Category: 3. Business

A clinically meaningful progression-free survival benefit (PFS) was observed with fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) plus pertuzumab (Perjeta), despite prior treatment, hormone receptor status, or PIK3CA mutations, when compared with taxol, trastuzumab, and pertuzumab (THP), for patients with HER2-positive advanced or metastatic breast cancer. The results were presented as a subgroup analysis for the phase 3 DESTINY-Breast09 trial (NCT04784715) at the European Society for Medical Oncology Congress 2025.

Prior Treatment Status

The PFS assessment for prior treatment status looked at those with de novo disease or recurrent disease. The median PFS for patients with de novo disease and treated with T-DXd plus pertuzumab was not calculable (NC; 95% CI, 36.5-NC) compared with 31.2 months (95% CI, 23.5-NC) for patients treated with THP (HR, 0.49; 95% CI, 0.35-0.70). The PFS for those with recurrent disease in the T-DXd plus pertuzumab arm was 38.0 months (95% CI, 26.9-NC) and 22.5 months (95% CI, 18.1-NC) for those in the THP arm (HR, 0.63; 95% CI, 0.46-0.87).

The confirmed objective response rate (cORR) for patients with de novo disease receiving T-DXd plus pertuzumab (n = 200) was 90.5% (95% CI, 85.6%-94.2%) with 16.5% of patients having a complete response (CR) and 74.0% having a partial response (PR) vs 82.0% (95% CI, 76.0%-87.1%) in the THP arm (n = 200) and 6.5% having a CR and 75.5% having a PR. For those with recurrent disease, the cORR for those with de novo disease (n = 183 vs 187) was 79.2 (95% CI, 72.6%-84.9%) with 13.7% having a CR and 65.6% having a PR vs a cORR of 74.9% (95% CI, 68.0%-80.9%) with 10.7% having a CR and 64.2% having a PR.

The median duration of response (DOR) for de novo disease in the T-DXd plus pertuzumab arm was 39.2 months (95% CI, 35.1-NC) vs 31.3 months (95% CI, 24.5-NC) for those in the THP arm. For those with recurrent disease, the median DOR was 35.3 months (95% CI, 27.3-NC) vs 21.9 months (95% CI, 18.4-NC) in the THP arm.

Baseline characteristics for those with de novo disease in the T-DXd plus pertuzumab arm compared with the THP arm was an ECOG performance status of 0 (68.0% vs 60.5%), brain metastases (5.0% vs 3.5%), visceral metastases (73.0% vs 68.5%), hormone receptor positive status (56.0% vs 53.0%), and PIK3CA mutations not detected (73.0% vs 72.5%). For those with recurrent disease, the characteristics included an ECOG performance status of 0 (65.6% vs 66.8%), brain metastases (8.2% vs 8.0%), visceral metastases (73.8% vs 70.1%), hormone receptor positive status (51.9% vs 55.1%), and PIK3CA mutations not detected (65.6% vs 64.7%).

For those with de novo or recurrent disease, any treatment-emergent adverse effects (TEAEs) occurred in 100% vs 99.4% of patients in the T-DXd arm vs 99.0% vs 98.9% in the THP arm. TEAEs of grade 3 or higher were noted in 57.0% vs 52.5% in the T-DXd arm and 51.0% vs 53.8% in the THP arm. Any TEAEs leading to discontinuation occurred in 23.0% vs 18.2% of patients in the T-DXd arm vs 33.3% vs 22.8% in the THP arm. Adjudicated drug-related interstitial lung disease (ILD)/pneumonitis occurred in 14.5% vs 9.4% in the T-DXd arm and 1.0% vs 1.1% in the THP arm.

Hormone Receptor Status

The median PFS for patients who were hormone receptor-positive was 38.0 months (95% CI, 36.0-NC) in the T-DXd plus pertuzumab arm and 27.7 months (95% CI, 22.4-NC) for patients in the THP arm (HR, 0.61; 95% CI, 0.44-0.,84). For patients who were hormone receptor-negative, the median PFS in the T-DXd plus pertuzumab arm was 40.7 months (95% CI, 40.7-NC) vs 22.6 months (95% CI, 17.3-32.7) in the THP arm (HR, 0.52; 95% CI, 0.37-0.73).

