissue. In a first-in-human dose-escalation study of 225Ac-J591, most high-grade adverse events were hematologic and appeared to increase with radioactivity exposure, while most other adverse events were low-grade. Maximum tolerated dose was not reached; the highest dose evaluated was recommended for phase 2 evaluation.46 In a phase 1/2 study that included 22 evaluable patients who were predominantly 177Lu-naïve, 225Ac-J591 produced a PSA decline of 50% (PSA50) in 67% of patients and a decline of 90% (PSA90) in 37%.47 Favorable circulating tumor cell responses were also observed; primary study completion is expected in June 2025. 225Ac-J591 is now licensed as CONV01-alpha; in April 2024, the manufacturer reported that the FDA cleared its investigational new drug application (IND).48 225Ac-J591 is also being studied in combination with 177Lu-PSMA-I&T.

Another investigational agent of interest is ARX517, a fully humanized anti-PSMA monoclonal antibody conjugated to amberstatin-269, a tubulin inhibitor. This stable antibody-drug conjugate demonstrated a wide therapeutic index and anti-prostate cancer activity in preclinical and nonhuman primate studies and is now being evaluated in a phase 1 trial of 262 patients with mCRPC.49,50 Initial results presented at ESMO 2023 suggested a favorable safety profile and showed substantial reductions in PSA and circulating tumor DNA, as well as confirmed RECIST v1.1 tumor responses in patients whose mCRPC had progressed on multiple prior lines of therapy. Primary completion of this study is anticipated in December 2025.

Xaluritamig (AMG 509) is a bispecific antibody that binds to two STEAP1 sites on tumor cells as well as the CD3 receptor on T cells, thereby inducing T-cell mediated tumor cell lysis. In a dose-ranging study of xaluritamig administered to 97 patients with mCRPC, the most common treatment-related adverse events were cytokine release syndrome (CRS; 72%), fatigue (45%), and myalgia (34%).51 As with most bispecific antibodies, CRS occurred primarily during cycle 1 and improved with premedication and step dosing. In all, 49% of patients had a PSA50, including 59% of patients who received target doses. Xaluritamig is being further evaluated in a phase 1 trial of patients with mCRPC that is refractory to ARPI and taxane chemotherapy or who are taxane-ineligible/refusing. Estimated enrollment is 461 patients, and primary completion is expected in 2026.

The bispecific T-cell engager JANX007 binds to both PSMA and the CD3 receptor to direct T-cell mediated tumor cell killing. After previously having shown favorable preclinical activity and safety, JANX007 is being evaluated in a trial of approximately 105 patients with mCRPC (ENGAGER-PSMA-01); primary completion is anticipated in March 2025.52

Human kallikrein 2 (hK2), which is closely related to PSA, is an interesting prostate cancer target because it is more strongly associated with prostate tumors and highly expressed on poorly differentiated tumor cells.53 JNJ-69086420 (JNJ-6420) is an antibody radioconjugate that targets hK2 with an actinium-225 radioisotope. In a phase 1 dose-escalation study of patients with previously treated mCRPC, JNJ-6420 produced promising efficacy signals, including prolonged treatment-free intervals in some patients.54 However, four treatment-related deaths occurred with repeated dosing, indicating that adaptive dosing will be crucial to limit potentially lethal side effects such as thrombocytopenia and interstitial lung disease.

Finally, 67Cu-SAR-bisPSMA contains two PSMA-targeting agents plus the copper isotope 77Cu, which is contained within a chelator to stop copper from leaking into the body. In the phase 1/2a SECuRE trial, PET imaging with 64Cu-SAR-bisPSMA is used to visualize PSMA-expressing lesions to identify candidates for 67Cu-SAR-bisPSMA therapy.55 Primary completion of this study is expected in 2026. The study sponsor recently announced that the first patient to receive two 8GBq doses achieved a complete treatment response based on RECIST criteria.56

Recent and upcoming trial results

At ESMO 2024, we heard the first efficacy results from the multicenter randomized phase 3 PEACE-3/EORTC-GUCG 1333 trial, in which 446 patients with asymptomatic or mildly symptomatic bone-metastatic mCRPC were randomly assigned to receive either 6 cycles of radium-223 (223Ra) plus enzalutamide or enzalutamide alone.57 rPFS, the primary endpoint, was a median of 3 months longer in the combination therapy arm, and this difference was statistically significant (median rPFS, 19.4 months with 223Ra plus enzalutamide vs 16.4 months with enzalutamide alone; HR, 0.69; 95% CI, 0.54-0.87; p=0.0009). Key secondary endpoints also favored the combination, including OS (HR, 0.69, p=0.0031) and time to next systemic treatment (HR, 0.57; p<0.0001). Results were consistent across all prespecified subgroups. 223Ra plus enzalutamide was associated with higher rates of grade >3 fractures (5.5% versus 1.3% in the enzalutamide-monotherapy arm), fatigue, neutropenia, and anemia compared with enzalutamide only. Note that PEACE-3 patients were not initially required to receive a bone-protecting agent (zoledronic acid or denosumab); a subsequent protocol amendment that mandated prophylactic BPA therapy led to the near-elimination of skeletal fractures in both arms of the study.58 This is an important reminder of the need to follow international clinical guidelines concerning preventive BPAs in patients with mCRPC, who are at increased risk for fractures due to multiple factors, including long-term androgen suppression, bone-metastatic disease, and age-related bone loss.

Also at ESMO 2024, we heard interim results from the randomized phase 3 SPLASH trial, which is evaluating the investigational PSMA-targeted radioligand 177Lu-PNT2002 for treating PSMA PET-positive mCRPC that has progressed on an ARPI.59 This trial enrolled 412 patients and met its primary endpoint: median rPFS was 9.5 months in the 177Lu-PNT2002 arm versus 6.0 months among patients who received an ARPI (HR, 0.71; 95% CI 0.55-0.92; p=0.0088). Interim OS data remain immature.177 In the interim safety analysis, 177Lu-PNT2002 was associated with lower rates of grade ≥3 treatment-emergent adverse events, serious TEAEs, and TEAEs leading to treatment discontinuation compared with ARPI therapy.

Another trial to watch is ECLIPSE, a randomized, phase 3, multicenter, open-label study comparing 177Lu-PSMA-I&T with standard-of-care abiraterone or enzalutamide in 439 patients with PSMA PET-positive mCRPC who have received a prior ARPI but not a PSMA-directed radioligand therapy.60 The primary endpoint is rPFS; patients who develop radiographic progression in the control arm can cross over to the experimental arm. We can expect initial results in 2024-2025.

Conclusions

Metastatic castration-resistant prostate cancer (mCRPC) is prostate cancer that has metastasized or progressed in the setting of a castrate testosterone level. There is an urgent unmet need for novel and targeted therapies for mCRPC, particularly for patients who have progressed on an ARPI. This need will persist as novel single agents and combinations continue to shift into earlier disease stages. Since 2022, regulatory agencies have approved the radioligand theranostic 177Lu-PSMA-617 and three PARP inhibitor-ARPI combinations for treating selected patients with HRR-mutated or BRCA-mutated mCRPC, which has substantially expanded our armamentarium. More additions are on the horizon, including novel radiopharmaceuticals, antibody-drug conjugates, bispecific T-cell engagers, and other agents that show promise for improving clinical outcomes and quality of life in this crucial patient population.

Written by: A. Oliver Sartor, MD, Medical Oncologist, Professor of Medicine, Urology and Radiology, Director, Radiopharmaceutical Trials, Mayo Clinic, Rochester, MN

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