Caroline Seymour

For patients with relapsed/refractory mantle cell lymphoma Lunsumio plus Polivy was associated with durable responses. Image generated by Google Gemini.

Among patients with relapsed/refractory mantle cell lymphoma (MCL) with prior exposure to BTK inhibition, treatment with Lunsumio (mosunetuzumab-axgb) plus Polivy (polatuzumab vedotin-piiq) was associated with durable responses and was found to be well tolerated, clinical trial results have shown.

Findings from an MCL dose-expansion cohort of a phase 2 trial were presented at the 2025 SOHO Annual Meeting.

Among all treated patients (42 patients), the overall response rate (ORR) was 88%; the complete response (CR) and partial response (PR) rates were 79% and 9%, respectively. The efficacy of this combination was observed across high-risk patient subgroups, including those at least 70 years of age (18 patients; ORR, 83%; CR rate, 78%; PR rate, 5%), those who had received prior CAR-T cell therapy (11 patients; 91%; 82%; 9%), those with a Ki-67 score of at least 50% (28 patients; 93%; 79%; 14%), those with pleomorphic or blastoid MCL (16 patients; 94%; 69%; 25%), and those with TP53 mutations or deletions (13 patients; 100%; 92%; 8%).

Overall response rate: patients who responded partially or completely to treatment.

Progression-free survival: the time a patient lives without their disease spreading or worsening.

Overall survival: the time a patient lives, regardless of disease status.

“[Lunsumio] and [Polivy], in my opinion, is going to be a good off-the-shelf option for relapsed/refractory MCL before or after CAR T-cell therapy,” lead study author Dr. Michael L. Wang, said in the presentation.

Wang is a professor in the Department of Lymphoma/Myeloma and the Department of Stem Cell Transplantation in the Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center in Houston.

What Was the Rationale for Investigating Lunsumio in Combination With Polivy in Patients With MCL?

Lunsumio is a CD20xCD3-directed, T-cell engaging bispecific antibody. Polivy is a CD79-directed antibody-drug conjugate.

“The two are complementary in their mechanisms of action,” Wang noted. “They were synergistic in preclinical studies.”

Previous findings from the dose-expansion large B-cell lymphoma (LBCL) cohort (98 patients) of the phase 2 study showed that at a median follow-up of 23.9 months, Lunsumio plus Polivy elicited an ORR of 59.2% and a CR rate of 45.9%. Furthermore, the median duration of CR was not reached.

What Was the Design of the MCL Portion of the Phase 2 Study of Lunsumio Plus Polivy in Relapsed/Refractory MCL?

This phase 2 study is investigating the efficacy, safety, pharmacokinetics and pharmacodynamics of Lunsumio plus Polivy in patients with B-cell non-Hodgkin lymphoma, including LBCL, follicular lymphoma and MCL.

Patients received the investigational combination in a fixed-duration treatment approach that included Lunsumio administered subcutaneously at 45 mg in 21-day cycles (5-mg step-up dosing occurred in cycle 1) for a total of 17 cycles; and intravenous Polivy administered at 1.8 mg/kg on day 1 of cycles 1 through 6. Hospitalization was not required. Patients received corticosteroid premedication before each dose in cycle 1.

What Were the Baseline Characteristics of Patients Included in the Trial?

Patients had a median age of 68 years and had received three prior lines of therapy. Prior therapies included BTK inhibition (100%), CAR T-cell therapy (26%) and autologous stem cell transplant (31%). In total, 93% of patients were refractory to their last prior therapy. TP53 mutations or deletions were present in 39% of patients, 38% of patients had blastoid or pleomorphic disease, and 43% of patients had bone marrow involvement. Ki-67 scores of at least 30% and at least 50% were reported in 76% and 67% of patients, respectively. Additionally, 48% of patients had a simplified International Prognostic Index for MCL score of at least 6. Overall, 71% of patients had at least three high-risk features.

