LYNPARZA® (Olaparib) plus Abiraterone Reduced Risk of Disease Progression by 34% vs. Standard-of-Care in 1st-Line Metastatic Castration-Resistant Prostate Cancer

Combination was well tolerated and allowed patients to maintain their quality of life vs. patients treated with abiraterone alone

PROpel Phase III trial results show clinically meaningful benefit in patients irrespective of homologous recombination repair gene mutations

Reno, Nevada (UroToday.com) -- Positive results from the PROpel Phase III trial showed AstraZeneca and MSD’s Lynparza (olaparib) in combination with abiraterone demonstrated a statistically significant and clinically meaningful improvement in radiographic progression-free survival (rPFS) versus current standard-of-care abiraterone as a 1st-line treatment for patients with metastatic castration-resistant prostate cancer (mCRPC) with or without homologous recombination repair (HRR) gene mutations.

These results will be presented on 17 February at the 2022 American Society of Clinical Oncology (ASCO) Genitourinary Cancers Symposium.

Prostate cancer is the second most common cancer in male patients, causing approximately 375,000 deaths in 2020.¹ Patients with advanced prostate cancer have a particularly poor prognosis and the five-year survival rate remains low.^1-3 Approximately half of patients with mCRPC receive only one line of active treatment, with diminishing benefit of subsequent therapies.^4-7 HRR gene mutations occur in approximately 20-30% of patients with mCRPC.⁸

Fred Saad, Professor and Chairman of Urology and Director of Genitourinary Oncology at the University of Montreal Hospital Center and principal investigator in the trial, said:

“It is clear to me that the prognosis for metastatic castration resistant prostate cancer (mCRPC) is extremely poor, and many patients are only able to receive one line of effective therapy. The results of the PROpel trial, which showed that olaparib in combination with abiraterone significantly delayed disease progression versus abiraterone by more than eight months, demonstrate the potential for this combination to become a new standard of care option in mCRPC if approved.”

Susan Galbraith, Executive Vice President, Oncology R&D, AstraZeneca, said: “This Lynparza combination has the potential to afford first-line patients more time without disease progression while also maintaining their quality of life. The PROpel results are impressive because active comparator trials set a high bar and, in this trial, Lynparza plus abiraterone showed a significant clinical improvement when compared to an active standard of care in patients with metastatic castration-resistant prostate cancer, regardless of whether they have an HRR gene mutation.”

Roy Baynes, Senior Vice President and Head of Global Clinical Development, Chief Medical Officer, MSD Research Laboratories, said: “Results from the PROpel trial showed that Lynparza in combination with abiraterone plus prednisone reduced the risk of disease progression or death by a third compared to abiraterone plus prednisone in the first-line setting for patients with metastatic castration-resistant prostate cancer, regardless of their biomarker status. We look forward to discussing these important results with global health authorities as quickly as possible. We thank the patients, caregivers and health care providers for participating in this study.”

In a predefined interim analysis, Lynparza in combination with abiraterone reduced the risk of disease progression or death by 34% versus abiraterone alone (based on a hazard ratio [HR] of 0.66; 95% confidence interval [CI] 0.54-0.81; p<0.0001). Median rPFS was 24.8 months for Lynparza plus abiraterone versus 16.6 for abiraterone alone.

Results also showed a favourable trend towards improved overall survival (OS) with Lynparza plus abiraterone versus abiraterone alone, however the difference did not reach statistical significance at the time of this data cut-off (analysis at 29% data maturity). The trial will continue to assess OS as a key secondary endpoint.

Additional data from efficacy endpoints such as time to first subsequent therapy (TFST), second progression-free survival (PFS2), objective response rate (ORR), as well as prostate-specific antigen levels and circulating-tumour-cell counts further support the treatment benefit of Lynparza and abiraterone compared to abiraterone alone in the overall trial population.

The safety and tolerability of Lynparza in combination with abiraterone was in line with that observed in prior clinical trials and the known profiles of the individual medicines. There was no increase in the rate of discontinuation of abiraterone in patients treated with Lynparza in combination with abiraterone, and no detrimental effect on health-related quality of life versus those treated with abiraterone alone (FACT-P (Functional Assessment of Cancer Therapy-Prostate) questionnaire).