“Patients with [hormone receptor-positive disease] could receive concurrent [endocrine therapy] benefit after 6 cycles of T-DXd or discontinuation of taxane [therapy], which occurred in 13.5% [of patients in the T-DXd plus pertuzumab arm] vs 38.3% [in the THP arm],” Sibylle Loibl, MD, PhD, chair of the German Breast Group and the Chief Executive Officer, and associate professor of obstetrics and gynecology at the Goethe University of Frankfurt, said in the presentation.

Regarding cORR for patients with hormone receptor-positive disease in the T-DXd plus pertuzumab arm (n = 207) was 81.2% (95% CI, 75.2%-86.2%), with 14.5% of patients having a CR and 66.7% having a PR. In the THP arm (n = 209), the cORR was 77.0% (95% CI, 70.7%-82.6%) with 7.2% of patients having a CR and 69.9% having a PR. For patients with hormone receptor-negative disease, the cORR in the T-DXd plus pertuzumab arm (n = 176) was 89.8% (95% CI, 84.3%-93.8%), with 15.9% of patients having a CR and 73.9% having a PR. In the THP arm (n = 178), the cORR was 80.3% (95% CI, 73.7%-85.9%) with 10.1% of patients having a CR and 70.2% having a PR.

The median DOR for patients with hormone receptor-positive disease receiving T-DXd plus pertuzumab was 35.3 months (95% CI, 34.8-NC) vs 26.4 months (95% CI, 22.3-NC) for patients in the THP arm. For those with hormone receptor-negative disease, the median DOR in the T-DXd plus pertuzumab arm was 39.2 months (95% CI, 398.2-NC) vs 26.3 months (95% CI, 20.2-NC) in the THP arm.

Baseline characteristics for patients who are hormone receptor-positive in the T-DXd plus pertuzumab vs THP arms included an ECOG performance status of 0 (68.1% vs 61.7%), brain metastases (4.8% vs 3.3%), visceral metastases 71.0% vs 67.5%), de novo disease (54.1% vs 50.7%), and PIK3CA mutations not detected (70.5% vs 69.4%). For patients who are hormone receptor-negative, the baseline characteristics included an ECOG performance score of 0 (65.3% vs 65.7%), brain metastases (8.5% vs 8.4%), visceral metastases (76.1% vs 71.3%), de novo status (50.0% vs 52.8%), recurrent status (50.0% vs 47.2%), and PIK3CA mutations not detected (68.2% vs 68.0%).

Regarding safety for hormone receptor-positive and hormone receptor-negative status, any TEAEs occurred in 1010% vs 99.4% in the T-DXd arm and 98.1% vs 100% in the THP arm; and TEAEs of grade 3 or higher occurred in 52.4% vs 57.7% in the T-DXd arm and 52.7% vs 52.0% in the THP arm; serious TEAEs were noted in 28.2% vs 25.7% compared with 29.0% vs 20.6%; TEAEs leading to discontinuation occurred in 17.0% vs 25.1% and 27.1% vs 29.7%; and adjudicated drug-related ILD/pneumonitis occurred in 9.7% vs 14.9% and 0.5% vs 1.7%, respectively.

PIK3CA Mutation Status

The median PFS for patients with PIK3CA mutations was 36.0 months (95% CI, 29.7%-NC) vs 18.1 months (95% CI, 15.1-25.6) in both arms, respectively, (HR, 0.52; 95% CI, 0.35-0.77). For those with PIK3CA not detected, the median PFS was 40.7 months (95% CI, 38.0-NC) for patients in the T-DXd plus pertuzumab arm and 32.7 months (95% CI, 24.2-NC) in the THP arm (HR, 0.57; 95% CI, 0.43-0.77).

