Yu Fujiwara, MD, from Mount Sinai Beth Israel in New York City, and colleagues conducted a systematic review and meta-analysis to examine how adding an immune checkpoint blockade to perioperative therapy affects treatment-related adverse events. Data were included from 28 randomized controlled trials with 16,976 cancer patients.

The researchers found no significant association for addition of an immune checkpoint blockade with increased treatment-related deaths, and this finding was consistent across immune checkpoint blockade subtypes. Across 9864 patients treated with an immune checkpoint blockade, 40 fatal toxicities were identified, with pneumonitis the most common (15.0%); among 7112 patients who were not treated with an immune checkpoint blockade, 13 fatal toxicities were identified. The incidence rates of grade 3 to 4 treatment-related adverse events, adverse events leading to treatment discontinuation, and treatment-related adverse events of any grade were increased with the addition of an immune checkpoint blockade (odds ratios, 2.73, 3.67, and 2.60, respectively). Increased incidence rates of treatment-related deaths and grade 3 to 4 adverse events were seen in association with an immune checkpoint blockade vs placebo design primarily used as adjuvant therapy (odds ratios, 4.02 and 5.31, respectively), while incidence was not increased with the addition of an immune checkpoint blockade in the neoadjuvant setting.

“Our analysis points to a need for further research into risk factors and identification of appropriate biomarkers to predict both efficacy and toxicity associated with cancer immunotherapy,” Fujiwara said in a statement.

Several authors disclosed ties to the biopharmaceutical industry.

Abstract/Full Text (subscription or payment may be required)

Editorial (subscription or payment may be required)

The Food and Drug Administration (FDA) has approved Akeega (niraparib and abiraterone acetate) for the treatment of adult patients with deleterious or suspected deleterious BRCA-mutated (BRCAm) metastatic castration-resistant prostate cancer (mCRPC), as determined by an FDA-approved test.

Akeega is an oral therapy that combines niraparib, a poly (ADP-ribose) polymerase (PARP) inhibitor, and abiraterone acetate, a CYP17 inhibitor into a single tablet. The approval was based on data from the randomized, placebo-controlled, double-blind, phase 3 MAGNITUDE study (ClinicalTrials.gov Identifier: NCT03748641).

Study participants with homologous recombination repair (HRR) gene-mutated (HRRm) mCRPC (Cohort 1) were randomly assigned to receive niraparib 200mg and abiraterone 1000 mg (n=212) or placebo and abiraterone (n=211) until unacceptable toxicity or progression. All patients received prednisone 10mg daily and a gonadotropin-releasing hormone (GnRH) analog or had prior bilateral orchiectomy. In this study population, 53% (n=225) had BRCA gene mutations. The primary endpoint was radiographic progression free survival (rPFS); overall survival (OS) was an additional outcome measure.

Findings showed a statistically significant improvement in rPFS with niraparib plus abiraterone compared with placebo plus abiraterone in the BRCAm subgroup (hazard ratio, 0.53 [95% CI, 0.36-0.79]; P =.0014). In the overall HRR population, the rPFS HR was 0.73 (95% CI, 0.56-0.96; P =.0217), while in the subgroup of patients with non-BRCA HRR mutations (n=198), the rPFS HR was 0.99 (95% CI, 0.67-1.44).

In an exploratory analysis, median OS in the BRCAm subgroup was reported to be 30.4 months (95% CI, 27.6, not estimable) for the niraparib plus abiraterone arm and 28.6 months (95% CI, 23.8-33.0) for the placebo plus abiraterone arm (OS HR, 0.79 [95% CI, 0.55-1.12). Among patients with non-BRCA HRR mutations, the OS HR was 1.13 (95% CI, 0.77-1.64).

“As a physician, identifying patients with a worse prognosis is a priority, especially those whose cancers have a BRCA mutation,” said Kim Chi, MD, Medical Oncologist at BC Cancer – Vancouver and principal investigator of the phase 3 MAGNITUDE study. “We prospectively designed the MAGNITUDE study to identify the subset of patients most likely to benefit from targeted treatment with Akeega and to help us understand how we can potentially achieve better health outcomes for patients.”

