Radium-223 (Xofigo) demonstrated efficacy with low rates of treatment-related adverse effects and treatment discontinuation in patients with metastatic castration-resistant prostate cancer (mCRPC) that metastasized to the bones, according to findings from a real-world study (NCT04232761) presented at the 2023 Genitourinary Cancers Symposium.

Although researchers assessed treatment with radium-223 in the first-, second-, and third-line settings, patients treated in the first-line setting had fewer treatment-related adverse events and higher rates of treatment completion with 6 injections.

A total of 224 patients were included in the multicenter observational trial in Taiwan, of whom 97 were in the safety analysis set. Of these patients, 22 received radium-223 as first-line treatment, 42 as second-line treatment, and 33 as third-line treatment.

Previous lines of therapy included abiraterone and/or enzalutamide (Xtandi) (72.2%; n = 70) as well as docetaxel (34%; n = 33).

Of note, 55% of patients received a full course (6 injections) of radium-223 injections, and 67% received 5 of the 6 injections. The most common reason for treatment discontinuation was disease progression (12%; n = 12).

In patients treated in the first-line setting, 36.4% experienced decreased PSA levels compared with 20% of patients in the second-line cohort and 14% in the third-line cohort. Total alkaline phosphatase levels decreased in 77% of patients in the first-line group, 82% in the second-line group and 60% in the third-line group, underscoring the enhanced efficacy of radium-223 as a front-line therapy, according to the researchers.

The most common reasons for treatment discontinuation of patients in this study were patient decision (9.3%), disease progression (12.4%), and adverse events (6.2%). In addition, 5% of patients in the second-line cohort and 12% of patients in the third-line cohort died before completing the injection course.

The most common treatment-related adverse events were hematological events (9.3%) and diarrhea (8.2%), bone pain (7.2%) and decreased appetite (7.2%).

The relatively low rate of treatment-related adverse events and lack of new safety concerns presented in this study demonstrates the safety of radium-223 under routine clinical practice in Taiwan treating bone metastases related to castration-resistant prostate cancer, according to the poster. A follow-up observation up to 2 years after initial injection is currently ongoing.

Pang ST, Huang CY, Huang CP, et al. Patient characteristics and safety of radium-223 dichloride in Taiwan: Analysis of real-world clinical practice. Presented at: 2023 American Society of Clinical Oncology Genitourinary Cancers Symposium; February 16-18, 2023; San Francisco, CA. Abstract 119.

Articles

Radium-223 demonstrated efficacy with low rates of treatment-related adverse effects and treatment discontinuation in patients with metastatic castration-resistant prostate cancer that metastasized to the bones.

Ra-223 Displays Efficacy, Safety in mCRPC With Bone Metastases

Treatment with darolutamide (Nubeqa) decreased the likelihood of developing metastatic disease or discontinuing treatment because of adverse effects (AEs) vs treatment with apalutamide (Erleada) or enzalutamide (Xtandi) in patients with non-metastatic castration-resistant prostate cancer (nmCRPC), according to findings from the DEAR study that were presented at the 2023 Genitourinary Cancers Symposium.

“The real-world evidence study reinforces the favorable safety profile of darolutimide in the ARAMIS study population,” said Daniel J. George, MD, professor of medicine and of surgery at Duke University School of Medicine in Durham, North Carolina, during the presentation. “It further demonstrates the importance of treatment tolerability and the potential for longer treatment duration with darolutamide compared to enzalutamide and apalutamide, which may in turn improve treatment outcomes.”

Researchers conducting the DEAR study compared three second-generation androgen receptor inhibitors, which are considered the current preferred treatment option for nmCRPC. This comparison was done to determine real-world utilization of the drugs and examine the incidence of AEs, which are the leading cause of treatment discontinuation for androgen receptor inhibitors.

Researchers assessed electronic medical records of 828 patients with nmCRPC. Patients were divided into 3 cohorts based on treatment: darolutamide (n = 340; median age, 80 years), enzalutamide (n = 367; median age, 79 years), and apalutamide (n = 121; median age, 80 years).