The cORR for patients with PIK3CA mutations in the T-DXd plus pertuzumab arm (n = 116) was 81.0% (95% CI, 72.7%-87.7%) with 14.7% of patients having a CR and 66.4% having a PR vs a cORR of 73.6% (95% CI, 64.8%-81.2%) in the THP arm (n = 121) with 4.1% having a CR and 69.4% having a PR. For those who did not have PIK3CA mutations detected, the cORR was 87.2% (95% CI, 862.6%-91.0%) with 15.4% having a CR and 71.8% having a PR in the T-DXd plus pertuzumab arm (n = 266) vs 80.8% (95% CI, 75.6%-85.4%) with 10.5% having a CR and 70.3% having a PR in the THP arm (n = 266).

The median DOR for patients with PIK3CA mutations was 34.8 months (95% CI, 34.8-NC) in the T-DXd plus pertuzumab arm vs 18.4 months (95% CI, 13.2-26.1) in the THP arm. For those with PIK3CA mutations not detected, the median DOR was 39.2 months (95% CI, 35.3-NC) vs NC (95% CI, 25.6-NC).

Baseline characteristics for patients with PIK3CA mutations between either arm included an ECOG performance status of 0 (61.2% vs 62.8%), brain metastases (6.9% vs 5.0%), visceral metastases (64.7% vs 63.6%), recurrent disease status (53.4% vs 54.5%), and hormone receptor positive status (52.6% vs 52.9%). For those with PIKik3CA mutations not detected, characteristics included an ECOG performance status of 0 (69.5% vs 63.9%), brain metastases (6.4% vs 6.0%), visceral metastases (77.1% vs 71.8%), de novo disease (54.9% vs 54.5%), and hormone receptor positive status (54.9% vs 54.5%).

For those with PIK3CA status detected or not detected, any TEAEs occurred in 100% vs 99.6% in the T-DXd arm and 99.2% vs 98.9% in the THP arm; grade 3 or higher TEAEs occurred in 53.0% vs 55.8% and 45.0% vs 55.7%; TEAEs leading to discontinuation in 17.4% vs 22.3% and 24.2% vs 30.2%; and adjudicated drug-related ILD/pneumonitis in 9.6% vs 13.2% and 2.5% vs 0.4%, respectively.

DESTINY-Breast09 Study Design

Patients were randomly assigned 1:1:1 to either T-DXd plus placebo (blinded until the PFS analysis; n = 387), T-DXd plus pertuzumab (n = 383), or THP (n = 387). This analysis focused on the T-DXd plus pertuzumab and THP arms.

The primary end point was PFS by blinded independent central review, with secondary end points including overall survival, PFS by investigator, ORR by BICR/investigator, DOR, PFS2 by investigator, and safety and tolerability.

The investigators noted that if patients discontinued T-DXd due to adverse effectsAEs except for higher than grade 2 interstitial lung disease, patients could switch to trastuzumab. For patients with hormone receptor-positive disease, concurrent use of endocrine therapy was allowed after 6 cycles of T-DXd or who discontinued taxane.

Patients were enrolled if they had first-line HER2-positive advanced/metastatic breast cancer; a disease-free interval of 6 months or more from last neoadjuvant or adjuvant therapy; 1 prior line of endocrine therapy for advanced/metastatic breast cancer; and asymptomatic brain metastases were allowed.

Reference

Loibl S, Jiang Z, Barroso-Sousa R, et al. Trastuzumab deruxtecan (T-DXd) + pertuzumab vs taxane + trastuzumab + pertuzumab (THP) for patients with HER2+ advanced/metastatic breast cancer: additional analyses of DESTINY-Breast09 in key subgroups of interest. Presented at the European Society for Medical Oncology Congress 2025, October 17-21, 2025; Berlin, Germany. LBA18.

