Clinical Updates: June 2023

Study: Active Surveillance for Prostate Cancer Is Increasing

Using active surveillance for patients with indolent prostate cancer continues to rise in the United States, but rates are lower in minority groups, low-income groups, and patients in rural areas, results of a recent study show.

For low- and some intermediate-risk prostate cancer cases, active surveillance (AS) has been increasingly recognized as the standard of care vs definitive treatment, and a research letter published in JAMA Internal Medicine suggests that the rate of AS use in the United States is increasing.¹

For patients with low- or intermediate-risk prostate cancer that is progressing very slowly, AS is a management strategy that can help avoid quality-of-life effects of radical treatment. Recent research suggests that patients with localized disease detected early by prostate-specific antigen (PSA) testing have similar prostate cancer–specific mortality outcomes whether they undergo active treatment or are under AS.²

The current study utilized data from the Surveillance, Epidemiology, and End Results Prostate with Watchful Waiting (SEER-WW) database from 2010 to 2018 of men older than 40 years with low-risk and favorable intermediate-risk prostate cancer. The SEER-WW data also included information on whether clinicians used AS or WW to monitor patients. Although AS entails monitoring cancer for progression, WW only involves observing the patient until they experience symptoms.

The Cochran-Armitage test (1-sided) was used to assess temporal trends, and linear regression analysis was assessed. The associations with AS or WW vs definitive treatment with patient demographics were assessed with multivariable logistic regression analysis. Over time, the rate of AS/WW increased. In patients with low-risk disease, the AS/WW rate rose from 16.4% to 59.9%, and the rate increased from 7.8% to 21.8% in patients with favorable intermediate-risk cancers. The median (IQR) age of patients whose low-risk prostate cancer under AS/WW decreased from 65 (range, 60-71) years to 64 (range, 59-69) years in the study period. Median (IQR) patient age for those with favorable intermediate-risk disease decreased from 70 (range, 64-76) years to 67 (range, 61-71) years.

The multivariable analyses showed that the use of AS/WW was associated with higher income, and Asian/Pacific Islander and Hispanic patients were less likely to be under AS/WW than White patients. The number of positive biopsy cores was linked to higher odds of definitive treatment, and patients in rural settings with low-risk prostate cancer were more likely to undergo definitive treatment.

“Interestingly, in low-risk disease, 2 positive cores were associated with an almost 50% decrease in AS use,” the authors wrote. “Although AS series have shown an association between cancer volume on biopsy and clinical outcomes, it is unclear whether the presence of a second positive core should have such an impact on AS use. This is worrisome, particularly with the increasing use of magnetic resonance imaging in biopsy, which may bias toward more positive cores and potentially higher rates of downgrading at prostatectomy.”

The study was limited in its inclusion of men with known treatment or surveillance rather than all prostate cancer patients, but its results still suggest that the use of AS continues to rise in the United States. Still, uptake has been slower in minority groups, low-income groups, and patients in rural areas, demonstrating persistent disparities that must be addressed, the authors noted. 

References

1. Al Hussein Al Awamlh B, Barocas DA, Zhu A, et al. Use of active surveillance vs definitive treatment among men with low- and favorable intermediate–risk prostate cancer in the US between 2010 and 2018. JAMA Intern Med. Published online April 3, 2023. doi:10.1001/jamainternmed.2022.7100
2. Hamdy FC, Donovan JL, Lane JA, et al; ProtecT Study Group. Fifteen-year outcomes after monitoring, surgery, or radiotherapy for prostate cancer. N Engl J Med. 2023;388(17)1547-1558. doi:10.1056/NEJMoa2214122

Ixazomib Shows PFS Benefit Across Age and Frailty Subgroups in MM

In an in-depth subgroup analysis of the phase 3 TOURMALINE-MM4 trial (NCT02312258), postinduction maintenance therapy with ixazomib demonstrated a progression-free survival (PFS) benefit vs placebo regardless of age or frailty status in patients with multiple myeloma (MM).