“This is a high-risk, heavily treated population,” Wang contextualized.

What Additional Efficacy Data Were Observed With Lunsumio Plus Polivy?

The responses observed with this combination were early and durable, Wang noted. At a median follow-up of 15.9 months, among all responders (37 patients), the median time to first response was 2.7 months, the median DOR was not reached and the 12-month response rate was 66%. Among complete responders (33 patients), the median time to first CR was 2.8 months, the median duration of CR was not reached and the 12-month response rate was 71.9%.

Among all treated patients, the median progression-free survival (PFS) was 18.6 months, and the 12-month PFS rate was 74.8%. The median overall survival (OS) was 20.7 months and the 12-month OS rate was 83.1%.

What Was the Safety Profile of Lunsumio Plus Polivy in Patients With MCL?

All patients experienced side effects, and 93% of patients experienced treatment-related side effects. The rates of grade 3 (severe)/4 (life-threatening) side effects and treatment-related side effects were 69% and 60%, respectively. Serious side effects and treatment-related side effects were reported in 62% and 41% of patients, respectively. Grade 5 (fatal) side effects and treatment-related side effects occurred in 12% and 2% of patients, respectively; these included COVID-19 pneumonia (three patients), pneumonia (one patient) and West Nile virus encephalitis (one patient). Treatment discontinuation related to side effects and treatment-related side effects occurred in 24% and 12% of patients, respectively. Patients received a median of 15 Lunsumio cycles and six Polivy cycles.

Side effects and treatment-related side effects that occurred in at least 20% of patients included fatigue, injection site reaction, neutropenia/decreased neutrophil counts, diarrhea, cytokine release syndrome (CRS), nausea, dyspnea, constipation, cough, headache, pyrexia, thrombocytopenia/decreased platelet counts, COVID-19 and myalgia. Side effects of interest included injection site reaction (grade 1 (mild), 52%; grade 2 (moderate), 5%), peripheral neuropathy (grade 1, 29%; grade 2, 12%), immune effector cell–associated neurotoxicity syndrome (grade 2, 2%), infections (any grade, 71%; grade 3/4, 14%; grade 5, 12%), tumor flare (grade 1, 5%; grade 2, 7%), neutropenia/decreased neutrophil counts (any grade, 45%; grade 3/4, 41%), and febrile neutropenia (grade 3, 5%).

Notably, B-cell depletion occurred rapidly during treatment, and investigators observed recovery of B-cell counts following treatment.

Wang ML, Kamdar M, Assouline S, et al. Fixed-duration outpatient subcutaneous mosunetuzumab + polatuzumab vedotin shows robust efficacy in a phase II study of relapsed/refractory post-BTKi mantle cell lymphoma. Presented at: 2025 SOHO Annual Meeting. September 3-6, 2025; Houston, TX. Abstract MCL-1493.

Budde LE, Olszewski AJ, Assouline S, et al. Mosunetuzumab with polatuzumab vedotin in relapsed or refractory aggressive large B cell lymphoma: a phase 1b/2 trial. 

. 2024;30(1):229-239. doi:10.1038/s41591-023-02726-5

A study to evaluate the safety and efficacy of mosunetuzumab (BTCT4465A) in combination with polatuzumab vedotin in B-cell non-Hodgkin lymphoma. ClinicalTrials.gov. Updated November 29, 2024. Accessed September 6, 2025. https://www.clinicaltrials.gov/study/NCT03671018

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Lunsumio (mosunetuzumab-axgb) combined with Polivy (polatuzumab vedotin-piiq) demonstrated significant efficacy and tolerability in patients with relapsed/refractory mantle cell lymphoma (MCL) previously treated with BTK inhibitors. The phase 2 trial showed an overall response rate of 88%, with complete and partial response rates of 79% and 9%, respectively. The combination was effective across high-risk subgroups, including those with prior CAR-T therapy and TP53 mutations. Despite a high incidence of side effects, the treatment was generally well-tolerated, with manageable safety profiles and durable responses.