Findings from the study indicate that the improvement observed with the combination therapy in the HRR gene-mutated population was primarily attributed to the results seen in the subgroup of patients with BRCAm.

As for safety, the most common adverse reactions (≥20%) reported were decreased hemoglobin, decreased lymphocytes, decreased white blood cells, musculoskeletal pain, fatigue, decreased platelets, increased alkaline phosphatase, constipation, hypertension, nausea, decreased neutrophils, increased creatinine, increased potassium, decreased potassium, and increased AST.

In the MAGNITUDE study, 27% of patients required a red blood cell transfusion, with 11% requiring multiple transfusions. Increased ALT, edema, dyspnea, decreased appetite, vomiting, dizziness, COVID-19, headache, abdominal pain, hemorrhage, urinary tract infection, cough, insomnia, increased bilirubin, decreased weight, arrhythmia, fall, and pyrexia were also observed (≥10%).

Akeega is supplied as a tablet in 2 dosage strengths: niraparib 50mg/abiraterone acetate 500mg and niraparib 100mg/abiraterone acetate 500mg.

The FDA has also approved the use of the FoundationOne^®CDx as a companion diagnostic for Akeega. Patients should be selected for treatment based on the presence of a BRCA gene alteration.

HealthDay News — For men with large prostates, the Aquablation procedure is safe, with durable efficacy, according to a study published online April 28 in The Journal of Urology.

Naeem Bhojani, MD, from the University of Montreal, and colleagues reported five-year safety and efficacy outcomes of the Aquablation procedure for treatment of symptomatic benign prostatic hyperplasia and large-volume prostate glands. Data were included for 101 men with moderate-to-severe benign prostatic hyperplasia symptoms and prostate volumes between 80 and 150mL (mean volume at baseline, 107mL), who underwent a robotic-assisted Aquablation procedure.

The researchers found that the study successfully met its safety and efficacy performance goal at 3 months, which was based on transurethral resection of the prostate outcomes typically done in smaller prostates. A significant improvement was seen in patient symptoms, with a change of 15.9 in the International Prostate Symptom Score (from 22.6 at baseline to 6.8 at 5 years). Improvement was also demonstrated in the mean maximum urinary flow rate, from 8.6 to 17.1mL/s at baseline and 5 years, respectively (change, 9.2mL/s). No difference was seen in efficacy outcomes through 5 years in a prespecified subgroup analysis using a baseline prostate volume cutoff of 100mL. At 5 years, freedom from a secondary benign prostatic hyperplasia procedure was 96.3%.

“With real-time ultrasound guidance and robotic execution, Aquablation has the potential to treat prostates of nearly any size,” the authors write. “The five-year data validate the durability of Aquablation.”

Several authors disclosed ties to PROCEPT BioRobotics, which funded the clinical study.

Abstract/Full Text

Atezolizumab, given with or without radiotherapy, has demonstrated activity in a subset of patients with penile cancer, according to research published in the Journal of Clinical Oncology.

Atezolizumab did not meet the primary efficacy endpoint in the overall cohort of this phase 2 study. However, researchers did observe antitumor activity in patients with high-risk human papillomavirus (hrHPV) positivity or high intratumoral CD3⁺CD8⁺ T-cell infiltration.

This trial, PERICLES (ClinicalTrials.gov Identifier: NCT03686332), included 32 patients with stage IV penile cancer. They were treated with atezolizumab at 1200 mg every 3 weeks. Patients who were expected to benefit from radiotherapy for locoregional control also received radiotherapy (n=20).  

The patients’ median age at baseline was 67 (range, 41-78) years, and 75% of them had metastatic disease. Most patients (75%) had received previous treatment, including radiotherapy (34.4%), chemoradiation (21.9%), systemic therapy (6.2%), and surgery (68.8%).

The primary endpoint was 1-year progression-free survival (PFS) of at least 15% per the null hypothesis and 35% per the alternative hypothesis. With a median follow-up of 29.1 months, the 1-year PFS rate in the full cohort was 12.5%, which failed to meet the primary endpoint. Similarly, the 1-year PFS rate in patients receiving atezolizumab plus radiotherapy did not meet the endpoint (10.0%; P =.36). However, in the patients treated with atezolizumab alone, the 1-year PFS rate was 16.7% (P <.001).