Adjuvant therapy can feasibly yield circulating tumor DNA (ctDNA) clearance in a portion of patients with colorectal cancer (CRC) and postoperative ctDNA positivity, with clearance correlating with superior disease-free survival (DFS) outcomes, according to findings from the INTERCEPT CRC study presented at the European Society for Medical Oncology (EMSO) Congress 2025.¹

ctDNA dynamics data after the time of surgery or ablation revealed that 69% of patients had ctDNA negativity on all tests, while 18% had positive results on all tests. Additionally, 3.1% had ctDNA clearance on at least 2 tests, 2.4% had clearance on 1 test, and 8% converted from ctDNA negativity to positivity. Furthermore, adjuvant therapy resulted in ctDNA clearance among 26% (n = 20/77) of patients with ctDNA-positive results after surgery, with 13 (17%) having clearance on at least 2 tests.

From the time of first ctDNA-positive test result in the stage I to III CRC population, DFS outcomes were significantly improved among those with clearance on at least 2 tests (P <.0001). Data revealed similarly significant outcomes among patients with stage IV disease (P <.0001).

Following adjuvant therapy, 70% of patients had ctDNA negativity on all tests, while 19% had positive results on all tests. Other data showed that 1.5% had ctDNA negativity on at least 2 tests, 1.4% had clearance on 1 test, and 9% converted from ctDNA negativity to positivity.

The study population included 403 patients who had ctDNA-positive results at any time after surgery and adjuvant treatment, with 4.2% showing at least 1 subsequent negative reading without any intervention. Furthermore, 2.1% of this population had ctDNA-negative results on at least 2 sequential tests without any intervention, and 1.7% had no recurrences at the time of follow-up. Among patients with spontaneous ctDNA clearance, the median duration of clearance was 11.2 months, and the mean tumor molecules per milliliter was 0.06 (range, 0.02-1.89).

“Adjuvant treatment can clear a quarter of the patients [who] are ctDNA positive postoperatively. Those with ctDNA clearance had superior DFS,” presenting author Emerik Osterlund, MD, PhD, a postdoctoral fellow in Gastrointestinal Medical Oncology at The University of Texas MD Anderson Cancer Center, stated in the presentation.¹ “The rate and durability of [spontaneous] ctDNA clearance was very low.”

According to Osterlund, previous studies have demonstrated how ctDNA can be employed to monitor minimal residual disease, with ctDNA positivity representing a strong risk factor for disease recurrence following procedures administered with curative intent.² However, he noted limited findings on the rates and durability of spontaneous ctDNA clearance, the process of transitioning from ctDNA positivity to negativity without any intervention. Consequently, Osterlund and colleagues aimed to evaluate the behavior and clearance of ctDNA following procedures with curative intent among patients with stage I to IV CRC.

As part of the INTERCEPT program, 1301 patients with newly diagnosed or previously treated resectable stage I to IV CRC enrolled on the study, with 53% having stage I to III disease and 47% having stage IV disease. Patients received standard-of-care therapy—surgical resection with or without neoadjuvant and adjuvant treatment—and underwent tissue collection and testing via ctDNA assays in the postoperative setting and/or following therapy. Investigators then conducted routine surveillance via imaging & labs, with ctDNA assay testing occurring approximately every 3 months at each surveillance visit.

“ctDNA clearance is useful for seeing potential benefit in novel therapeutic studies,” Osterlund concluded.¹

References

1. Osterlund E, Maddalena G, Pellatt AJ, et al. Circulating tumour DNA (ctDNA) clearance and correlation with outcome in the INTERCEPT colorectal cancer (CRC) study. Presented at the European Society for Medical Oncology (ESMO) Congress 2025; October 17-21, 2025; Berlin, Germany. Abstract 732MO.
2. Dasari A, Morris VK, Allegra CJ, et al. ctDNA applications and integration in colorectal cancer: an NCI Colon and Rectal-Anal Task Forces whitepaper. Nat Rev Clin Oncol. 2020;17(12):757-770. doi:10.1038/s41571-020-0392-0.