For patients with relapsed/refractory mantle cell lymphoma Lunsumio plus Polivy was associated with durable responses.

Lunsumio plus Polivy Associated With Responses in MCL

Responses also occurred in patients who had received at least two prior ROS TKIs, with an ORR of 38%.

Among patients with advanced ROS1-positive non-small cell lung cancer (NSCLC) who had previously received one to four lines of prior ROS1 tyrosine kinase inhibitor therapy with or without chemotherapy, treatment with zidesamtinib resulted in an objective response rate (ORR) of 44% and a complete response (CR) rate of 1%, clinical trial results have shown.

Data from the phase 1/2 ARROS-1 trial were presented at the International Association for the Study of Lung Cancer (IASLC) 2025 World Conference on Lung Cancer and showed that among those who had previously received either Xalkori (crizotinib) or Rozlytrek (entrectinib) with or without chemotherapy, the ORR was 51% with a CR rate of 2%. The ORR in patients who had received only Xalkori with or without chemotherapy was 68%; the ORR in patients who had received only Rozlytrek with or without chemotherapy was 33%.

Responses also occurred in patients who had received at least two prior ROS TKIs, with an ORR of 38%. Patients who were previously exposed to Augtyro (repotrectinib) experienced an ORR of 47%, with duration of response (DOR) ranging from 3.5 months to 17.2 months. Patients who had received prior Ibtrozi (taletrectinib) had an ORR of 43%, with a DOR ranging from 5.2 months to seven-plus months. 

 patients who responded partially or completely to treatment.

the time a patient lives without their disease spreading or worsening.

“In the pivotal dataset for TKI pretreated patients with advanced ROS1-positive NSCLC, zidesamtinib demonstrated a clinical profile consistent with its preclinical design goals,” Dr. Alexander E. Drilon, lead study author and chief of the Early Drug Development Service at Memorial Sloan Kettering Cancer Center in New York, said during the presentation. “[We saw] durable activity, including in heavily pretreated patients who have exhausted available options, including prior [Augtyro] and [Ibtrozi], and patients with the ROS1 G2032R resistance mutation.”

What Was the Design of the ARROS-1 Trial?

ARROS-1 is a global, first-in-human trial evaluating the safety and efficacy of zidesamtinib in patients with advanced ROS1-positive NSCLC and other solid tumors. Phase 1 evaluated the agent at doses ranging from 25 mg to 150 mg once daily in ROS1 TKI–pretreated patients with ROS1-positive solid tumors. In phase 2, patients with either ROS1 TKI–pretreated or naive disease received the recommended phase 2 dose (RP2D) of 100 mg once daily.

A total of 514 patients had been enrolled in the pooled phase 1 and 2 populations. The pivotal safety population included 432 patients with advanced ROS1-positive NSCLC who had received the RP2D of the agent. The pivotal efficacy population included 117 patients with ROS1 TKI–pretreated NSCLC with measurable disease by BICR who had been treated by May 31, 2024, and had at least six months of DOR follow-up. Preliminary findings for the ROS1 TKI–naive cohort were also shared for the 35 patients who had been treated by August 31, 2024.

Baseline characteristics of the pivotal efficacy population revealed that the median age was 57 years. Most patients were female (56%), never smokers (68%) and resided in North America (42%) or Europe (32%). Most patients had an ECOG performance status of 1 (62%) versus 0 (38%), and 49% had active central nervous system (CNS) disease. A secondary ROS1 mutation was present in 36% of cases (G2032R, 22%).

The median number of prior anticancer therapies was two, and 53% of patients had received prior chemotherapy. A total of 47% of patients had received prior Xalkori (51%) or Rozlytrek (49%). Only four patients (3%) received either Augtyro or Ibtrozi. Among patients who had received at least two prior lines of therapy (50%), 93% had received Lorbrena (lorlatinib), Augytro or Ibtrozi.

