Jason M Broderick

Adjuvant Lynparza benefits patients with BRCA1/2 mutation-positive, HER2-negative breast cancer, six-year OlympiA trial data show.

Patients with BRCA1/2 mutation-positive, HER2-negative high-risk breast cancer have continued to experience clinically meaningful results from treatment with adjuvant Lynparza (olaparib), study results have shown.

Six-year results from the third pre-specified analysis of the phase 3 OlympiA trial were reported at the reported at the 2024 San Antonio Breast Cancer Symposium.

The analysis occurred at a median follow-up of 6.1 years and 2.6 years since the previous analysis. The updated data for all first invasive disease-free survival (iDFS) events — the primary end point of the trial — demonstrated that distant (11.5% versus 16.3%), regional (1.2% versus 2.4%) and local recurrences (1.2% versus 1.3%) all continued to be less frequent in the Lynparza arm versus the placebo arm, Dr. Judy Garber reported at the symposium. This translated to a 9.4% absolute difference in the six-year iDFS rate favoring Lynparza versus placebo.

The iDFS benefit was consistent across all prespecified patient subgroups, including hormone receptor–positive patients and triple-negative patients.

Adjuvant: treatment that follows primary treatment.

Invasive disease-free survival: the time a patient lives without cancer.

Distant disease-free survival: the time a patient lives without the present of distant metastases, or sites where cancer has spread from its original location.

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

Neoadjuvant: treatment that precedes primary treatment.

“At this updated analysis, the magnitude of the benefit remains similar with more than 30% reduction in both groups,” said Garber, who is the Susan F. Smith Chair and chief of the Division of Cancer Genetics and Prevention at Dana-Farber Cancer Institute and a Professor of Medicine at Harvard Medical School, both in Boston.

The absolute difference in the six-year distant disease-free survival (DDFS) rate also favored Lynparza at 7.8%. The DDFS benefit was consistent across all subgroups.

At the time of the updated analysis, there had been 107 (11.6%) deaths in the Lynparza arm and 143 (15.6%) deaths in the placebo arm. The primary cause of death in both arms was breast cancer recurrence (10.2%, Lynparza arm; 14%, placebo arm). The absolute difference in the six-year overall survival (OS) rate was 4.4% favoring Lynparza. As with iDFS and DDFS, the OS benefit was consistent across all subgroups.

“These data continue to support adjuvant [Lynparza] as standard of care for patients with BRCA+ high-risk HER2-negative primary breast cancer and therefore highlight the importance of germline BRCA testing for treatment planning,” said Garber.

The safety population included 911 patients in the Lynparza arm and 904 patients in the placebo arm. Adverse events (AEs, side effects) of special interest continued to be higher in the placebo arm. AEs of special interest occurring at any time were reported in 6.3% of the Lynparza arm versus 9.3% in the placebo arm.

There were fewer second primary malignancies in the Lynparza group at 4.9% versus 7.5%. “Of note, with further follow-up the incidence of MDS/AML events, in particular, remains low with four in the [Lynparza] arm and six in the placebo arm,” said Garber. 

OlympiA Trial Design and Patient Characteristics

The multicenter OlympiA trial enrolled 1,836 patients with HER2-negative breast cancer harboring a germline BRCA1/2 mutation. Patients were randomized evenly to receive 300 milligrams (mg) of oral Lynparza twice daily for a year (921 patients) or placebo (915 patients). Additionally, patients had to have been treated for stage 2 or 3 breast cancer, and have completed surgery and chemotherapy, with or without radiotherapy. Inclusion criteria also required that patients have a high risk of disease recurrence. Prior treatment with a PARP inhibitor was not allowed.

Patient characteristics were well balanced between the study arms, with a median age of about 43 years. About 70% of patients in each cohort had a BRCA1 mutation, with about 30% having a BRCA2 mutation. Around 60% of patients in each arm were premenopausal and nearly 75% had received mastectomy. Approximately 80% of patients in each arm were triple-negative. About half of the patients in each cohort received adjuvant chemotherapy and about half received neoadjuvant chemotherapy. About 90% of the hormone receptor­–positive patients in the study groups received concurrent endocrine therapy.