Relacorilant plus nab-paclitaxel (Abraxane) produced a progression-free survival (PFS) benefit vs nab-paclitaxel alone in a subgroup of patients with platinum-resistant ovarian cancer (PROC) who had received prior PARP inhibitor treatment, including those who had progressed during PARP inhibitor treatment, according to findings from a pre-planned subgroup analysis of the phase 3 ROSELLA trial (NCT05257408), which were presented at the 2025 ESMO Congress.¹

In the subgroup of patients who had prior exposure to a PARP inhibitor, relacorilant plus nab-paclitaxel (n = 114) elicited a median blinded independent central review (BICR)–assessed PFS of 7.36 months (95% CI, 5.59-8.18) vs 4.63 months (95% CI, 3.55-5.72) with nab-paclitaxel alone (n = 120; HR, 0.60; 95% CI, 0.42-0.85; nominal P = .0035). The investigator-assessed overall response rates (ORRs) in these respective groups were 39.5% and 30.8%.

Furthermore, in the subgroup of patients who had progressed on a prior PARP inhibitor, the BICR-assessed median PFS with relacorilant plus nab-paclitaxel (n = 86) was 7.36 months (95% CI, 5.39-8.44) vs 3.94 months (95% CI, 3.32-5.72) with nab-paclitaxel alone (n = 97; HR, 0.56; 95% CI, 0.37-0.84; nominal P = .0046). The investigator-assessed ORRs in these respective groups were 34.9% and 26.8%.

“Consistent benefit was reported in this subgroup analysis in PARP [inhibitor]–pretreated patients [with] relacorilant plus nab-paclitaxel,” presenting author Domenica Lorusso, MD, PhD, said.

Lorusso is director of the Gynaecological Oncology Unit at Humanitas Hospital San Pio X, as well as a full professor of obstetrics and gynecology at Humanitas University, Rozzano, in Milan, Italy.

What Were the Rationale and Design of the ROSELLA Trial?

Ovarian cancers harbor glucocorticoid receptor expression, which is a marker of poor prognosis. Relacorilant is a novel, selective glucocorticoid receptor antagonist that restores cancer sensitivity to cytotoxic chemotherapy.

ROSELLA enrolled patients with epithelial ovarian, primary peritoneal, or fallopian tube cancer who had an ECOG performance status of 0 or 1, had progressed less than 6 months after their last dose of platinum therapy, and had received 1 to 3 prior lines of therapy, including prior bevacizumab. Patients were randomly assigned 1:1 to receive nab-paclitaxel at 80 mg/m² on days 1, 8, 15 of each 28-day cycle, in combination with relacorilant at 150 mg on the day before, the day of, and the day after nab-paclitaxel infusion; or nab-paclitaxel monotherapy at 100 mg/m² on the same nab-paclitaxel dosing schedule.

PFS by BICR and overall survival (OS) served as the dual primary end points. Secondary end points included investigator-assessed PFS, ORR, duration of response, clinical benefit rate, and safety.

What Data Have Been Previously Reported From ROSELLA?

Previously, data presented at the 2025 ASCO Annual Meeting showed that the addition of relacorilant to nab-paclitaxel extended median PFS by BICR compared with nab-paclitaxel alone across the entire population of patients with PROC (HR, 0.70; 95% CI, 0.54-0.91; log-rank P = .0076).^1,2 Furthermore, data from the interim OS analysis showed that the addition of relacorilant generated a clinically meaningful median OS improvement across the full analysis set, at 16.0 months vs 11.5 months (HR, 0.69; 95% CI, 0.52-0.92; nominal log-rank P = .0121).

What Additional Efficacy Data Were Seen in the Analysis of Prior PARP Inhibitor–Exposed Patients in ROSELLA?

The addition of relacorilant to nab-paclitaxel also showed a trend toward improved OS among patients who had received a prior PARP inhibitor, although these data were only at 50% maturity at the time of this interim analysis.¹ The median OS was 15.61 months (95% CI, 12.02-not reached) with relacorilant plus nab-paclitaxel vs 12.58 months (95% CI, 10.09-15.18) with nab-paclitaxel alone (HR, 0.77; 95% CI, 0.53-1.13; nominal P = .1834).