Ixazomib (Ninlaro), an oral proteasome inhibitor, showed a favorable safety profile and efficacy across subgroups in the trial’s original analysis. Results of the new analysis, which was published in Clinical Lymphoma, Myeloma & Leukemia, add additional safety, efficacy, and quality-of-life (QOL) data to the previous findings.

MM typically affects elderly patients—more than 30% of whom are 75 years or older, the authors noted. They are more likely to have impaired QOL and experience reduced survival compared with younger patients, and comorbidities, early discontinuation of treatment, and toxicity concerns are often the causes of these outcomes.

“Elderly [patients with MM] are a heterogeneous population with greatly varying levels of physical and psycho-social functioning,” the authors wrote. “Assessment tools incorporating patients’ functionality that can predict outcomes and help determine the most suitable treatment are important for stratifying this population.” The validated International Myeloma Working Group (IMWG) frailty score is the current standard for classification.

Patients with nontransplant, newly diagnosed MM who experienced at least a partial response to 6 to 12 months of standard-of-care induction therapy were enrolled in the study. Patients were randomly assigned to receive either ixazomib or a placebo within 60 days of their last dose of induction therapy. Of 706 patients, 425 received ixazomib and 281 received a placebo.

In the overall cohort, 10% of patients were younger than 65 years, 52% were aged 65 to 74 years, and 38% were 75 years or older. A total of 699 patients had data available on IMWG classification: 41% were classified as fit, 35% as intermediate fit, and 24% as frail. Across subgroups, the rates of treatment discontinuation were similar.

In the age subgroups, the percentages of patients considered intermediate fit and frail increased with age; and in the frailty subgroups, the proportion of elderly patients was higher as fitness decreased.

PFS benefit was demonstrated across age groups with ixazomib treatment vs the placebo. The HRs were 0.576, 0.615, and 0.740 in patients younger than 65 years, aged 65 to 74 years, and 75 years or older, respectively.

In frailty subgroups, PFS benefit was seen regardless of status. The group considered fit showed an HR of 0.530, intermediate-fit patients had an HR of 0.746, and frail patients had an HR of 0.733.

The rates of grade 3 or higher treatment-emergent adverse events (TEAEs) and serious TEAEs were higher with ixazomib treatment vs placebo, and both arms showed increased grade 3 or higher and serious TEAEs with age. Rates of discontinuation were similar in patients younger than 65 years or aged 65 to 74 years but higher in patients 75 years or older. Patient-reported QOL scores were similar across age groups and frailty cohorts.

“This subgroup analysis of TOURMALINE-MM4 demonstrated the tolerability of ixazomib maintenance regardless of age and frailty status, although with some differences in TEAE rates and treatment exposure across subgroups,” the authors wrote.

The findings are in line with data from other phase 3 trials of continuous or continuous vs fixed-term therapy in patients with nontransplant newly diagnosed MM, although differences in treatment regimens, durations of therapy, and study populations are potential confounding factors for comparisons between studies, the authors noted.

Still, the authors conclude that ixazomib as postinduction therapy in patients with MM not undergoing transplant is a well-tolerated and effective treatment option.

“Our data indicate that ixazomib could provide a valuable single-agent maintenance option for elderly/frail patients and may also have utility in the nontransplant postinduction setting in combination with other agents, such as immunomodulatory drugs and monoclonal antibodies,” the authors concluded. 

Reference

Bringhen S, Pour L, Benjamin R, et al. Ixazomib versus placebo as post-induction maintenance therapy in newly diagnosed multiple myeloma patients: an analysis by age and frailty status of the TOURMALINE-MM4 study. Clin Lymphoma Myeloma Leuk. Published online March 28, 2023. doi:10.1016/j.clml.2023.03.007

SORAYA Data Shed Light on Responses to Mirvetuximab Soravtansine
After Prior Bevacizumab Exposure

Clinicians now have more nuanced information on how the antibody-drug conjugate mirvetuximab soravtansine (Elahere; ImmunoGen) works in patients with FRα-high platinum-resistant ovarian cancer based on their prior exposure to bevacizumab (Avastin; Genentech), thanks to updated data from the phase 3 SORAYA trial (NCT04296890).¹