Significant benefits for IDFS and DDFS with Lynparza had been previously demonstrated in the first interim analysis of the OlympiA trial, as well as a significant OS benefit in the second analysis.

Based on the initial data from the OlympiA trial, the FDA previously approved Lynparza for the adjuvant treatment of patients with germline BRCA-mutated, HER2-negative, high-risk early breast cancer who have previously received chemotherapy either before or after surgery.

In her concluding remarks, Garber noted that blinded follow-up for the final planned analysis of the OlympiA trial is continuing until June 2029.

OlympiA- Phase 3, multicenter, randomized, placebo-controlled trial of adjuvant olaparib after (neo)adjuvant chemotherapy in patients w/ germline BRCA1/BRCA2 pathogenic variants & high risk HER2-negative primary breast cancer; longer term follow.-up, presented by Dr. Judy Garber at San Antonio Breast Cancer Conference; Dec. 10 to 13, 2024; San Antonio, Texas.

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Articles

The OlympiA trial's six-year analysis reveals that adjuvant Lynparza (olaparib) continues to provide significant benefits for patients with BRCA1/2 mutation-positive, HER2-negative high-risk breast cancer. The trial demonstrated a 9.4% absolute improvement in invasive disease-free survival (iDFS) and a 7.8% improvement in distant disease-free survival (DDFS) with Lynparza compared to placebo. Overall survival (OS) also favored Lynparza with a 4.4% difference. Adverse events were lower in the Lynparza group, supporting its use as a standard care option for this patient population.

Adjuvant Lynparza remains beneficial for patients with BRCA1/2 mutation–positive, HER2-negative high-risk breast cancer, study results have shown. 

Lynparza Continues to Benefit in BRCA1/2+, HER2- Breast Cancer

Padcev plus Keytruda outperformed chemotherapy when it came to overall survival and progression-free survival in frontline advanced bladder cancer treatment. 

Padcev (enfortumab vedotin-ejfv) plus Keytruda (pembrolizumab) led to better overall survival (OS; time from treatment until death of any cause) compared with chemotherapy in patients with previously untreated locally advanced or metastatic (spread to other parts of the body) urothelial carcinoma, a type of bladder cancer, according to findings from the phase 3 EV-302 clinical trial.

Findings, which were presented at the 2023 

, showed that at a median follow-up of 17.2 months, treatment with Padcev plus Keytruda — a regimen the researchers referred to as “EVP” — reduced the risk of death by 53% versus chemotherapy.

The median OS was 31.5 months in the EVP arm compared with 16.1 in the chemotherapy arm. The OS benefit was observed regardless of whether patients in the control arm received cisplatin or carboplatin and was not impacted by PD-L1 status or existence of visceral metastases.

Treatment with the combination also led to a significant improved in progression-free survival (PFS; time from treatment until disease gets worse or patients die) versus chemotherapy. The median PFS was 12.5 months with EVP compared with 6.3 months with chemotherapy, translating to a 55% reduction in the risk of disease progression or death. The PFS benefit was sustained across all pre-specified subgroups, such as those defined by cisplatin eligibility, PD-L1 status and visceral metastases.

“This is the first time (in urothelial carcinoma) we've managed to beat chemotherapy in the first-line setting for overall survival, despite multiple previous attempts. (Padcev) and (Keytruda) showed significant decrease in the risk of death and a decrease in the risk of progression compared to chemotherapy. These results support (Padcev) plus (Keytruda) as a standard of care in this setting,” said lead study author Dr. Thomas B. Powles, director, Barts Cancer Centre at St. Bartholomew’s Hospital in London.

The open-label EV-302 trial included 886 patients with previously untreated locally advanced or metastatic urothelial carcinoma with an ECOG performance status of 2 or lower, indicating that they can perform most of their daily tasks with minimal help, who were eligible for cisplatin- or carboplatin-containing chemotherapy. The median age in both arms was 69 years and about three-fourths of patients were male. The majority of patients in the trial were White, making up 69.7% and 65.3% of the EVP and control arms, respectively. About 97% of patients in both arms had an ECOG performance status of 0 or 1.

