Ovarian cancer is typically a second-tier newsmaker at the world’s premier oncology conferences, but at the European Society for Medical Oncology (ESMO) Congress 2019, this tumor type generated universal buzz. Impressive findings were presented for three PARP inhibitors in front-line maintenance therapy for patients with newly diagnosed advanced disease—and not just those with BRCA mutations. Experts predicted that the findings will reshape the treatment landscape of advanced ovarian cancer.
Robert L. Coleman, MD
Mansoor Raza Mirza, MD
Susana Banerjee, MD, PhD
Ana Oaknin, MD, PhD
“It’s a great day for women with ovarian cancer who are seeking treatment,” said Robert L. Coleman, MD, of The University of Texas MD Anderson Cancer Center, Houston. Dr. Coleman presented findings from one of three phase III trials during ESMO’s Presidential Symposium.
“The time has come to offer all patients [with advanced ovarian cancer] a PARP inhibitor,” said invited discussant Mansoor Raza Mirza, MD, Chief Oncologist at Copenhagen University Hospital. This point was echoed by Susana Banerjee, MD, PhD, of The Royal Marsden NHS Foundation Trust and Institute of Cancer Research, London, who commented at a press briefing: “The key message is, we need to give more women PARP inhibitors. That is now very clear.”
“We are witnessing a paradigm shift in the first-line treatment of patients with advanced ovarian cancer,” Ana Oaknin, MD, PhD, Head of the Gynecologic Cancer Program at Vall d’Hebron Institute of Oncology, Barcelona, added.
In women with newly diagnosed stage III/IV ovarian cancer, PRIMA/ENGOT-OV26/GOG-3012, PAOLA-1/ENGOT-ov25, and VELIA/GOG-3005 evaluated three inhibitors of poly (ADP-ribose) polymerase (PARP): niraparib (as maintenance), olaparib plus bevacizumab (as maintenance), and veliparib (with chemotherapy, then maintenance). Currently, olaparib, rucaparib, and niraparib are indicated for high-grade epithelial ovarian cancer, but only olaparib is approved as maintenance therapy for patients with deleterious BRCA mutations after response to first-line chemotherapy. The main findings and implications of these trials follow.
PRIMA/ENGOT-OV26/GOG-3012: Niraparib
Antonio González-Martin, MD, PhD
This study evaluated niraparib vs placebo in 733 patients who responded to platinum-based chemotherapy.1 In PRIMA, but not the other two trials, patients with stage III disease were required to have visible residual disease after debulking. Results were reported by Antonio González-Martin, MD, PhD, of Grupo Espanol de Investigacion en Cancer de Ovario and Clinica Universidad de Navarra, Spain.1 The results were simultaneously published in The New England Journal of Medicine.2
“Niraparib is the first PARP inhibitor to demonstrate benefit in patients across biomarker subgroups after front-line platinum-based chemotherapy, consistent with prior clinical studies of niraparib in recurrent ovarian cancer,” Dr. González-Martin said.
Patients receiving maintenance niraparib had a median progression-free survival of 13.8 months vs 8.2 months (hazard ratio [HR] = 0.62; P < .001). In the 51% of patients whose tumors had homologous recombination deficiency (HRD), the median progression-free survival was 21.9 months vs 10.4 months (HR = 0.43; P < .001). At 24 months, overall survival rates were 84% and 77%, respectively (HR = 0.70; 95% confidence interval [CI] = 0.44–1.11). Benefit was shown regardless of the presence or absence of HRD, although the greatest benefit was seen in HRD-positive patients.
“Niraparib monotherapy after first-line platinum-based chemotherapy should be considered a new standard of care,” concluded Dr. González-Martin.
PAOLA-1/ENGOT-ov25: Olaparib
Isabelle Ray-Coquard, MD, PhD
This study evaluated olaparib plus bevacizumab maintenance in 806 patients who responded to -platinum-based chemotherapy plus bevacizumab as a standard of care for most patients in first-line treatment.3 Outcomes were evaluated according to BRCA mutation status and to HRD. The study was -presented by Isabelle Ray-Coquard, MD, PhD, of the Centre Leon Bérard, Université Claude Bernard, Lyon, and President of the GINECO Group, France.
Compared with bevacizumab and placebo, maintenance therapy with the combination improved median progression-free survival from 16.6 months to 22.1 months (hazard ratio = 0.59; P < .0001) in the overall population, regardless of BRCA mutation status or surgical outcome. Then, patients received their first-line therapy for a median time of 7 months before randomization, so they benefited with a median time of 29.1 months without relapse since the beginning of systemic treatment in the combination maintenance arm. Although all patient subsets benefited from olaparib, the magnitude was greatest for those whose tumors tested positive for BRCA1/2 mutations—37.2 vs 21.7 months (HR = 0.31; 95% CI = 0.20–0.47)—and was consistent with previously reported data for olaparib in SOLO-1, despite an active treatment in the control arm.