Treatment discontinuation or progression to metastatic disease occurred in 37% of patients (n = 340) treated with darolutamide compared with 51% (n = 187) of patients treated with enzalutamide and 51% (n = 62) of those treated with apalutamide. The median time to discontinuation or progress to metastatic disease was not reached in the darolutamide group (95% CI, 30.1-NA). In contrast, these events occurred at a median of 23.1 months (95% CI, 18.2-26.4) in the enzalutamide group and 20.5 months (95% CI, 12.3-27.2) in the apalutamide group.

The most common reasons for treatment discontinuation included AEs, progression to metastatic disease or death, and switching to another androgen receptor inhibitor. George noted that a lower proportion of patients in the darolutamide experienced these events compared with the other two groups.

In particular, AEs occurred in 9.7% of patients in the darolutamide cohort, 14.4% in the enzalutamide cohort and 15.7% in the apalutamide cohort. Progression to metastatic disease or death was observed in 8.8% of patients treated with darolutamide, 12% in those treated with enzalutamide and 13.2% in patients treated with apalutamide.

Study authors posit the favorable outcomes in patients treated with darolutamide may be attributed to “to darolutamide being a structurally distinct (androgen receptor inhibitor) with low potential for blood–brain barrier penetration,” the researchers wrote in the abstract.

George DJ, Khan N, Constantinovici N, et al. Real-world use of darolutamide, enzalutamide, and apalutamide for non-metastatic castration-resistant prostate cancer (DEAR). Presented at: 2023 American Society of Clinical Oncology Genitourinary Cancers Symposium; February 16-18, 2023; San Francisco, CA. Abstract 332.

Treatment with darolutamide decreased the likelihood of developing metastatic disease or discontinuing treatment because of adverse effects vs treatment with apalutamide or enzalutamide in patients with non-metastatic castration-resistant prostate cancer.

Darolutamide Demonstrates Favorable Tolerability, Decreased Metastatic Progression in nmCRPC

Iberdomide (CC-220) monotherapy or in combination with anti-CD20 antibodies was well tolerated and found to elicit encouraging responses in patients with relapsed or refractory lymphoma, according to data from an ongoing open-label, phase 1/2 study (NCT04464798) presented at the 2022 ASH Annual Meeting.

In the total population (n = 54), the overall response rate (ORR) was 50% (95% CI, 36%-64%); this included a complete response (CR) rate of 30% (95% CI, 18%-44%) and a partial response (PR) rate of 20%. The stable disease (SD) rate was 9%, and 20% of patients experienced progressive disease (PD).

In cohort A (n = 24), iberdomide monotherapy induced an ORR of 38%, which included a CR rate of 29% and a PR rate of 8%; 8% of patients had SD and 33% had PD. In cohort B (n = 14), the combination of iberdomide and rituximab (Rituxan) resulted in an ORR of 57%, which included a 29% CR rate and a 29% PR rate; in this group, the SD and PD rates were 7% and 14%, respectively. The highest ORR was achieved in cohort C (n = 16), who had received iberdomide plus obinutuxumab (Gazyva). In this group, the ORR was 63%, which comprised a CR rate of 31% and a PR rate of 31%; 13% of patients had SD and 6% had PD.

Notably, 6 of the 12 patients previously treated with CAR-T therapy achieved a CR with study treatment; 1 of these patients experienced a PR.

In her presentation, Catherine Thieblemont, MD, lead study author and head of the hemato-oncology department of Hôpital Saint-Louis in Paris, France, explained iberdomide’s function as a cereblon E3 ligase modulator (CELMoD) and the newly understood function of these drugs on cereblon to enhance tumor degradation: “What we have learned recently about cereblon is that cereblon has 2 states: an inactive open state and an active closed conformation, and these drugs… will drive these states from the open state to a closed conformation,” she said.

Patients diagnosed with relapsed/refractory lymphoma who were at least 18 years of age and who had been previously treated with 2 or more lines of therapy were eligible for the study. Patients were also required to have measurable disease per Lugano 2014 criteria and an ECOG performance status of 0 to 2.

The 54 patients enrolled were divided into 3 dose-escalation cohorts where the following would be examined: iberdomide monotherapy in patients with any lymphoma subtype (cohort A), iberdomide plus ritixumab in patients with B-cell lymphomas (cohort B), and iberdomide plus obinutuzumab in patients with indolent non-Hodgkin lymphoma (NHL; cohort C).