What Was the Safety Profile of Relacorilant Plus Nab-Paclitaxel in Patients in ROSELLA Who Had Received Prior PARP Inhibition?

Lorusso noted that relacorilant plus nab-paclitaxel continued to be well tolerated in the prior PARP inhibitor subgroup. Any treatment-emergent adverse effects (TEAEs) were observed in all patients in this subgroup. Among safety-evaluable patients with prior PARP inhibitor exposure who received relacorilant plus nab-paclitaxel, grade 3 or higher TEAEs were seen in 71.1%, and serious AEs were reported in 31.6%. TEAE-related dose reductions of relacorilant (7.0%), dose reductions of nab-paclitaxel (46.5%), treatment interruptions (72.8%), and treatment discontinuations (8.8%) were also observed.

Among safety-evaluable patients with prior PARP inhibitor exposure who received nab-paclitaxel alone (n = 117), grade 3 or higher TEAEs were seen in 64.1%, and serious AEs were reported in 21.4%. TEAE-related dose reductions of nab-paclitaxel (29.1%), treatment interruptions (58.1%), and treatment discontinuations (6.8%) were also observed.

“The safety profile in the trial subgroup was very similar to that [seen in] the overall population,” Lorusso concluded.

Disclosures: Lorusso reported receiving grants from or having contracts with AstraZeneca, Clovis, Genmab, GSK, Immunogen, Incyte, MSD, Novartis, PharmaMar, Seagen, and Roche; receiving consulting fees from AstraZeneca, Clovis Oncology, Genmab, GSK, Immunogen, MSD, PharmaMar, Seagen, and Novartis; receiving payment or honoraria from AstraZeneca, Clovis, Corcept, Genmab, GSK, Immunogen, MSD, Oncoinvest, PharmaMar, Seagen, and Sutro; receiving support for attending meetings and/or travel from GSK, AstraZeneca, Clovis, and MSD; and participating on Data Safety Monitoring or Advisory Boards for AstraZeneca, Clovis, Corcept, Genmab, GSK, Immunogen, MSD, Oncoinvest, PharmaMar, Seagen, and Sutro.

References

1. Lorusso D, Quesada S, Chan JK, et al. ROSELLA (GOG3073, ENGOTov72, APGOT-OV10): relacorilant + nab-paclitaxel in the subgroup of patients with platinum-resistant ovarian cancer (PROC) previously exposed to a PARP inhibitor. Presented at: 2025 ESMO Congress; October 17-21, 2025; Berlin, Germany. Abstract LBA45.
2. Olawaiye A, Gladieff L, Gilbert L, et al. ROSELLA: a phase 3 study of relacorilant in combination with nab-paclitaxel versus nab-paclitaxel monotherapy in patients with platinum-resistant ovarian cancer (GOG-3073, ENGOT-ov72). J Clin Oncol. 2025;43(suppl 17):LBA5507. doi:10.1200/JCO.2025.43.17_suppl.LBA5507

Radiographic progression-free survival (rPFS) improved when adding capivasertib (Truqap) to abiraterone acetate, prednisone, and androgen deprivation therapy (ADT) among patients with PTEN-deficient de novo metastatic hormone-sensitive prostate cancer (HSPC), according to data from the phase 3 CAPItello-281 trial (NCT04493853) presented at the European Society for Medical Oncology (ESMO) Congress 2025.¹

After a median follow-up of 18.4 months, the median rPFS with the addition of capivasertib was 33.2 months (95% CI, 25.9-44.2) compared with 25.7 months (95% CI, 22.0-29.9) for placebo (HR, 0.81; 95% CI, 0.66-0.98; P = .034). Median overall survival (OS) was not yet reached at the time of the analysis for either arm. There had been 267 events at the time of the assessment, with 129 in the capivasertib arm and 138 in the placebo group (HR, 0.90; 95% CI, 0.71-1.15; P = .401).

