PARP inhibitors have generated huge excitement with their recent approvals in ovarian and breast cancer, these agents are making a meaningful impact in the health and survival of patients.

AstraZeneca’s Lynparza (olaparib) captured the biggest headlines of ESMO 2018 Congress with results released of the SOLO-1 trial in ovarian cancer. Decision Resources Group expects Lynparza will drastically change the front-line management of advanced-stage, BRCA-mutated patients.

In addition, Clovis Oncology’s Rubraca (rucaparib) also showed promising clinical data in metastatic castrate resistant prostate cancer (mCRPC), supporting the rationale for the ongoing pivotal Phase III trial TRITON3.

 

SOLO-1: Lynparza maintenance shows an impressive PFS benefit in first-line BRCA-mutated ovarian cancer

Results from the SOLO-1 trial were widely anticipated following AstraZeneca's announcement in June that Lynparza met the primary endpoint of PFS in first-line advanced-stage BRCA-mutated ovarian cancer1.

After almost 3 years and a half (41 months) of follow-up, the mPFS for patients treated with Lynparza was not reached, the mPFS was 13.8 months (HR 0.30 [95% CI 0.23-0.41], p<0.001) for patients receiving placebo. Lynparza reduced the risk of disease progression or death by 70% by demonstrating a statistically significant and clinically meaningful improvement in PFS compared to placebo. At 3 years of follow-up (36 months), 60% of the patients who were treated with Lynparza were progression-free, compared to 27% in the placebo group2.  

Additionally, the secondary endpoint progression after the next line of therapy (PFS2), was significantly improved which suggests that first-line Lynparza maintenance treatment will not negatively impact the outcome of subsequent treatments among patients that progress. Lynparza was well tolerated and the adverse events were consistent with the those previously reported in SOLO-2 and Study-19.

How will these results impact the management of ovarian cancer disease?

Only 10% - 15% of newly-diagnosed advanced-stage ovarian cancer patients experience a long-term disease survival3, so there is a high unmet need for new therapies that can cure the disease or can deliver a durable remission.

PFS is an indicator of effectiveness and many attempts have failed to improve PFS in the first-line setting4. Avastin is the only therapy that has shown a mPFS improvement of 6.2 months5, and is currently approved in first-line ovarian cancer in combination with platinum-based chemotherapy followed by Avastin maintenance, but this mPFS improvement is dwarfed by the huge improvement seen at 3 years follow-up with Lynparza maintenance.

Therefore, we anticipate that Lynparza maintenance will become the first PARP inhibitor treatment for newly diagnosed advanced-stage patients with a BRCA mutation, and will likely be widely prescribed.

It will be crucial to test BRCA mutations at diagnosis to determine which treatment is more suitable. In 2020, we expect to see clinical data from the PRIMA trial, where Tesaro’s Zejula (niraparib) is being investigated in advanced-stage first-line ovarian cancer, regardless BRCA status. If positive, Zejula could drastically change the front-line management in a wider population of ovarian cancer.

 

TRITON2: Promising activity with Rubraca in mCRPC

Initial results from the TRITON2 trial were also hotly anticipated, after Clovis Oncology announced the FDA had awarded Rubraca breakthrough therapy designation (BTD) in early October6. The BTD is granted for the use of Rubraca in patients with BRCA-mutated mCRPC patients who have received at least one prior androgen receptor-directed therapy and taxane-based chemotherapy.

A total of 85 patients enrolled in TRITON2 with a DNA damage repair (DDR) defect were evaluable for PSA response rate (defined as a 50% decrease in PSA). Rubraca demonstrated a PSA response of 51.1% among the 45 BRCA mutated patients (23/45 [35.8 – 66.3]).

The co-primary endpoint was overall response rate (ORR) for patients with measurable disease at baseline; a total of 46 patients were evaluable, including 25 with a BRCA mutation. Rubraca achieved an ORR of 44% in patients with BRCA alteration (11/25 [24.4 – 65.1]).7

Rubraca is a promising therapy for BRCA-mutated mCRPC if we consider that Zytiga (COU-AA-301 trial) and Xtandi (AFFIRM trial) showed PSA responses (38% and 54%, respectively) and ORR (14% and 29%, respectively)8,9 not greater than the results observed in TRITON2. However, Rubraca’s data is only preliminary from a Phase II study. A longer follow up with a larger patient population is needed to confirm Rubraca’s activity in mCRPC.