Final overall survival and additional efficacy data were presented in March at the 2023 Society of Gynecologic Oncology (SGO) Annual Meeting on Women’s Cancer in Tampa, Florida. This followed the FDA’s accelerated approval on November 14, 2022, for mirvetuximab soravtansine for adult patients with FRα-high platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer who have received 1 to 3 prior systemic treatment regimens.²

Approval was based on initial SORAYA results that showed that in 104 patients, the overall response rate (ORR), the trial’s primary end point, was 31.7%% (95% CI, 22.9%-41.6%). The key secondary end point, median duration of response, was 6.9 months (95% CI, 5.6-9.7).³

All patients in the study had received prior bevacizumab—some in the frontline setting, some in the platinum-sensitive setting, and some in the platinum-resistant setting. (Six patients had received bevacizumab in more than 1 setting.) Results for 105 patients published in the Journal of Clinical Oncology (JCO) in January, after a median follow-up of 13.4 months, showed that 51% of patients in SORAYA had received 3 prior lines of therapy and 48% had received a prior PARP inhibitor.⁴

Robert L. Coleman, MD, FACOG, FACS, presented the subgroup analysis of the SORAYA trial. The updated data showed a confirmed ORR of 32.4% (95% CI, 23.6%-42.2%), including 5 complete responses.¹ In the subgroup analysis involving previous bevacizumab exposure, the results were as follows:

The 94 patients treated with mirvetuximab soravtansine after receiving bevacizumab for platinum-sensitive ovarian cancer achieved an ORR of 34.0% (95% CI, 24.6%-44.5%). The 17 patients who were administered mirvetuximab soravtansine after receiving bevacizumab in the platinum-resistant setting had an ORR of 17.6% (95% CI, 3.8%-43.4%).

Among the 66 patients who received mirvetuximab soravtansine as their first treatment in the platinum-resistant setting, investigators reported an ORR of 34.8% (95% CI, 24%-44.5%). Among the 39 who had other therapies as their first treatment in this setting, the ORR was 28.2% (95% CI, 15.0%-44.9%).

Coleman noted that updated safety outcomes for mirvetuximab soravtansine were consistent with prior data from SORAYA. Data reported after a median follow-up of 13.4 months in JCO showed that the most common treatment-related adverse events (TRAEs), all grade and grade 3 to 4, were blurred vision (41% and 6%, respectively), keratopathy (29% and 9%), and nausea (29% and 0%). TRAEs led to discontinuation in 9% of patients.⁴

References

1. Coleman RL. Mirvetuximab soravtansine (MIRV) in patients with platinum-resistant ovarian cancer with high folate receptor alpha (FRα) expression: evaluation of sequence of therapy on antitumor activity in the SORAYA study. Presented at: 2023 Society of Gynecologic Oncology Annual Meeting on Women’s Cancer; March 25-28, 2023; Tampa, FL.
2. Joszt L. FDA approves mirvetuximab soravtansine-gynx for platinum-resistant ovarian cancer. The American Journal of Managed Care.. November 15, 2022. Accessed April 26, 2023. https://www.ajmc.com/view/fda-approves-mirvetuximab-soravtansine-gynx-for-platinum-resistant-ovarian-cancer
3. Matulonis U, Lorusso D, Oaknin A, et al. Efficacy and safety of mirvetuximab soravtansine in patients with platinum-resistant ovarian cancer with high folate receptor alpha expression: results from the SORAYA trial (LBA 4). Gynecol Oncol. 2022;166(suppl 1):S50. doi:10.1016/S0090-8258(22)01297-5
4. Matulonis UA, Lorusso D, Oaknin A, et al. Efficacy and safety of mirvetuximab soravtansine in patients with platinum-resistant ovarian cancer with high folate receptor alpha expression: results from the SORAYA study. J Clin Oncol. 2023;41(13):2436-2445. doi:10.1200/JCO.22.01900