In the EVP arm, the primary tumor location was upper tract for 30.5% of patients and lower tract for 69.0%. The rates were 23.4% and 76.4%, respectively, in the chemotherapy arm. Fifty-four percent of patients in each arm were cisplatin eligible and 72% had visceral metastases. Regarding PD-L1 status, 58% of in each arm had high expression (combined positive score [CPS] ≥10), with the remaining 42% having low expression (CPS <10).

Patients were randomly assigned to receive standard of care chemotherapy consisting of gemcitabine plus cisplatin or carboplatin for a maximum of 6 cycles (444 patients) or Padcev on days 1 and 8 and Keytruda on day 1 of 3-week cycles (442 patients). The maximum number of Keytruda cycles allowed was 35 and there was no maximum number of cycles for Padcev. The co-primary end points were OS and PFS.

The confirmed objective response rate (ORR; percentage of patients whose disease responded to treatment) was 67.7% in the EVP arm compared with 44.4% in the chemotherapy arm. The ORR in the EVP group consisted of a complete response (CR; meaning that there were no tracible signs of cancer after treatment) rate of 29.1% and a partial response (PR) rate of 38.7%. The stable disease (SD) rate was 18.8% and the progressive disease (PD) rate was 8.7%. In the chemotherapy arm, the ORR consisted of a CR rate of 12.5% and a PR rate of 32%. The SD rate was 33.8% and the PD rate 13.6%.

The median number of cycles received was 12 (range, 1-46) for EVP and six (range, 1-6) for chemotherapy. Overall, 67% of patients in the EVP arm and 45.7% of patients in the chemotherapy arm remained on study at the time of the analysis. In the EVP arm, 34.6% of patients discontinued treatment due to progressive disease compared with 16.4% of patients in the chemotherapy arm. Side effect-related discontinuations occurred in 21.9% and 14.0% of the two arms, respectively. Regarding subsequent immunotherapy in the chemotherapy arm, 59% received a PD-1/L1 inhibitor and 30% of patients received maintenance Bavencio (avelumab).

“The safety profile of EVP was generally manageable, with no new safety signals observed,” said Powles. “Hematological toxicity was more prominent with chemotherapy, while peripheral neuropathy, rash, and hyperglycemia are adverse events of special interest with EVP.”

The safety data showed that 56% of patients receiving EVP and 70% of patients in the chemotherapy arm experienced grade 3 or higher treatment-related side effects. Serious side effects occurred in 27.7% vs 19.6% of the two arms, respectively.

FDA granted an accelerated approval to Keytruda plus Padcev

 for the first-line treatment of patients with locally advanced or metastatic urothelial carcinoma who are ineligible for cisplatin-containing chemotherapy.

For the first time, a drug combination (Padcev plus Keytruda) outperformed frontline chemotherapy for patients with locally advanced or metastatic urothelial carcinoma. 

Padcev Plus Keytruda Reduces Risk of Death, Disease Progression in Advanced Bladder Cancer

The combination of Welireg (belzutifan) and Lenvima (lenvatinib) showed promising clinical activity with manageable toxicity in patients with advanced clear cell renal cell carcinoma (ccRCC) and disease progression after receiving a PD-1/L1 inhibitor and a VEGF-TKI, according to initial results from arm B5 of the phase 1/2 KEYMAKER-U03B study.

 showed that at a median follow-up of 6.9 months, a regimen combining Welireg and the VEGF-TKI Lenvima elicited an objective response rate (percentage of patients whose disease shrunk or disappeared as a result of treatent) of 50% among 24 patients who had received at least two follow-up scans after enrolling in the trial. All of the responses were partial responses, meaning that the disease got smaller, but did not disappear entirely.

Data from the phase 1/2 KEYMAKER-U03B study showed promising results for the use of Welireg plus Lenvima to treat patients with clear cell renal cell carcinoma. 