“The primary end point was met, showing a statistically significant rPFS benefit with the combination of capivasertib and abiraterone, with consistent benefits observed across clinical end points,” lead investigator Karim Fizazi, MD, PhD, a medical oncologist at Institut Gustave Roussy and Centre Oscar Lambret, said during a presentation of the results. “The rPFS in the control arm was only 25.7 months, highlighting the poor prognosis of a PTEN population.”

In the CAPItello-281 trial, 1012 patients were treated with abiraterone acetate at 1000 mg with prednisone at 5 mg daily plus ADT. Patients were randomly selected to receive capivasertib at 400 mg twice daily for 4 days on and 3 days off (n = 507) or a matched placebo (n = 505). PTEN deficiency was defined as more than 90% of malignant cells with no specific cytoplasmic staining by IHC. Of those screened, approximately 25% matched these requirements.

The primary end point of the study was investigator-assessed rPFS. Secondary end points included overall survival (OS). The analysis presented at ESMO was the final analysis for rPFS. A final OS analysis is still planned.

The baseline characteristics were similar between groups. In the capivasertib and placebo arms, respectively, the median ages were 67 and 68 years. The total Gleason score was 8 or more for 78.5% and 79% of patients and the disease risk was high for 61.3% and 65.9% of those in the capivasertib and placebo groups, respectively. The primary location of disease metastases was the bone for 91.1% and 92.5% in the investigational and control arms, respectively. Nearly two-thirds of patients had an ECOG performance score of 0 with the remainder having a score of 1. Nearly three-fourths of patients had high-volume disease.

“Consistent with the poor prognosis of this PTEN-deficient prostate cancer population, most patients had high-risk, high-volume, high Gleason score disease,” said Fizazi.

In prespecified subgroup analyses, similar improvements in rPFS were seen with the addition of capivasertib, although none passed the bar for statistical significance. In those with high-volume disease with visceral metastases, the hazard ratio was 0.77 favoring the capivasertib arm (95% CI, 0.52-1.14) and in those with a Gleason score of 8 or more the hazard ratio was 0.82 (95% CI, 0.65-1.02). In those with a score lower than 8, the hazard ratio was 1.06 (95% CI, 0.66-1.69).

The time to next treatment was 37.0 months with capivasertib compared with 28.5 months with placebo (95% CI, 0.75-1.11). The median symptomatic skeletal event-free survival was 42.5 months with capivasertib compared with 37.3 months for placebo. Events for this end point included pathological fracture, spinal cord compression, use of radiation, surgical intervention, and death. There were 150 of these events in the capivasertib group and 176 in the placebo group (HR, 0.82; 95% CI, 0.66-1.02; P = .079).

“Roughly half of patients are still on drug and another analysis of overall survival is planned at another time cutoff,” Fizazi said. “There was a numerical improvement of 5.2 months prolongation in event-free survival in the capivasertib arm.”

The time to castration resistance was 29.5 months in the capivasertib group and 22.0 months for placebo (HR, 0.77; 95% CI, 0.63-0.94). For this study, Fizazi noted, castration resistance was defined as radiographic disease progression, PSA progression, and development of a skeletal event. The median time to PSA progression was not calculable at the time of the analysis, with 60 events recorded in the capivasertib arm compared with 82 in the placebo group (HR, 0.73; 95% CI, 0.52-1.01). Pain progression was still too early to measure, as too few events had occurred.

“Interestingly, the Kaplan-Meier curves for time to PSA progression defined by PCWG3 are much higher than those for time to castration resistance, indicating that many patients with PTEN loss tend to first experience a detrimental clinical event, such as an imaging-based progression or bone mobility, prior to a PSA rise of greater than 25%,” said Fizazi.

