AstraZeneca and Merck’s LYNPARZA® Phase 3 PAOLA-1 Trial Presented

| By | AstraZeneca, Cancer Drugs, Clinical Trials, Merck
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AstraZeneca and Merck, known as MSD outside the United States and Canada, announced detailed positive results from the Phase 3 PAOLA-1 trial showing LYNPARZA added to bevacizumab demonstrated a statistically significant and clinically meaningful improvement in progression-free survival (PFS) in women with newly-diagnosed advanced ovarian cancer who had a complete or partial response to first-line treatment with platinum-based chemotherapy and bevacizumab.

The trial compared LYNPARZA when added to standard-of-care (SoC) bevacizumab versus bevacizumab alone in women in the first-line maintenance setting, irrespective of their genetic biomarker status or outcome from previous surgery. Investigator-assessed results showed LYNPARZA added to bevacizumab reduced the risk of disease progression or death by 41% and improved PFS to a median of 22.1 months versus 16.6 months for those treated with bevacizumab alone (HR 0.59 [95% CI, 0.49-0.72], p<0.0001).

The sensitivity analysis of blinded independent central review (BICR) of PFS was consistent, showing a similar improvement with a median of 26.1 months for LYNPARZA added to bevacizumab versus 18.3 months for bevacizumab alone (HR 0.63 [95% CI, 0.51-0.77], p<0.0001).

The safety and tolerability profile of LYNPARZA and bevacizumab were consistent with those known from previous trials for each medicine.

The results were presented at the Presidential Symposium of the 2019 European Society of Medical Oncology (ESMO) congress in Barcelona, Spain (Abstract #LBA2_PR).

Dr. José Baselga, executive vice president, Oncology R&D, AstraZeneca, said,

“This trial was designed to reflect everyday clinical practice and used a global standard-of-care treatment with LYNPARZA. We are working with regulatory authorities to bring LYNPARZA to these patients as quickly as possible.”

Dr. Roy Baynes, senior vice president and head of global clinical development, chief medical officer, Merck Research Laboratories, said,

“PAOLA-1 is the second positive Phase 3 trial involving LYNPARZA in the first-line maintenance setting for advanced ovarian cancer. Following the positive SOLO-1 trial, we are encouraged by the PAOLA-1 results which reaffirm AstraZeneca and Merck’s ongoing commitment to exploring potential treatment options for more women with ovarian cancer.”

Isabelle Ray Coquard, principal investigator of the PAOLA-1 trial and medical oncologist, Department of Medical Oncology at the Clinical Science Institute of the Léon Bérard Centre and President of the GINECO (Groupe d’Investigateurs National des Etudes des Cancers Ovariens et du sein) group, said, “The goal of first-line, including maintenance treatment for women with newly-diagnosed advanced ovarian cancer, is to delay relapse. Unfortunately, the risk of relapse is high, as two out of three women relapse within three years of initial diagnosis. In PAOLA-1, the results of LYNPARZA added to bevacizumab were significant and have the potential to change clinical practice in how women with advanced ovarian cancer are treated in the first-line maintenance setting.”

The trial also included exploratory sub-group analyses including BRCA-mutated (BRCAm) and broader homologous recombination deficiency (HRD) populations. In the BRCAm-positive sub-group, LYNPARZA added to SoC bevacizumab vs. bevacizumab alone resulted in median PFS of 37.2 months versus 21.7 months (HR 0.31 [95% CI, 0.20-0.47]) and 18.9 months versus 16 months in the non-BRCAm sub-group (HR 0.71 [95% CI, 0.58-0.88]). For the HRD-positive sub-group, median PFS for LYNPARZA added to bevacizumab was 37.2 months versus 17.7 months with bevacizumab alone (HR 0.33 [95% CI, 0.25-0.45]). In the HRD-positive, non-BRCAm sub-group, there was a median PFS of 28.1 months with LYNPARZA added to bevacizumab versus 16.6 months on bevacizumab alone (HR 0.43 [95% CI, 0.28-0.66]). The HRD-negative/unknown sub-group results showed a median PFS of 16.9 months for LYNPARZA added to bevacizumab vs. 16 months for bevacizumab alone (HR 0.92 [95% CI, 0.72-1.17]).

Summary of PFS in overall population:

Median in months

Hazard Ratio (95% CI)

LYNPARZA
+
bevacizumab

bevacizumab
alone

PFS (investigator assessed)

(n=806)

22.1

16.6

0.59 (0.49-0.72)

p<0.0001

PFS (BICR)

26.1

18.3

0.63 (0.51-0.77)

p<0.0001

Summary of PFS in exploratory subgroup analyses:

Median in months

Hazard Ratio (95% CI)

LYNPARZA
+
bevacizumab

bevacizumab
alone

PFS by BRCAm status

BRCAm (n=237)

37.2i.

21.7

0.31 (0.20-0.47)

Non-BRCAm (n=569)

18.9

16.0

0.71 (0.58-0.88)

PFS by HRD status

HRD-positive (n=387)

37.2i.

17.7

0.33 (0.25-0.45)

HRD-positive, non-BRCAm (n=152)

28.1i.

16.6

0.43 (0.28-0.66)

HRD-negative/unknown (n=419)

16.9

16.0

0.92 (0.72-1.17)

The median PFS estimate is immature at this time (below 50% maturity) and will evolve with additional follow up

The most common adverse events (AEs) ≥20% for LYNPARZA plus bevacizumab compared to bevacizumab alone were nausea (53% vs. 22%), fatigue (53% vs. 32%), hypertension (46% vs. 60%), anemia (41% vs. 10%), lymphopenia (24% vs. 10%), vomiting (22% vs. 11%) and arthralgia (22% vs. 24%). Overall Grade 3 or above (AEs) were 57% for LYNPARZA added to bevacizumab and 51% for bevacizumab alone. Grade 3 or above AEs were hypertension (19% vs. 30%), anemia (17% vs. 0.4%), lymphopenia (7% vs. 1%), fatigue (5% vs. 2%), neutropenia (6% vs 3%), nausea (2% vs. 1%), diarrhea (2% each), leukopenia (2% vs. 1%), vomiting (2% each) and abdominal pain (1% vs. 2% AEs led to dose interruption in 54% of patients on LYNPARZA plus bevacizumab vs. 24% on bevacizumab alone, while 20% of patients on LYNPARZA plus bevacizumab discontinued treatment vs. 6% on bevacizumab alone.

LYNPARZA, which is being jointly developed and commercialized by Merck and AstraZeneca, is currently approved in 64 countries, including those in the EU, for the maintenance treatment of platinum-sensitive relapsed ovarian cancer regardless of BRCA status. It is approved in the U.S. as first-line maintenance treatment in BRCAm advanced ovarian cancer following response to platinum-based chemotherapy. It is also approved in 38 countries, including the U.S., countries in the EU, and Japan, for germline BRCAm HER2-negative metastatic breast cancer previously treated with chemotherapy; in the EU this includes locally advanced breast cancer. LYNPARZA has been used to treat over 25,000 patients worldwide.

LYNPARZA is the only PARP inhibitor with positive Phase 3 trials in four different cancer types.

SOURCE: mrknewsroom.com
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