The clinical benefit rate (patients whose disease responded and was stable for six or more months) was 54% and the median duration of response was not reached. Nearly three-fourths (74%) of responders remained in response for 12 months or longer. One patient had progressive disease.

Among all enrolled patients, the median progression-free survival (average time from treatment until disease worsened) was 11.2 months and at six months, 55% of patients did not experience disease progression.

“Preliminary results…from arm B5 of KEYMAKER-U03B showed promising antitumor activity with (Welireg) plus (Lenvima) in patients with (clear cell renal cell carcinoma) that progressed on PD-1/L1 inhibitors and VEGF-TKIs, a population that has limited efficacious treatment options,” said first study author Dr. Laurence Albiges, from the Institut Gustave Roussy, Villejuif, France.

Overall, the multicenter, multi-arm, open-label, adaptive, phase 1/2 KEYMAKER-U03B study is exploring various treatment combinations in patients with heavily pretreated clear cell renal cell carcinoma who have progressed after receiving a PD-1/L1 inhibitor and a VEGF-TKI, either in combination or given in sequence. As of the cutoff date of Sept. 29, 2022, 32 patients had been enrolled in arm B5, 30 had been treated and 23 remained on treatment.

The median patient age was 60.5 years, 78% of patients were male, and 78% of patients had intermediate/poor IMDC risk disease. The ECOG performance status was 0 for 17 patients and 1 for 15 patients. Seventy-eight percent of patients had prior nephrectomy, which is the surgical removal of one or both of the kidneys.

Patients in arm B5 were treated with Welireg at 120 mg orally each day and Lenvima at 20 mg orally each day. Patients received a median of 3.5 treatment cycles (range, 1.0-13.0)

There were no new side effects compared with the safety profiles of Welireg and Lenvima reported in previous research.In the safety lead-in phase of the trial, only 1 of 10 evaluable patients had a dose-limiting toxicity, which was difficult or labored breathing (grade 1).

In the overall safety analysis, which included all 30 treated patients, 93% (28 patients) of patients experienced at least one treatment-related side effect. The side effects that occurred in at least 30% of patients were anemia (43%), fatigue (43%), hypertension (43%), proteinuria (33%), diarrhea (33%), nausea (33%) and decreased appetite (30%).

Moderate or severe (grade 3/4) side effects occurred in half (15) of the patients. The most common grade 3/4 side effects were hypertension (27%) and anemia (17%). Side effects led to one patient discontinuing both study drugs, two patients discontinuing Lenvima and two patients discontinuing Welireg. There were no deaths due to side effects.

The combination is being further examined in the phase 3 LITESPARK-011 study, which is evaluating Welireg plus Lenvima compared with Cabometyx (cabozantinib) in patients with advanced kidney cancer and disease progression after treatment with a PD-1/L1 inhibitor.

Nearly three-fourths of patients with clear cell renal cell carcinoma had a disease response lasting 12 months or longer after being treated with Welireg and Lenvima, study data showed. 

Welireg Plus Lenvima Has ‘Promising Antitumor Activity’ in Kidney Cancer Subset

Bavencio (avelumab) plus Inlyta (axitinib) proved to be an effective option for the neoadjuvant (presurgical) treatment of patients with high-risk, non-metastatic clear-cell renal cell carcinoma, a common type of kidney cancer, according to findings from the NeoAvAx trial presented at the 2022 ASCO GU Symposium.

In the phase 2 trial, neoadjuvant Bavencio/Inlyta induced a partial response in 12 (30%) of 40 patients. On average, patients’ primary tumors shrunk by 20%. Among patients with a partial response, 10 of 12 were disease-free at the study data cutoff.

At a median follow-up of 23.5 months, the average length of overall survival (OS; defined as how long patients live after treatment) and median disease-free survival (DFS; meaning that there are no signs of the disease) had not yet been reached since many study participants are still alive. No patients had progression of their primary tumor.