Additional analyses were completed looking at different PTEN expression levels, following the suggestion of an impact from other studies looking at AKT inhibitors. Of those with PTEN loss on 95% of cells or more, the median rPFS was 33.2 months with capivasertib and 22.7 months with placebo (HR, 0.75; 95% CI, 0.60-0.94). When PTEN loss was 99% or more, the median rPFS was 34.1 months with capivasertib vs 22.4 months for placebo (HR, 0.71; 95% CI, 0.52-0.97). When there was 100% PTEN loss, the median rPFS was 34.1 months compared with 22.1 months for capivasertib and placebo, respectively (HR, 0.68; 95% CI, 0.48-0.96).

“In the capivasertib arm, we see strongly consistent rPFS irrespective of the degree of PTEN deficiency; however, with increasing PTEN deficiency there is worsening prognosis in the control arm,” said Fizazi. “The same phenomenon of increasing treatment effect was also seen for overall survival.” For those with 100% PTEN loss, the early hazard ratio for OS was 0.77 (95% CI, 0.51-1.14).

The increase in treatment benefit was also seen across all secondary end points, when assessing higher levels of PTEN loss. At 100% PTEN loss, the hazard ratio for symptomatic skeletal event-free survival was 0.70 favoring capivasertib (95% CI, 0.48-1.01). For time to castration resistance the hazard ratio was 0.63 (95% CI, 0.45-0.89) and for time to PSA progression it was 0.55 (95% CI, 0.29-1.01). “It was exactly the same trend,” Fizazi said.

A grade 3 or higher adverse event (AE) was experienced by 67% of patients treated with capivasertib compared with for 40.4% of those in the placebo arm. A serious AE was experienced by 42.5% of those in the capivasertib group compared with for 26% of patients in the placebo arm. There was 36 AEs leading to death in the investigational arm compared with 26 in the placebo group.

Adverse events led to discontinuation of capivasertib or placebo for 18.3% and 4.8% of patients, respectively. For capivasertib and placebo, respectively, dose interruptions were required for 62.8% and 26.8% of patients and dose reductions were needed for 29% and 3.6% of patients. An AE led to discontinuation of abiraterone acetate for 9.5% and 5.4% of patients in the investigational and control arms, respectively.

The most common AEs in the capivasertib arm and placebo group, respectively, were diarrhea (51.9% vs 8.0%), hyperglycemia (38% vs 12.9%), rash (35.4% vs 7%), anemia (23.9% vs 12.7%), and hypokalemia (22.1% vs 12.7%). “Adverse events typical of abiraterone, such as hypertension, hypokalemia, and transaminase increase, were even between arms,” said Fizazi.

In early 2025,² another study exploring capivasertib in prostate cancer was halted following an interim analysis that showed a potential lack of efficacy. This study, CAPItello-280 (NCT05348577), was exploring capivasertib in combination with docetaxel and ADT.

Outside of prostate cancer, capivasertib has gained FDA approval in combination with fulvestrant (Faslodex) for the treatment of patients with hormone receptor–positive, HER2-negative, locally advanced or metastatic breast cancer harboring 1 or more PIK3CA, AKT1, or PTEN alterations following progression on at least 1 endocrine-based regimen in the metastatic setting or recurrence on or within 12 months of completing adjuvant therapy.³

References

1. Fizazi K, Clarke NW, De Santis M, et al. A phase III study of capivasertib (capi) + abiraterone (abi) vs placebo (pbo) + abi in patients (pts) with PTEN deficient de novo metastatic hormone-sensitive prostate cancer (mHSPC): CAPItello-281. Presented at: 2025 ESMO Congress; October 17-21, 2025; Berlin, Germany. Abstract 2383O.
2. Update on CAPItello-280 phase III trial of Truqap in metastatic castration-resistant prostate cancer. News release. AstraZeneca. April 29, 2025. Accessed October 19, 2025. https://www.astrazeneca.com/media-centre/press-releases/2025/update-on-capitello-280-phase-iii-trial.html
3. FDA approves capivasertib with fulvestrant for breast cancer. FDA. November 16, 2023. Accessed May 1, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-capivasertib-fulvestrant-breast-cancer