PARP inhibitors emerge as frontline treatment in metastatic castration-resistant prostate cancer, immunotherapy combinations improve quality of life in advanced renal cell carcinoma, and antibody drug conjugates show promise in cisplatin-ineligible urothelial cancer.
Patients with metastatic castration-resistant prostate cancer (mCRPC) and homologous recombination repair (HRR) gene alterations who received frontline treatment with niraparib (Zejula), abiraterone acetate (Zytiga), and prednisone experienced superior radiographic progression-free survival (rPFS) compared with those who received placebo plus abiraterone/prednisone, according to findings from the phase 3 MAGNITUDE trial (NCT03748641). These findings were presented during the 2022 American Society of Clinical Oncology Genitourinary Cancers Symposium.1
In the BRCA1/2 population, the median rPFS was 16.6 months with niraparib/ abiraterone vs 10.9 months with placebo/ abiraterone (HR, 0.53; 95% CI, 0.36-
0.79; P = .0014) at a median follow-up of 18.6 months. The investigator-assessed rPFS was 19.3 months with niraparib/ abiraterone and 12.4 months with placebo/ abiraterone (HR, 0.50; 95% CI, 0.33-0.75; P = .0006).
Among all patients with HRR gene alterations, the median rPFS was 16.5 months vs 13.7 months, respectively (HR, 0.73; 95% CI, 0.56-0.96; P = .0217). Here, the investigator-assessed rPFS was 19.0 months and 13.9 months, respectively (HR, 0.64; 95% CI, 0.49-0.86; nominal P = .0022).
As many as 30% of patients with mCRPC will harbor alterations in genes associ- ated with HRR. Although these alter- ations reflect poor prognosis, they have also shown increased sensitivity to PARP inhibitors, such as niraparib. Notably, the addition of an antiandrogen agent like abiraterone has been theorized to augment responses in all-comers, serving as the rationale for the randomized, double-blind MAGNITUDE trial, which evaluated the value of adding niraparib to abiraterone in patients with mCRPC with and without HRR gene alterations.
“The MAGNITUDE study results support niraparib plus abiraterone as a new first- line treatment option for patients with mCRPC and alterations in genes associ- ated with HRR,” lead study author Kim N. Chi, MD, senior research scientist at the Vancouver Prostate Centre, chief medical officer and vice president for BC Cancer, medical oncologist at BC Cancer–Vancouver, and professor in the Department of Medicine at The University of British Columbia in Canada, said in a presentation of the data.
Chi KN, Rathkopf DE, Smith MR, et al. Phase 3 MAGNITUDE study: first results of niraparib (NIRA) with abiraterone acetate and prednisone (AAP) as first-line therapy in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) with and without homologous recombination repair (HRR) gene alterations. J Clin Oncol. 2022;40(suppl 6):12. doi:10.1200/JCO.2022.40.6_suppl.012
Patients with advanced renal cell carcinoma who received the frontline combination of nivolumab (Opdivo) plus cabozantinib (Cabometyx) maintained superior health-related quality of life (HRQOL) compared with those on sunitinib (Sutent), according to longer follow-up of the CheckMate 9ER trial (NCT03141177). The maintained effects, which were presented during the 2022 American Society of Clinical Oncology Genitourinary Cancers Symposium, were seen across multiple defi- nitions of deterioration, suggesting that the benefit with the combination is sustainable in the long term.1
In a 32.9-month follow-up, patient- reported outcomes (PRO) scores revealed that patients receiving nivolumab/ cabozantinib had maintained or improved HRQOL compared with patients in the sunitinib arm. The longitudinal changes from baseline consequently showed statis- tical significance (P < .05) in favor of the experimental regimen for all scores except FKSI-19 functional well-being.
In the 151 weeks following baseline, patients receiving nivolumab/cabozantinib experienced a –0.47 least square (LS) mean change from baseline FKSI-19 total score compared with a –2.84 decline with those in the sunitinib arm (overall difference in mean change, 2.37; P < .0001). For the FKSI-19 disease-related symptoms score, patients receiving nivolumab/cabozantinib experienced an LS mean change from base- line of 0.71 compared with –0.46 in the sunitinib arm (1.17; P < .0001).