Treatment was administered as part of 28-day cycles (24 cycles for all lymphomas and 12 cycles for indolent NHL). Iberdomide was given at doses ranging from 0.6 mg to 2.0 mg on days 1 to 21. Rituximab was administered intravenously at a dose of 375 mg/m2 on days 1, 8, 15, and 22 of the first cycle; the agent was subsequently given at 1400 mg subcutaneously or 375 mg/m2 intravenously on day 1 of cycles 2 to 5. Obinutuzumab was given intravenously at a dose of 1000 mg on days 1, 8, and 15 of cycle 1 and on day 1 of cycles 2 to 6.

The primary end point of the trial was to establish he maximum tolerated dose (MTD) and the recommended phase 2 dose of iberdomide alone and in combination with either rituximab or obinutuzumab. Secondary end points included safety, pharmacokinetics, and efficacy.

In the total population, the median patient age was 67.5 years (range, 28-83); 69% of patients were male. Regarding disease, 39% had aggressive B-cell NHL; of these patients, 20% previously received CAR T-cell therapy and 15% had prior lenalidomide (Revlimid). Moreover, 24% of patients had follicular lymphoma 1 to 3a, 15% had marginal zone lymphoma, and 22% had other.

Regarding Ann Arbor disease stage at diagnosis, 17% had stage I/II disease and 80% had stage III/IV disease. The median number of pior regimens received was 4 (range, 1-12). In terms of ECOG performance status, most patients (85%) had a status of 0 to 1, and the remainder (13%) had a status of 2.

At the time of data cutoff, which was September 1, 2022, 7 patients completed treatment, 14 patients were still receiving treatment, and 33 patients had discontinued treatment. Of those who discontinued, 31 continued to the follow-up period with 23 ongoing treatment and 8 ultimately discontinuing treatment.

Reasons for discontinued treatment include PD (n = 18), death (n = 6), adverse effects (AEs) unrelated to any study drug (n = 3), physician decision (n = 3), withdrawal (n = 2), or a second primary malignancy (multiple myeloma) unrelated to iberdomide or any study drug developed (n = 1). Patients who discontinued follow-up did so due to death (n = 7) or patients discretion (n = 1).

The median treatment duration in the overall population was 4.4 months; this was shortest with iberdomide monotherapy (3.0 months) and the longest for iberdomide plus ritixumab (6.4 months). The median treatment duration in those who received iberdomide and obinutuzumab was 5.2 months.

Overall, 72% of safety-evaluable patients (n = 54) experienced a grade 3 or 4 AE, with the majority being hematological events. Fifty percent of patients experienced neutropenia, and they were treated with granulocyte colony–stimulating factor. Other hematological adverse effects of the same grade include anemia (17%), thrombocytopenia (15%) and febrile neutropenia (6%). Some patients also experienced any-grade constipation (22%) and diarrhea (19%).

In the overall safety population, 80% of patients were evaluable for dose-limiting toxicities (DLTs) and 16% of patients were reported to have them. DLTs occurred in 1 patient who was receiving single-agent iberdomide and had thrombocytopenia, 2 patients who were receiving iberdomide plus rituximab who both had neutropenia, and 4 patients who were receiving iberdomide and obinutuzumab who had neutropenia (n = 2), hypercalcemia (n = 1), or face angioedema (n = 1).

Eighty-nine percent of patients required at least 1 dose interruption of iberdomide, 70% of these cases were due to toxicities. Moreover, 15% of patients required dose reductions of iberdomide. The median relative dose intensity was 89% (range, 12%-101%).

No cohort achieved the MTD. Twenty-four percent (n = 13) of patients dided during the study; 4 deaths were because of toxicities (acute respiratory failure, sepsis, COVID-19, and respiratory failure associated with COVID-19). However, none of the deaths were from TEAEs.

The higher response rate in cohorts who received iberdomide in addition to a monoclonal antibody indicate “promising activity and combinability of CELMoD agents in (relapsed/refractory) lymphoma,” Thieblemont concluded. “Oral administration may offer an attractive outpatient treatment option.”

Thieblemont C, Munoz J, Tucci A, et. al. Iberdomide (CC-220) monotherapy or in combination with an anti-CD20 monoclonal antibody as effective therapy in patients with relapsed/refractory lymphoma: early results from a phase 1/2 study. 