Rubraca also showed a few responses in patients with other DDR mutations (CDK12, FANCA, BRIP1), which differ to the data released for Lynparza (TOPARP trial).10 For instance, Lynparza confirmed responses in patients with ATM mutations, while Rubraca showed no response in patients with this alteration.

Therefore, longer follow-up and more data is needed to better assess the target populations for DDR deficient beyond BRCA mutations with Rubraca treatment. This will be key to develop a marketing strategy to differentiate Rubraca from Lynparza, which is also seeking for approval in a similar mCRPC patient population and is expected to enter first in the market.

 

What does this mean for the industry?

PARP inhibitors have shown extremely encouraging data that could help pave the way for an entirely new treatment algorithm in both ovarian and prostate cancer, and new options for patients.

We expect PARP inhibitors to be a commercially successful drug class, capturing almost $4 billion by 2026 in the major-markets across different indications.

Decision Resources Group expect the approvals and label expansions of four PARP inhibitors in multiple markets in the upcoming years.

 

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References:

  1. AstraZeneca press release “Lynparza significantly delays disease progression in Phase III 1st-line SOLO-1 trial for ovarian cancer”, 27 June 2018. Available at: https://www.astrazeneca.com/media-centre/press-releases/2018/lynparza-significantly-delays-disease-progression-in-phase-iii-1st-line-solo-1-trial-for-ovarian-cancer.html
  2. Moore K, et al. Maintenance Olaparib in Patients with Newly Diagnosed Advanced Ovarian Cancer. N Engl J Med. 2018; DOI: 10.1056/NEJMoa1810858.
  3. Armstrong DK. Relapsed Ovarian Cancer: Challenges and Management Strategies for a Chronic Disease. The Oncologist. 2002; 7(5): 20-28; DOI: 10.1634/theoncologist.7-suppl_5-20.
  4. Ledermann JA. First-line treatment of ovarian cancer: questions and controversies to address. Ther Adv Med Oncol. 2018; 10: 1758835918768232.
  5. Genentech press release “FDA Approves Genentech’s Avastin (Bevacizumab) Plus Chemotherapy as a Treatment for Women With Advanced Ovarian Cancer Following Initial Surgery”, 13 June 2018. Available at: https://www.gene.com/media/press-releases/14729/2018-06-13/fda-approves-genentechs-avastin-bevacizu
  6. Clovis Oncology press release “Clovis Oncology Receives Breakthrough Therapy Designation for Rubraca® (rucaparib) for Treatment of BRCA1/2-Mutated Metastatic Castration Resistant Prostate Cancer (mCRPC)”, 2 October 2018. Available at: https://ir.clovisoncology.com/investors-and-news/news-releases/press-release-details/2018/Clovis-Oncology-Receives-Breakthrough-Therapy-Designation-for-Rubraca-rucaparib-for-Treatment-of-BRCA12-Mutated-Metastatic-Castration-Resistant-Prostate-Cancer-mCRPC/default.aspx
  7. Abida W, et al. Preliminary results from TRITON2: a phase 2 study of rucaparib in patients with metastatic castration-resistant prostate cancer (mCRPC) associated with homologous recombination repair (HRR) gene alterations. Presented at ESMO, 19–23 October 2018. Abstract 793PD.
  8. de Bono JS, et al. Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med. 2011 May 26;364(21):1995-2005. doi: 10.1056/NEJMoa1014618.
  9. Scher HI, et al. Increased Survival with Enzalutamide in Prostate Cancer after Chemotherapy. N Engl J Med. 2012; 367:1187-1197. DOI: 10.1056/NEJMoa1207506.
  10. Mateo J, et al. DNA-Repair Defects and Olaparib in Metastatic Prostate Cancer. N Engl J Med 2015; 373:1697-1708. DOI: 10.1056/NEJMoa1506859.