What DOR and PFS Data Were Shared During IASLC 2025 World Conference on Lung Cancer?

At a median follow-up of 11.1 months, the median PFS was 9.7 months in patients who had received any prior ROS1 TKI. The median DOR was 22 months. The percentages of patients who remained in response for at least six, 12 and 18 months were 84%, 78% and 62%, respectively. The six-, 12-, and 18-month PFS rates were 57%, 48% and 40%, respectively.

At a median follow-up of 11.8 months, the median PFS was 23.8 months in patients who had received one prior ROS1 TKI. The median DOR was 22 months. The percentages of patients who remained in response for at least six, 12 and 18 months were all 93%. The six-, 12- and 18-month PFS rates were 70%, 68% and 68%, respectively.

Drilon also reported that there were no progression events in patients who received only Xalkori. The 6-, 12-, and 18-month PFS rates were all 89% and the median was not reached in this population.

A total of 71% and 56% of patients who received at least two prior ROS1 TKIs remained in response for six and 12 months, respectively.

Did Zidesamtinib Show Activity in the CNS and in ROS1

Among patients who had received any prior ROS1 TKI and had an acquired ROS1 G2032R mutation, the ORR, six-month DOR, and 12-month DOR rates were 54%, 79% and 60%, respectively.

Among patients who had previously received Xalkori or Rozlytrek and had an acquired ROS1 G2032R mutation, the ORR, six-month DOR and 12-month DOR rates were 83%, 80% and 80%, respectively.

Drilon also noted that responses occurred in patients with the ROS1 G2032R mutation after treatment with two or more prior ROS1 TKIs, including Lobrena or Augtyro, as well as in other mutational subtypes, including G1957A, L1982V, S1986F, F2004C/V, G2032K, and D2033N.

Within the population of patients who had measurable CNS lesions at baseline and had received any prior ROS1 TKI, the intracranial ORR (IC-ORR), six-month IC-DOR and 12-month IC-DOR rates were 48%, 79% and 71%, respectively.

Within the population of patients who had measurable CNS lesions at baseline and had received Xalkori only, the IC-ORR, six-month IC-DOR and 12-month IC-DOR rates were 85%, 91% (95% CI, 51%-99%), and 91% (95% CI, 51%-99%), respectively. The IC-CR rates were 20% and 54% in patients who had received any prior ROS1 TKI or crizotinib as their only prior TKI, respectively.

Drilon explained that CNS responses were observed also in patients who had received at least 1 prior brain-penetrant TKI, including entrectinib, lorlatinib, repotrectinib, or taletrectinib. In this population, the IC-ORR was 37% (95% CI, 23%-53%), including 4 IC-CRs. No CNS progression occurred in patients who entered the study without brain metastases at baseline.

What Was the Safety Profile of Zidesamtinib in the ARROS-1 Trial?

All patients had received at least one dose of the study drug. The median duration of exposure was five months. Treatment-emergent side effects that occurred in at least 15% of patients who received the RP2D of zidesamtinib included peripheral edema (all grade, 36%; grade 3 or higher, 0.7%), constipation (17%; 0%), elevated blood creatine phosphokinase ([CPK]; 16%; 3.5%), fatigue (16%; 0.7%) and dyspnea (15%; 3.0%).

Ten percent of patients required dose reduction because of a treatment-emergent side effect, the most common being peripheral edema (eight patients), increased blood CPK (four patients), peripheral sensory neuropathy (four patients), arthralgia (three patients), and paresthesia (three patients). Two percent of patients discontinued treatment because of a treatment-emergent side effect, and the most common reason was pneumonia (three patients).

“[The agent was] generally well tolerated, with low rates of dose reduction and treatment discontinuation, and a safety profile consistent with its ROS1-selective, TRK-sparing design,” Drilon reported.

The only treatment-related adverse effect that occurred in more than 15% of patients was peripheral edema (29%).

What Were the Preliminary Data in the ROS TKI–Naive Cohort?