In an exploratory biomarker analysis, the median PFS was 5.3 months in patients with hrHPV-positive tumors and 2.6 months for patients with hrHPV-negative tumors (P =.003). Similarly, patients with high infiltration of intratumoral CD3⁺CD8⁺ T cells had longer PFS than those with low infiltration, 5.1 months and 2.6 months, respectively (P =.037).

The objective response rate was 16.7% in the overall cohort, in the radiotherapy arm, and in the atezolizumab-alone arm. The median duration of response was not reached in the overall cohort, 6.7 months in the radiotherapy arm, and not reached in the atezolizumab-alone arm.

The median overall survival was 11.3 months in the overall cohort, 12.0 months with radiotherapy, and 8.9 months without radiotherapy.

“[A]lthough this study did not meet the primary endpoint of 1-year PFS, clinical activity of checkpoint inhibitor was observed, including durable responses in a limited number of patients,” the researchers wrote. “Our study suggests hrHPV positivity and intratumoral CD3⁺CD8⁺ T-cell infiltration as possible biomarkers to select a broader population of patients with penile cancer who are more likely to derive clinical benefit to checkpoint inhibition in future clinical trials.”

Disclosures: This research was supported by Hoffmann-La Roche. Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of disclosures.

Breakthroughs in targeted therapy and immunotherapy are partly responsible for the recent decline in cancer deaths seen in the United States, according to the AACR Cancer Progress Report 2023.¹

The overall rate of cancer death in the US fell by 33% between 1991 and 2020, which translates to 3.8 million lives saved, according to the report. Death rates have decreased for lung cancer, colorectal cancer, prostate cancer, female breast cancer, and melanoma.

“These gains have really reflected a whole variety of different advances, but mostly this has been about efforts in basic science,” AACR President Philip D. Greenberg, MD, of Fred Hutchinson Cancer Research Center in Seattle, said during a presentation about the AACR report.

Dr Greenberg noted that initiatives such as the Human Genome Project and The Cancer Genome Atlas have enabled the creation of targeted therapies, which are “increasingly precise and decreasingly toxic.”

Immunotherapy breakthroughs have also reduced the toxicity of treatments, leading to improved quality of life for patients. “Precision oncology, personalized medicine; it’s about creating drugs and using them to very selectively target the disease and not injure the person,” Dr Greenberg summarized.

The AACR report highlighted several targeted therapies with unique mechanisms of action that have been approved by the US Food and Drug Administration (FDA) since the early 2000s, including gefitinib in 2003, crizotinib in 2011, and sotorasib in 2021.

All of these therapies were approved to treat lung cancer, and these approvals coincided with declining lung cancer deaths. The decrease in lung cancer deaths per year grew from 0.9% between 1995 and 2005 to nearly 5% between 2014 and 2020.

The report also highlighted more recent FDA approvals. Between August 1, 2022, and July 31, 2023, the FDA approved 14 new cancer therapies and expanded the approved use of 12 therapies to encompass new cancers. The therapies include a range of cell-signaling inhibitors, antibody-drug conjugates, bispecific antibodies, and immune checkpoint inhibitors.

“A decade ago, there was 1 single immune checkpoint inhibitor,” Dr Greenberg pointed out. “Now . . . 11 checkpoint inhibitors have now been approved by the FDA up through 2023. And rather than using it to treat the single disease that it was approved for a decade ago, we now use it to treat 20 diseases.”

Two new imaging agents — pafolacianine and flotufolastat fluorine-18 —were also approved by the FDA between August 1, 2022, and July 31, 2023.

Ongoing Challenges

“Of course, despite all this progress, there’s a whole lot of work that needs to be done,” Dr Greenberg said. “There are still, even now, structural barriers for lots of people. There’s clearly disproportionate medical care being delivered to medically underserved populations. This includes, of course, racial and ethnic minorities, but it also includes the rural populations, which is not commonly appreciated, but rural populations participate very minimally in cancer trials.”

“Similarly, although precision medicine has really improved outcomes, we need ways of expanding that so that it includes more diseases,” Dr Greenberg added. “Pancreatic cancer, for example, and glioblastoma still have horrible 5-year relative survival rates, and so we need new advances.”