Similarly, patients receiving nivolumab/ cabozantinib experienced an EQ-5D-3L health status score of 2.73 compared with –0.95 in the sunitinib group (3.68; P = .0001). The EQ-5D-3L UK utility index score demonstrated that patients receiving nivolumab/cabozantinib experienced an LS mean change from baseline of –0.01 compared with –0.06 in the sunitinib arm (0.05; P = .001).
At baseline, both arms demonstrated a high PRO completion rate of at least 90%. By week 151, the rates were over 75% and 73% in the nivolumab/cabozantinib and sunitinib arms, respectively. At baseline, both arms demonstrated relatively low symptom burden.
“At nearly 3 years of follow-up, patients continued to report improved HRQOL with nivolumab/cabozantinib compared with sunitinib,” lead study author and coinvestigator David Cella, FASCO, PhD, chair of the Department of Medical Social Sciences and director of the Institute for Public Health and Medicine at Robert H. Lurie Comprehensive Cancer Center of Northwestern University in Chicago, Illinois, wrote in a poster presentation of the findings. “Treatment with [nivolumab/ cabozantinib] was observed to reduce the risk of clinically meaningful deterioration in HRQOL scores in comparison with suni- tinib, regardless of definition of deterioration.”
Cella D, Motzer RJ, Blum SI, et al. Health-related quality of life (HRQoL) in previously untreated patients with advanced renal cell carcinoma (aRCC): CheckMate 9ER updated results. J Clin Oncol. 2022;40(suppl 6):323. doi:10.1200/ JCO.2022.40.6_suppl.323
Darolutamide (Nubeqa), an androgen receptor inhibitor, yielded positive responses in patients with nonmetastatic castration-resistant prostate cancer (CRPC), who were also being treated with concomitant medications or had comorbidities, according to phase 3 data presented at the 2022 American Society of Clinical Oncology Genitourinary Cancers Symposium.1 Patients with nonmetastatic CRPC from the ARAMIS trial (NCT02200614) were randomized 2:1 to receive either darolutamide (n = 955) or placebo (n = 554) while continuing treat- ment with androgen deprivation therapy.
At the final data cutoff date of November 15, 2019, overall survival (OS) and adverse events were evaluated in patients with a median of 6 or fewer or more than 6 comorbidities and 10 or fewer or more than 10 concomitant medications. Comorbidities evaluated included metabolic, cardio- vascular (CV), and other (osteoarthritis, arthralgia, back pain, benign prostatic hyperplasia, constipation, gastroesoph- ageal reflux, and renal insufficiency).
Concomitant medication classes/subclasses included gastrointestinal/metabolic, CV (antihypertensives and nonantihyperten- sives), pain/inflammation, and urologic.
“[Over] 50% of the patients in the ARAMIS trial, which was a very significant number of patients...had a minimum of 6 or more comorbidities of significance,” study coauthor Neal Shore, MD, FACS, US Chief Medical Officer of Surgery and Oncology at GenesisCare USA, and director of the Carolina Urologic Research Center, said in a presentation during the meeting. Specifically, 795 of the total cohort of 1509 patients had at least 6 comorbidities, and 813 patients had received at least 10 concomitant medications.
The investigators reported that, in patients with at least 6 and more than
6 comorbidities, darolutamide prolonged OS compared with placebo (HR, 0.65 and 0.73, respectively). The OS benefit for darolutamide was found to be consistent in patients with metabolic, CV, and other comorbid disorders (HR range, 0.39-0.88). OS was also prolonged in patients receiving at least 10 and more than 10 concomitant medications (HR, 0.76 and 0.66, respectively).