The ORR in this cohort was 89%, and 96% of patients remained in response for at least 12 months. The IC-ORR was 83% and there were no cases of CNS progression among confirmed CNS responders.

“Encouraging preliminary data in a TKI-naïve population support ongoing investigation in the frontline setting,” Drilon concluded.

Pivotal data from the trial will serve as the basis for the developer’s ongoing rolling new drug application submission for the agent to the Food and Drug Administration in the TKI-pretreated population. According to the developer, the company is expected to complete the application in the third quarter of 2025.

Drilon AE, Cho BC, Lin JJ, et al. Pivotal ARROS-1 efficacy and safety data: zidesamtinib in TKI-pretreated patients with advanced/metastatic ROS1+ NSCLC. Presented at: 2025 International Association for the Study of Lung Cancer 2025 World Conference on Lung Cancer; September 6-9, 2025; Barcelona, Spain. Abstract 4540.

Nuvalent presents pivotal data from ARROS-1 clinical trial of zidesamtinib for TKI pre-treated patients with advanced ROS1-positive NSCLC at WCLC 2025. News release. Nuvalent. September 7, 2025. Accessed September 7, 2025. https://www.prnewswire.com/news-releases/nuvalent-presents-pivotal-data-from-arros-1-clinical-trial-of-zidesamtinib-for-tki-pre-treated-patients-with-advanced-ros1-positive-nsclc-at-wclc-2025-302548220.html

Zidesamtinib demonstrated promising efficacy in advanced ROS1-positive NSCLC patients previously treated with ROS1 TKIs, achieving an ORR of 44% and a CR rate of 1%. The ARROS-1 trial highlighted its effectiveness, particularly in those with prior Xalkori or Rozlytrek exposure, and in patients with the ROS1 G2032R resistance mutation. The trial also showed significant CNS activity and a favorable safety profile, with peripheral edema being the most common side effect. Preliminary data in TKI-naïve patients were encouraging, supporting further investigation in frontline settings.

Patients with advanced, pretreated ROS1-positive NSCLC treated with zidesamtinib saw an objective response rate of 44%.

Zidesamtinib Elicits Responses in ROS1-Positive NSCLC

In patients with EGFR-mutated NSCLC ivonescimab plus chemotherapy was associated with significant progression-free survival.

Among patients with EGFR-mutated non-small cell lung cancer (NSCLC) who experienced disease progression following a third-generation tyrosine kinase inhibitor, treatment with ivonescimab plus carboplatin/pemetrexed was associated with significant and clinically meaningful progression-free survival (PFS) versus placebo plus carboplatin/pemetrexed, study results have shown.

Data from the phase 3 HARMONi trial were presented at the International Association for the Study of Lung Cancer 2025 World Conference on Lung Cancer, and the findings revealed that at a median follow-up of 22.3 months, the median PFS was 6.8 months and 4.4 months in the ivonescimab plus carboplatin/pemetrexed (172 patients) and the placebo plus carboplatin/pemetrexed (173 patients) arms, respectively. Specifically, at six and 12 months in the ivonescimab arm, the PFS rates were 54.% and 25.4%, respectively; these rates were 34.7% and 8.3% in the placebo arm.

“The efficacy of [ivonescimab] was consistent across subgroups, with perhaps more benefit [in patients] with brain metastases,” Dr. Jonathan Goldman, a professor of medicine in the Division of Hematology/Oncology, the director of Clinical Trials in Thoracic Oncology, and the associate director of Early Drug Development at the University of California Los Angeles, said in a presentation of the data.

Objective response rate: patients who responded partially or completely to treatment.

Anemia: low count of healthy red blood cells.

Increased alanine aminotransferase levels: an indicator of liver damage.

Increased aspartate aminotransferase levels: an indicator of liver and heart damage.

What Was the Background and Design of the HARMONi Study?