. 2022;140(suppl 1):569-572. doi:10.1182/blood-2022-162559

Iberdomide monotherapy or in combination with anti-CD20 antibodies was well tolerated and found to elicit encouraging responses in patients with relapsed or refractory lymphoma.

Iberdomide Alone or in Combination With Anti-CD20 Monoclonal Antibodies Shows Early Efficacy in R/R Lymphoma

Chemotherapy prior to treatment with endocrine therapy could increase the risk of cancer-related cognitive impairment compared with endocrine therapy alone in women with breast cancer, irrespective of menopausal status, according to patient-reported outcomes (PROs) from the phase 3 RxPONDER trail (NCT01272037) presented at the 2022 San Antonio Breast Cancer Symposium.

“Cancer-related cognitive impairment seems to persist over time in a significant proportion of patients,” said Irene Kang, MD, medical director of women’s health breast oncology at City of Hope Orange County in Irvine, California, during the presentation of the data.

In the RxPONDER study, 5,083 women with HR+, HER2- breast cancer with 1 to 3 positive lymph nodes without distant metastasis were randomly assigned wither chemotherapy followed by endocrine therapy or endocrine therapy alone. The PRO substudy included 274 patients from the chemotherapy followed by endocrine therapy group and 294 patients from the endocrine therapy alone group.

In the substudy, participants completed an 8-item questionnaire on a 5-point Likert scale assessing cognitive function at baseline, 6 months, 12 months, and 36 months.

The primary endpoint of the RxPONDER PRO substudy was mean cognitive function score by treatment arm and menopausal status. In particular, 139 women were premenopausal (median age, 48 years) and 429 women were postmenopausal (median age, 62 years).

Scores indicating perceived cognitive function concerns were similar between both treatment groups at baseline. In patients assigned endocrine therapy alone, these scores decreased from baseline to 6 months and 12 months but recovered to baseline at 36 months, according to the abstract. In contrast, patients assigned chemotherapy and endocrine therapy also had the same decrease at 6 months and 12 months, although their scores did not return to baseline at 36 months.

The mean score difference between the chemotherapy and endocrine therapy group and the endocrine therapy alone group was -3.02 (

 = .01) for premenopausal women and -2.36 for postmenopausal women (

Of note, 42% of premenopausal women assigned chemotherapy followed by endocrine therapy experienced a sustained and clinically significant decline in cognitive function as opposed to 28% for endocrine therapy. For postmenopausal women, these declines were 41% and 36%, respectively.

During the presentation, Kang noted that these results differ from the findings of a similar trial, TAILORx, which used a different cognitive function scale. Results from that trial demonstrated that the differences in cancer-related cognitive impairment between chemotherapy followed by endocrine therapy and endocrine therapy alone “vanished” at 12-month follow-up, she said.

Limitations to the study, as acknowledged by Kang, included participant drop-off over time, small sample size particularly in the premenopausal group, and that participants in the premenopausal group could theoretically have begun menopause at any point during the study’s duration. Participants were also overwhelmingly White (84.2%) and non-Hispanic (91.6%).

“Our study highlights the need for future investigation of cancer-related cognitive impairment in a more diverse population, as well as understanding who will develop cognitive impairment and who will recover,” Kang said during the presentation.

Kang I, Forschmiedt J, Loch M, et al. Patient-reported cognitive impairment in women participating in the RxPONDER trial (SWOG S1007) by menopausal status. Presented at: 2022 San Antonio Breast Cancer Symposium; December 6-10, 2022; San Antonio, TX. Abstract GS1-04.

Chemotherapy prior to treatment with endocrine therapy could increase the risk of cancer-related cognitive impairment compared with endocrine therapy alone in women with breast cancer, irrespective of menopausal status. 

Chemotherapy Followed by Endocrine Therapy Could Increase Cognitive Impairment in Breast Cancer, Irrespective of Menopausal Status

Pembrolizumab (Keytruda) plus abiraterone acetate (Zytiga) and prednisone demonstrated continued efficacy and tolerability in patients with chemotherapy-naïve metastatic castration-resistant prostate cancer (mCRPC), according to findings from the phase 1b/2 KEYNOTE-365 trial (NCT02861573) presented at the 2022 ESMO Congress.