NeoAvAx is the first trial combining these types of drugs — Bavencio is an immune checkpoint inhibitor and Inlyta is a tyrosine kinase inhibitor — for this particular patient population. Since the findings were so promising, it could lead to future studies where the drug duo is compared to other standards of care for high-risk clear cell RCC.

“This is the first neoadjuvant trial reporting results from a combination of an immune checkpoint inhibitor and VEGFR-TKI for locally advanced high-risk RCC,” said lead study author Dr. Axel Bex, of the Netherlands Cancer Institute.“The DFS data are encouraging, supporting further evaluation, although currently there are no randomized neoadjuvant versus adjuvant (immune checkpoint inhibitor) trials or neoadjuvant versus adjuvant ICI/VEGFR-TKI combination (trials in this setting).”

Explaining the background of the NeoAvAx trial, Bex said, “Antibodies targeting PD-1/PD-L1 combined with VEGF inhibitors are a first-line standard of care for metastatic RCC. Neoadjuvant use of these combinations may lead to downstaging and reduce the risk of recurrence.”

Overall, there were 40 patients enrolled in the trial between May 2018 and October 2021.

The median patient age was 63 years and 70% of patients were male.

Researchers considered each patient’s World Health Organization (WHO) performance status, which ranks patients’ restrictions on a scale of 0 (no restrictions to daily life as a result of the disease/treatment) to 4 (completely disabled) and 5 (dead). The WHO performance status was 0 for 30 patients and 1 (restricted for strenuous activity but allowed to do light/sedentary work) for 10 patients.

Ninety percent of patients’ disease was classified as stage T3 or higher, indicating that the cancer has grown into major veins within the kidney or nearby tissue.

Across the population, 42.5% of patients were clinically node positive.

Patients in the trial received Inlyta at 5 mg twice daily and Bavencio at 10mg/kg every two weeks. The main goal of the study was partial response (cancer shrinking) at week 12. Secondary endpoints included DFS, OS, and safety, and biomarker analysis on sequential tissue was an exploratory end point.

Overall, 13 (32.5%) patients had disease recurrence and three patients died of disease.

Bex said there were no new side effects with the neoadjuvant regimen as compared with previously reported safety data for Inlyta and Bavencio.

The majority of side effects were considered mild or bothersome, but not serious or severe. There were six total grade 3 side effects, comprising one case each of high blood pressure, infusion-related reaction, fatigue, nausea, hand-foot syndrome (defined as redness, swelling and blistering on the palms of the hands and soles of the feet) and elevated liver function tests.

Addressing the safety profile of the subsequent surgery patients received after the neoadjuvant regimen, Bex said, “Surgical adverse events were as expected in this patient population with locally advanced RCC.”

Bex also summarized the findings from the exploratory biomarker analysis. Patients with a higher concentration of CD8+ T cells tended to have better outcomes. Now, the researchers are continuing to further investigate other tumor differences that may impact outcomes.

"Spatial transcriptomics of post-treatment primary tumor tissue revealed focal intratumoral differences in immune signatures and we are currently investigating this further to see whether this may be one of the reasons why these patients have recurrence,” Bex said.

Bavencio and Inlyta is currently Food and Drug Administration approved

 for the frontline treatment of patients with advanced RCC. The approval was based on results from the pivotal phase 3 JAVELIN Renal 101 trial, which showed that the combination was associated with a 31% reduction in the risk of disease progression or death compared with Sutent (sunitinib) in patients with advanced RCC that has not previously been treated.

In a recent clinical trial, treatment with Bavencio plus Inlyta produced promising outcomes in the presurgical treatment of patients with non-metastatic, clear cell renal cell carcinoma.

Jason M Broderick

Lynparza Continues to Benefit in BRCA1/2+, HER2- Breast Cancer

Padcev Plus Keytruda Reduces Risk of Death, Disease Progression in Advanced Bladder Cancer

Welireg Plus Lenvima Has ‘Promising Antitumor Activity’ in Kidney Cancer Subset

Drug Duo Sparks Encouraging Outcomes in Treatment of Clear Cell Kidney Cancer

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