Summary of PROpel results

	LYNPARZA + abiraterone (n=399)		Placebo + abiraterone (n=397)
rPFS by Investigator ¹
Number of patients with events (%)	168 (42)		226 (57)
Median PFS (in months)	24.8		16.6
HR (95% CI) p-value	0.66 (0.54, 0.81) <0.0001
rPFS by BICR²
Number of patients with events (%)	157 (39)		218 (55)
Median PFS (in months)	27.6		16.4
HR (95% CI) p-value⁵	0.61 (0.49, 0.74) <0.0001
OS³
Number of patients with events (%)	107 (27)		121 (30)
Median OS (in months)	NC⁴		NC
HR (95% CI) p-value	0.86 (0.66, 1.12) 0.2923
PFS2
Number of patients with events (%)	70 (18)		94 (24)
Median (in months)	NC		NC
HR (95% CI) p-value⁵	0.69 (0.51, 0.94) 0.0184
TFST
Number of patients with events (%)	183 (46)		221 (56)
Median (95% CI) (in months)	25.0 (22.2, NC)		19.9 (17.1, 22.0)
HR (95% CI) p-value⁵	0.74 (0.61, 0.90) 0.0040
Objective Response Rate
Number of evaluable patients⁶	161		160
Number of patients with responses (%)	94 (58)		77 (48)
Odds ratio (95% CI)	1.60 (1.02, 2.53)
p-value⁵	0.0409
rPFS by HRR gene mutation status⁷
HRRm
Number of patients randomized	111	115
Number of patients with events (%)	43 (39)	73 (63)
Median (in months)	NC	13.9
HR (95% CI)	0.50 (0.34, 0.73)
Non-HRRm
Number of patients randomized	279	273
Number of patients with events (%)	119 (43)	149 (55)
Median (95% CI) (in months)	24.1 (19.6, 27.6)	19.0 (14.3, 21.9)
HR (95% CI)	0.76 (0.60, 0.97)

1. Investigator-assessed PFS data; Interim analysis with 50% maturity (394 events in 796 patients) 2. Assessed by blinded independent central review (BICR) 3. OS analysis was done at 29% maturity (228 events in 796 patients) and boundary for significance 0.001 (2-sided); statistical significance not reached. Survival follow up continues and further analyses were planned. 4. Not calculable 5. Nominal 6. Patients with measurable disease at baseline as per RECIST 1.1 criteria, investigator assessment. 7. Exploratory subgroup analysis by HRR status. The HRRm status of patients in PROpel was determined retrospectively using results from tumour tissue and plasma ctDNA HRRm tests. Patients were classified as HRRm if (one or more) HRR gene mutation was detected by either test; patients were classified as non-HRRm if no HRR gene mutation was detected by either test; 18 patients did not have a valid HRR testing result from either a tumour tissue or ctDNA test and were excluded from this subgroup analysis. The analysis was performed using a Cox proportional hazards model including terms for treatment group, the subgroup factor, and a treatment by subgroup interaction.

References:

IARC. Cancer Today – Estimated number of new cases in 2020, worldwide, both sexes, all ages. Available at https://gco.iarc.fr/today/home. Accessed January 2022.
Moreira D, et al. Predicting Time From Metastasis to Overall Survival in Castration-Resistant Prostate Cancer: Results From SEARCH. Clin Genitourin Cancer. 2017;15(1):60-66.e2.
Chowdhury S, et al. Real-world outcomes in first-line treatment of metastatic castration-resistant prostate cancer: the prostate cancer registry. Target Oncol. 2020;15(3):301-15.
George DJ, et al. Treatment Patterns and Outcomes in Patients With Metastatic Castration-resistant Prostate Cancer in a Real-world Clinical Practice Setting in the United States. Clin Genitourin Cancer. 2020; 18(4):284-294.
de Bono JS, et al. Subsequent Chemotherapy and Treatment Patterns After Abiraterone Acetate in Patients with Metastatic Castration-resistant Prostate Cancer: Post Hoc Analysis of COU-AA-302. Eur Urol. 2017;71(4):656-664.
Ryan CJ, et al. Abiraterone acetate plus prednisone versus placebo plus prednisone in chemotherapy-naive men with metastatic castration-resistant prostate cancer (COU-AA-302): final overall survival analysis of a randomised, double-blind, placebo-controlled phase 3 study. Lancet Oncol. 2015;16(2):152-160.
Beer TM, et al. Enzalutamide in Men with Chemotherapy-naïve Metastatic Castration-resistant Prostate Cancer: Extended Analysis of the Phase 3 PREVAIL Study. Eur Urol. 2017;71(2):151-154
Mateo, J, et al (2015). DNA-repair defects and olaparib in metastatic prostate cancer. The New England Journal of Medicine, 373(18), pp.1697 - 1708.

Source: Lynparza. 2022. "Lynparza Plus Abiraterone Reduced Risk Of Disease Progression By 34% Vs. Standard-Of-Care In 1St-Line Metastatic Castration-Resistant Prostate Cancer". Astrazeneca.Com.

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