To address some of these challenges, the AACR has launched a new initiative known as the AACR Cancer Centers Alliance.²  The initiative aims to encourage collaboration among US cancer centers and “accelerate the pace of discovery by providing an ongoing mechanism for transferring new knowledge, sharing resources . . ., and driving innovation that impacts cancer science, cancer care delivery, and science and health policy.”²

Dr Greenberg suggested that the future of cancer research is bright. “I really enthusiastically look forward to what can happen,” he said. “I think there’s no reason not to be optimistic. . . . We’re in this time of unparalleled opportunities.”

Disclosures: Dr Greenberg has relationships with Affini-T, Rapt Therapeutics, Elpiscience, Fibrogen, Immunoscape, Metagenomi, Earli, Catalio, and Nextech. No disclosures were provided in relation to the AACR Cancer Progress Report 2023. Some authors of the Cancer Discovery article declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the article for a full list of disclosures.

Chemotherapy-Induced Nausea and Vomiting Prophylaxis

The cisplatin shortage that has affected cancer centers and patients across the US is nearly resolved, according to a statement from the Biden Administration.¹

The White House reported last week that the cisplatin supply has been restored to almost 100% of pre-shortage levels.

According to the US Food and Drug Administration’s (FDA) drug shortage database, 3 companies had cisplatin available on allocation as of September 18.² Additional supplies of cisplatin are expected to be released this month and next month.

The shortage of cisplatin has occurred alongside prolonged shortages of several other cancer drugs, including methotrexate and carboplatin.³ In June, the National Comprehensive Cancer Network (NCCN) published survey results reporting that cisplatin was in short supply at 70% of included cancer centers, and carboplatin was in short supply at 93%.⁴

The FDA has worked to alleviate these shortages over the past several months.¹ In June, the FDA announced that it would work with Chinese drugmaker Qilu Pharmaceutical and Canadian pharmaceutical company Apotex to temporarily import cisplatin.⁵ According to the FDA, distribution of this product has been completed.²

The FDA also worked with various drug manufacturers to increase production of cisplatin, carboplatin, and methotrexate.¹ According to the FDA database, several companies have methotrexate and carboplatin available now, and additional supplies of both drugs are expected this month and next month.²

“The Administration will continue to work through the FDA, the Department of Health and Human Services, and other agencies to address and prevent drug shortages and mitigate impacts to people facing a cancer diagnosis,” the White House said in its statement.¹

For patients with advanced prostate cancer, financial toxicity associated with use of oral androgen inhibitors can be reduced by comparing Medicare Part D plans.

Enzalutamide and abiraterone are increasingly prescribed by urologists for earlier prostate cancer stages and for longer periods.

In a study, Benjamin Pockros, MD, of the University of Michigan in Ann Arbor, and colleagues compared the costs associated with these drugs across plans available in 12 different zip codes using the free online Medicare Part D Plan Finder. Available plans ranged from 19 in New York, New York (Manhattan) to 28 in Phoenix, Arizona.

Median annual out-of-pocket (OOP) costs were $11,626 for enzalutamide and $9275 for abiraterone, the investigators reported in Urology Practice. Enzalutamide out-of-pocket costs ranged from $9854 to $13,061 per year and abiraterone costs from $1379 to $13,274 per year. The costs reflect both hospital and mail-order pharmacies. Financial assistance programs were excluded.

Less than 30% of patients report comparing drug costs before selecting a Medicare Part D plan. Within certain zip codes, patients could potentially save $2512 on enzalutamide and $9321 on abiraterone annually by choosing the least vs most expensive plan, Dr Pockros and colleagues reported. The median difference in OOP costs between enzalutamide and abiraterone was $8758.

The investigators noted that there is currently no limit on individual OOP spending under Part D coverage.

“Open enrollment season for plan selection occurs annually from October 15 to December 7. Physicians should reach out to their patient panel during these weeks, emphasize that OOP drug costs can substantially vary between Part D plans, disseminate the link to www.medicare.gov/plan-compare, and encourage their patients to compare costs before selecting a new drug plan.”