“Subgroups of [patients] receiving concomitant medications for gastrointes- tinal/metabolic disorders, CV disease, urologic disorders, and pain/inflammation achieved similar OS benefit with [darolut- amide vs placebo] with an [HR range of 0.45–0.80],” the authors wrote.
“What we’re showing here is that the OS benefit [and] the safety analysis [were rather significant], regardless of the number of comorbidities,” Shore said.
Fizazi K, Shore ND, Smith MR, et al. Efficacy and safety outcomes of darolutamide in patients with nonmeta- static castration-resistant prostate cancer with comor- bidities and concomitant medications from ARAMIS. J Clin Oncol. 2022;40(suppl 6):256. doi:10.1200/ JCO.2022.40.6_suppl.256
Patients with muscle-invasive bladder cancer (MIBC) who were not eligible for cisplatin experienced promising antitumor responses after receiving neoadjuvant enfortumab vedotin (Padcev), according to preliminary findings from cohort H of the phase 1b/2 EV-103 trial (NCT03288545). These findings were presented during the 2022 American Society of Clinical Oncology Genitourinary Cancers Symposium.1
Investigators reported a pathological complete response rate of 36.4% (95% CI, 17.2%-59.3%) among those treated with enfortumab vedotin (n = 22) and a pathological downstaging rate of 50.0% (95% CI, 28.2%-71.8%).
“This first disclosure of data support the ongoing phase 2 and 3 programs evaluating enfortumab vedotin alone or in combi- nation with pembrolizumab (Keytruda) in MIBC,” lead study author Daniel P. Petrylak, MD, professor of medical oncology and urology at the Yale Cancer Center in New Haven, Connecticut, said in a presentation of the data.
Patients received 1.25 mg/kg of neoad- juvant enfortumab vedotin monotherapy on days 1 and 8 per 21-day cycle for 3 cycles. Within 4 weeks of treatment, patients underwent radical cystectomy plus pelvic lymph node dissection, followed by imaging every 12 weeks for the first 2 years, then every 24 weeks after.
The most common reason for cisplatin ineligibility was creatinine clearance between less than 60 and 30 or more mL per minute (50.0%), followed by grade 2 or greater hearing loss (40.9%). A total of 86% of patients completed all 3 cycles of neoadjuvant therapy.
Any-grade enfortumab vedotin–related treatment-emergent adverse events (TEAEs) were seen in all patients. Common TEAEs included fatigue (45.5%), alopecia (36.4%), dysgeusia (36.4%), diarrhea (27.3%), nausea (27.3%), peripheral sensory neuropathy (27.3%), dry eye (22.7%), and maculopap- ular rash (22.7%). Four patients experienced grade 3 or higher TEAEs, and no grade 4 TEAEs or deaths were reported. Grade 3 TEAEs related to treatment with enfortumab vedotin included asthenia, dehydration, erythema multiforme, and hyperglycemia.
In the safety analysis, 3 enfortumab vedotin–related TEAEs leading to dose interruptions, 2 TEAEs leading to dose reductions, and 3 TEAEs leading to discon- tinuations were observed. Most adverse events (AEs) of special interest were grade 1 and 2. Any-grade AEs of interest included peripheral neuropathy (36.4%), skin reac- tion (63.6%), hyperglycemia (22.7%), ocular disorder (40.9%), and infusion-re- lated reactions (9.1%). Grade 3 or greater AEs of special interest were skin reactions (9.1%) and hyperglycemia (13.6%).
“The observed safety profile of neoad- juvant enfortumab vedotin monotherapy in patients with cisplatin-ineligible MIBC is consistent with the known AE profile of enfortumab vedotin in other settings,” Petrylak said.
Petrylak DP, Flaig TW, Mar N, et al. Study EV-103 cohort H: antitumor activity of neoadjuvant treatment with enfor- tumab vedotin monotherapy in patients (pts) with muscle invasive bladder cancer (MIBC) who are cisplatin-inel- igible. J Clin Oncol. 2022;40(suppl 6):435. doi:10.1200/ JCO.2022.40.6_suppl.435