Topline results from the HARMONi trial revealed that the study met the PFS primary end point and showed a positive trend in the other primary end point of overall survival (OS) with ivonescimab plus carboplatin/pemetrexed compared with placebo plus carboplatin/pemetrexed in patients with EGFR-mutated NSCLC who experienced disease progression after treatment with a third-generation TKI.

The double-blind, multicenter trial includes patients at least 18 years of age with histologically or cytologically confirmed unresectable locally advanced or metastatic non-squamous NSCLC with an EGFR-sensitizing mutation.

Patients included on the study are randomly evenly assigned to receive either ivonescimab plus carboplatin/pemetrexed (219 patients) or placebo plus carboplatin/pemetrexed (219 patients). Those included in the investigational arm are treated with 20 mg/kg of ivonescimab every three weeks plus carboplatin at area under the curve 5 every three weeks for four 21-day cycles and pemetrexed at 500 mg/m

 every three weeks. Patients included in the placebo arm were treated with carboplatin and pemetrexed at the same dosing levels as those in the investigational arm.

What Were the Additional Efficacy and Safety Findings From the HARMONi Study?

At an overall median follow-up of 29.7 months, the median OS was 16.8 months and 14 months in the ivonescimab and placebo arms, respectively. Furthermore, the objective response rate (ORR) was 45% in the ivonescimab arm compared with 34% in the placebo arm. The disease control rate (DCR) was 84% vs 73% in the respective arms. Notably, the median duration of response (DOR) in the ivonescimab (98 patients) and placebo (75 patients) arms were 7.6 months and 4.2 months, respectively.

Regarding safety, any-grade treatment-related side effects were observed in 95% and 93.1% of patients from the ivonescimab and placebo arms, respectively. In the ivonescimab arm, grade 3 (severe) or greater side effects and serious side effects occurred in 50% and 28% of patients, respectively; these occurred in 42.2% and 15.1% of patients in the placebo arm. Treatment-related side effects that led to discontinuation of ivonescimab or placebo, respectively, were observed in 7.3% and 5% of patients. Moreover, treatment-related side effects that led to death were reported in 1.8% and 2.3% of patients, respectively.

In the ivonescimab arm, the most common treatment-related side effects observed included anemia (any grade, 49.1%; grade 3 or higher, 10.1%), decreased white blood cell count (45%; 12.8%), decreased neutrophil count (42.7%; 19.3%) and decreased platelet count (32.6%; 12.4%). The most common treatment-related side effects reported in the placebo arm included anemia (56.4%; 12.4%), decreased white blood cell count (44%; 11%), decreased neutrophil count (42.2%; 16.5%) and decreased platelet count (28.0%; 6.4%).

Of note, grade 3 or higher immune-related side effects occurred in 9.6% and 6% of patients in the ivonescimab and placebo arms, respectively; grade 3 or higher VEGF-related treatment-related side effects occurred in 7.3% and 3.2% of patients. In particular, the most common irAEs occurring in at least five patients in the ivonescimab arm included hypothyroidism (any grade, 8.3%; grade 3 or higher, 0.5%), hyperthyroidism (any grade, 4.1%), increased alanine aminotransferase levels (2.8; 0.9%), and increased aspartate aminotransferase levels (any grade, 3.2%). Additionally, the most common VEGF-related treatment-related side effects occurring in the ivonescimab arm included proteinuria (13.8%; 0.9%), hypertension (13.3%; 3.7%) and hemorrhage (10.6%; 0.9%).

Goldman JW, Passaro A, Laskin J, et al. Ivonescimab vs placebo plus chemo, phase 3 in patients with EGFR+ NSCLC progressed with 3rd gen EGFR-TKI treatment: HARMONi. Presented at: International Association for the Study of Lung Cancer 2025 World Conference on Lung Cancer; September 6-9, 2025; Barcelona, Spain. Abstract 4808.