In an accompanying editorial, Daniel Carson, MD, and Yaw A. Nyame, MD, MS, MBA, of the University of Washington in Seattle, noted:

“Featuring other tools (ie, GoodRx and Mark Cuban Cost Plus Drug Company) and pending legislation (Inflation Reduction Act, beginning 2025) aimed to mitigate rising costs for medications are key as we work toward making the affordability and access to cancer medications equitable for patients with prostate cancer.”

Drug-Induced Photosensitivity

The Food and Drug Administration (FDA) has accepted for Priority Review the supplemental New Drug Application (sNDA) for enzalutamide for the treatment of patients with non-metastatic castration-sensitive prostate cancer (nmCSPC) with high-risk biochemical recurrence (BCR).

Enzalutamide is an androgen receptor inhibitor currently marketed under the brand name Xtandi for the treatment of patients with castration-resistant prostate cancer and metastatic castration-sensitive prostate cancer. 

The sNDA is supported by data from the phase 3 EMBARK trial (ClinicalTrials.gov Identifier: NCT02319837), which enrolled 1068 patients with nmCSPC with high-risk BCR. Study participants were randomly assigned to receive either enzalutamide plus leuprolide (n=355), placebo plus leuprolide (n=358), or enzalutamide monotherapy (n=355). The primary endpoint was metastasis-free survival compared between the enzalutamide plus leuprolide and placebo plus leuprolide arms.

Findings showed enzalutamide plus leuprolide significantly reduced the risk of metastasis or death by 58% vs placebo plus leuprolide (hazard ratio [HR]: 0.42; 95% CI, 0.30-0.61; P <.0001). The combination was also associated with a 93% reduction in the risk of PSA progression, as well as a 64% reduction in the risk of progressing to a new antineoplastic therapy, when compared with placebo plus leuprolide. The most common adverse events reported with enzalutamide plus leuprolide were fatigue, hot flush, and arthralgia.

“The FDA’s granting of a Priority Review designation reinforces the need to bring new treatment options for patients with high-risk biochemical recurrent nmCSPC,” said Chris Boshoff, MD, PhD, Chief Oncology Research and Development Officer, Executive Vice President, Pfizer. “We believe the EMBARK data demonstrate the potential of Xtandi, if approved, to help patients earlier in the course of their disease, building on Xtandi’s foundation as an existing standard of care in prostate cancer.”

A regulatory decision is expected in the fourth quarter of 2023.

Combination treatment with enzalutamide and leuprolide is associated with improved metastasis-free survival compared with leuprolide therapy alone in patients with nonmetastatic hormone-sensitive prostate cancer (nmHSPC) who have high-risk biochemical recurrence (BCR), according to data presented at the American Urological Association’s 2023 Annual Scientific Meeting in Chicago, Illinois.

The finding is from the phase 3 EMBARK trial (ClinicalTrials.gov: NCT02319837), which enrolled 1068 patients who had high-risk BCR after definitive therapy for prostate cancer. The investigators defined high-risk BCR as a PSA doubling time of 9 months or less, a PSA level of 1 ng/mL or higher if they had a radical prostatectomy, with or without radiation therapy, as primary treatment for prostate cancer, or a PSA level of 2ng/mL or more above nadir for patients who had only radiation therapy as primary treatment.

The investigators, led by Neal D. Shore, MD, Director, CPI, of Carolina Urologic Research Center and practitioner at Atlantic Urology Clinics in Myrtle Beach, South Carolina, randomly assigned 355 patients to received enzalutamide (160mg/day) plus leuprolide, 358 to placebo plus leuprolide, and 355 to enzalutamide monotherapy. The median follow-up duration was 60.7 months.

Compared with placebo recipients, the combination arm and enzalutamide monotherapy arm had a significant 58% and 37% lower risk for metastasis, respectively, as well as a significant 93% and 67% lower risk for PSA progression, respectively, Dr Shore reported.

In addition, the combination arm and enzalutamide monotherapy arm had a 64% and 46% decreased risk, respectively, of requiring new antineoplastic therapy.

The most common adverse events were fatigue and hot flashes. The investigators reported observing no new safety signals.

Disclosure: This research was supported by Pfizer Inc. and Astellas Pharma Inc. Please see the original reference for a full list of disclosures.