At a median follow-up of 28.2 months (range, 20.2-37.6), the objective response rate was 16.2% among patients with RECIST-measurable disease. The ORRs comprised 1 complete response and 5 partial responses. Across the overall population, 56.3% of patients had a confirmed PSA response and 78.6% achieved a PSA reduction from baseline—either confirmed or unconfirmed.

The ongoing open-label, nonrandomized KEYNOTE-365 trial is exploring various combinations of the PD-1 inhibitor pembrolizumab with other therapies in men with mCRPC. The pembrolizumab plus abiraterone/prednisone arm is cohort D of the study. Cohort D included 103 chemotherapy-naïve men with mCRPC who had an ECOG performance status of 0 or 1 and disease progression within 6 months of screening.

Patients had no prior next-generation hormonal agents (NHAs) for mCRPC or had received the NHA enzalutamide (Xtandi) for mCRPC but had progressed on or were intolerant to the drug. Of the 103 patients treated in cohort D, 75 (72.8%) had no prior NHAs and 27 (26.2%) had prior enzalutamide. (There was 1 patient had prior enzalutamide and abiraterone.)

Patients received 200 mg of pembrolizumab intravenously every 3 weeks in addition to oral doses of 1000 mg of abiraterone daily and 5 mg of prednisone twice daily.The primary study end points were PSA response (≥50% decrease from baseline), confirmed ORR per RECIST v1.1 by blinded independent central review (BICR), and safety. Secondary end points included radiographic progression-free survival (rPFS), disease control rate (DCR), duration of response (DOR), and overall survival (OS).

The cutoff date for the data shared at ESMO was February 14, 2022. The 16.2% ORR among patients with RECIST-measurable disease (37 patients) comprised an ORR of 21.7% in patients with no prior NHAs and an ORR of 7.7% in patients with prior enzalutamide. Of note, there were 2 patients with RECIST non-measurable disease who had a CR. The median DOR for all responders was not reached (range, 2.1+ to 24.4+). The DCR was 44.7% across all patients, 58.7% in those with no prior NHAs, and 7.4% in the prior enzalutamide group.

The median OS was 29.7 months and the 36-month OS rate was 49.5%. The median rPFS was 15.1 months and the 24-month rPFS rate was 33.3%.

Regarding safety, 91.3% of patients experienced a treatment-related adverse event (TRAE). Grade 3/5 TRAEs occurred in 38.8% of patients. Across the population, 18.4% had grade 3/4 ALT elevation and 12.6% had grade 3/4 AST elevation. One patient died of treatment-related myasthenic syndrome.

The FDA approved abiraterone plus prednisone in 2012 for the treatment of patients with mCRPC who had not received prior chemotherapy. Pembrolizumab does not currently have a specific FDA-approved indication for prostate cancer; however, the PD-1 inhibitor does have a tumor-agnostic approval for patients with microsatellite instability high or mismatch repair deficient solid tumors.

Linch M, Ferrario C, Stoeckle M, et al. Two-year follow-up of KEYNOTE-365 cohort D: Pembrolizumab (pembro) plus abiraterone acetate (abi) and prednisone in patients with chemotherapy-naive metastatic castration-resistant prostate cancer (mCRPC). 

. 2022;33(suppl 7):S616-S652. doi:10.1016/annonc/annonc1070

Pembrolizumab plus abiraterone acetate and prednisone demonstrated continued efficacy and tolerability in patients with chemotherapy-naïve metastatic castration-resistant prostate cancer. 

Miranda Lankas

Articles

Ra-223 Displays Efficacy, Safety in mCRPC With Bone Metastases

Darolutamide Demonstrates Favorable Tolerability, Decreased Metastatic Progression in nmCRPC

Iberdomide Alone or in Combination With Anti-CD20 Monoclonal Antibodies Shows Early Efficacy in R/R Lymphoma

Chemotherapy Followed by Endocrine Therapy Could Increase Cognitive Impairment in Breast Cancer, Irrespective of Menopausal Status

Pembrolizumab Plus Abiraterone/Prednisone Shows Sustained Efficacy in Chemotherapy-Naïve mCRPC