Ivonescimab plus chemotherapy demonstrates statistically significant and clinically meaningful improvement in progression-free survival in patients with EGFR-mutant non-small cell lung cancer after EGFR TKI therapy in global study. News release. Summit Therapeutics. May 30, 2025. Accessed September 7, 2025. https://www.smmttx.com/wp-content/uploads/2025/05/2025_PR_0530-_-HARMONi-Data-_-FINAL.docx.pdf

Phase III study of AK112 for NSCLC patients. ClincialTrials.gov. Updated October 8, 2024. Accessed September 7, 2025. https://clinicaltrials.gov/study/NCT06396065

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Ivonescimab combined with carboplatin/pemetrexed significantly improved progression-free survival (PFS) in patients with EGFR-mutated NSCLC who progressed after third-generation TKI therapy, compared to placebo. The phase 3 HARMONi trial showed a median PFS of 6.8 months for ivonescimab versus 4.4 months for placebo. The study also indicated a positive trend in overall survival (OS) and higher objective response and disease control rates with ivonescimab. Safety profiles were comparable, with common side effects including anemia and decreased blood cell counts.

Ivonescimab Plus Chemo Delays NSCLC Progression

Akeega delayed progression and symptoms in patients with HRR-positive castration-sensitive prostate cancer.

A 37% reduction in the risk of radiographic progression or death was observed with Akeega (niraparib plus abiraterone acetate [Zytiga]) plus prednisone compared with Zytiga, prednisone, and placebo (AAP), in patients with metastatic castration-sensitive prostate cancer (mCSPC) who had homologous recombination repair (HRR) gene alterations and had previously received androgen deprivation therapy (ADT), according to results from the phase 3 AMPLITUDE trial presented at the 

After a median follow-up of 30.8 months, the median radiographic progression-free survival (rPFS) was not estimable in the Akeega group compared with 29.5 months in the placebo arm. Furthermore, Akeega significantly reduced the risk symptomatic progression by 50% compared with AAP and placebo. Overall survival (OS) was not statically significant at the analysis, with trends beginning to emerge showing improvement with Akeega.

“Improvements in rPFS are supported by a statistically significant benefit in time to symptomatic progression and a trend toward improved OS,” lead investigator Dr. Gerhardt Attard, Cancer Institute, University College London, said during a presentation of the findings. “In my opinion, AMPLITUDE supports [Akeega] as a treatment option for patients in this poor prognostic disease group.”

HRR gene alterations: changes in genes like BRCA1 or BRCA2 that affect the cell’s ability to repair DNA damage.

Radiographic progression-free survival (rPFS): time during and after treatment that a patient lives without cancer getting worse on scans.

Overall survival (OS): time from start of treatment until death from any cause.

PARP inhibitor: a type of drug that blocks a protein cancer cells use to repair DNA damage, making them more likely to die.

Androgen deprivation therapy (ADT): treatment that lowers testosterone to slow prostate cancer growth.

De novo M1: metastatic cancer present when the disease is first diagnosed.

High-volume metastatic disease: cancer that has spread widely, often to multiple bones or organs.

Patient Demographics and Additional Findings From AMPLITUDE

In the study, 696 patients were evenly randomized to receive Akeega (348 patients) or placebo plus AAP (348 patients). The median age of enrolled patients was 68 years. Overall, 78% of patients had high-volume metastatic disease (M1), of which 87% were de novo M1. All patients had received ADT for six months or less and 16% of patients had received prior docetaxel. All patients in the study had an alteration in genes associated with HRR, which included BRCA1/2 alterations for 55.6% of patients. Remaining alterations could have been in BRIP1, CDK12, CHEK2, FANCA, PALB2, RAD51B or RAD54L.

For patients specifically with BRCA mutations, the improvements in rPFS were more pronounced. In this group, there was a 48% reduction in the risk of radiographic progression or death with the addition of the PARP inhibitor. The median for the Akeega arm was not estimable compared with 26 months with AAP.

“This was a really exciting result,” said Attard. “This is the first study to show efficacy for PARP inhibition and androgen receptor inhibition in CSPC, the benefit [of which] might be greatest in patients with BRCA mutations.”

Those with BRCA1/2 mutations also had a significant reduction in the risk of symptomatic progression. In this subgroup, there was a 56% reduction in the risk of symptom progression with the PARP inhibitor compared with the androgen synthesis inhibitor and placebo.

“This is a patient-centric end point, measuring the time to worsening of symptoms, which includes needing radiation or a procedure or intervention or further cancer treatment,” said Attard. “Very convincingly we show a clear benefit with [Akeega].”

OS was still immature across the study. At the analysis, the BRCA1/2 subgroup showed similar trends as in the full population of those with HRR gene alterations. In this group, there was an early 25% reduction in the risk of death observed with Akeega.

“Half the number of patients have died from the target number we would require for the final analysis, but in my view, there’s a clear trend for favoring survival in the patients randomized to [Akeega],” said Attard.

Diving Into the Safety and Possible Implications

Grade 3 (severe) or 4 (life-threatening) adverse effects (AEs; side effects) were observed in 75.2% of those receiving Akeega compared with 58.9% of those in the control arm. The most common AEs were anemia (29.1% with Akeega versus 4.6% with placebo) and hypertension (26.5% versus 18.4%). Of those with anemia, the majority required a transfusion.

Dose interruptions were required for 66.9% of patients in the Akeega arm compared with 42.4% for the control arm. Dose reductions were needed to address AEs for 21.9% of those in the Akeega arm compared with 6.9% of those in the placebo group. Treatment was discontinued for 14.7% of those in the Akeega arm compared with 10.3% of those in the placebo group. Treatment-emergent AEs led to death for 14 patients in the investigational arm compared with seven in the control group.

“We’re used to the side effect profile with these drugs, and we aren’t seeing any new side effects but clearly those randomized to [Akeega] have more AEs than those randomized to placebo,” said Attard. “But critically, I think, the proportion of patients who [were] required to discontinue treatment was fewer than 5% for those on [Akeega] versus placebo.”

In 2023, Akeega was approved by the FDA in combination with AAP for patients with deleterious or suspected deleterious BRCA-mutated castration-resistant prostate cancer, based on findings from the phase 3 MAGNITUDE study. Results from the AMPLITUDE study could expand this approval to those with castration-sensitive disease.

“This is really exciting news for our patients,” ASCO expert commentator Dr. Bradley McGregor, from Dana-Farber Cancer Institute, said of the results. “PARP inhibitors have been a mainstay in the treatment of metastatic castrate-resistant prostate cancer for those patients with HRR alterations, and this is the first time we’ve seen data for these in the hormone-sensitive setting. As you heard this is a very poor prognostic group, so I think this is incredibly exciting.”

“Phase 3 AMPLITUDE trial: Akeega for metastatic castration-sensitive prostate cancer with homologous recombination repair gene alterations” by Dr. Gerhardt Attard, et al., 

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The addition of the PARP inhibitor Zejula to Zytiga and prednisone significantly reduced the risk of radiographic progression or death by 37% in patients with metastatic castration-sensitive prostate cancer (mCSPC) with HRR gene alterations, as shown in the phase 3 AMPLITUDE trial. The trial demonstrated a 50% reduction in symptomatic progression risk and a trend towards improved overall survival. However, Zejula was associated with higher rates of severe adverse effects, including anemia and hypertension, necessitating dose adjustments and treatment discontinuations in some cases.

Akeega delayed cancer growth and symptoms in patients with castration-sensitive prostate cancer and HRR gene mutations.

Caroline Seymour

Lunsumio plus Polivy Associated With Responses in MCL

Zidesamtinib Elicits Responses in ROS1-Positive NSCLC

Ivonescimab Plus Chemo Delays NSCLC Progression

Akeega Combo Delays Progression in HRR+ Castration-Sensitive Prostate Cancer

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