An additional key finding from the study was the substantial benefit reported in the HRD-positive subgroup (including BRCA-mutated), where the median progression-free survival was also impressive among HRD-positive patients, a group that included both those with BRCA-mutation and BRCA wild-type disease: 37.2 months vs 17.7 months (HR = 0.33; 95% CI = 0.25–0.45). In HRD-positive patients lacking a BRCA mutation, the benefit remains substantial, with a median progression-free survival of 28.1 months with olaparib compared with 16.6 months with placebo (HR = 0.43; 95% CI = 0.28–0.92).
“PAOLA-1 met its primary objective, demonstrating a statistically significant and clinically meaningful improvement in progression-free survival when olaparib was added to first-line standard-of-care bevacizumab maintenance treatment in the majority of patients with advanced ovarian cancer in the first-line setting, as patient selection was not restricted by surgical outcome or BRCA mutation status,” said Dr. Ray-Coquard. “This new regimen demonstrated the longest median progression-free survival ever reached in the first-line treatment of ovarian carcinoma and should therefore be expected to change clinical practice for all patients with advanced ovarian carcinoma.”
VELIA/GOG-3005: Veliparib
This study tested veliparib earlier in the disease continuum—as maintenance after its concurrent use with first-line chemotherapy (carboplatin/paclitaxel)—in 1,140 patients.4 The results, presented by Dr. Coleman, were simultaneously published in The New England Journal of Medicine.5
Patients who received veliparib throughout treatment had a significantly improved progression-free survival, and again, the effect was most pronounced in HRD-positive patients. In VELIA/GOG-3005, HRD included patients who carried a germline BRCA mutation or with a deleterious BRCA mutation in the tumor, as well as those without a BRCA mutation who had HRD as assessed by a tissue-based assay. For the overall population, the median progression-free survival was 23.5 months with veliparib and 17.3 months with placebo (HR = 0.68; P < .001), but the benefit rose to 34.7 months vs 22.0 months, respectively (HR = 0.44; P < .001), for the cohort with a BRCA mutation and to 31.9 months and 20.5 months, respectively (HR = 0.57; P < .001), for HRD-positive patients. One of the arms evaluated veliparib given during chemotherapy but not continued as maintenance, and outcomes in this arm were not significantly better than those in the control arm.
“Veliparib added to chemotherapy and continued as maintenance significantly extended progression-free survival in all patient cohorts in newly diagnosed high-grade serous ovarian carcinoma regardless of biomarker, choice of surgery, or paclitaxel regimen,” Dr. Coleman said. “We believe these data support veliparib administered during chemotherapy and continued as maintenance as a new standard of care.”
Efficacy Appears Equivalent Among Agents
At the ESMO Congress, several thought leaders aimed to put the findings of these three important phase III trials into context and perspective. All emphasized there are enough differences in the patient populations—especially in terms of risk features—that the studies should not be directly compared, especially in terms of median progression-free survival, since patient characteristics varied among the studies. Instead, the outcomes should be interpreted in terms of hazard ratios, according to several discussants.
“With their hazard ratios, you see that in all populations, these three trials showed significant clinical benefit,” noted Dr. Mirza. “And if you divide patients into subgroups according to HRD status, you see that the HRD/BRCA-mutant population has a clear and unprecedented benefit in progression-free survival in all.”
Jonathan Ledermann, MD
Jonathan Ledermann, MD, Professor of Medical Oncology at UCL Cancer Institute and University College Hospital, London, noted that the median progression-free survival was lowest for niraparib (13.8 months; HR = 0.62) compared with olaparib/bevacizumab (22.1 months; HR = 0.59) and veliparib (23.5 months; HR = 0.68). However, he maintained, “that really doesn’t matter, because the hazard ratios in the intent-to-treat populations were similar, and we know we’re dealing with different populations of patients.”
“All three trials show clear evidence of the benefit of PARP inhibitors as maintenance in first-line therapy. The greatest effect is in patients with BRCA mutations, and we see a sequential diminishing effect of activity in patients with BRCA wild-type/HRD-positive tumors and HRD-negative tumors. It’s in the BRCA-negative group that we need to start making our clinical decisions as how best to use these drugs in practice,” proposed Dr. Ledermann. Dr. Mirza added: “We have to sequence these treatments, talk to the patient, decide which treatment to give first.”
Unanswered Questions
Dr. Ledermann pointed out that the studies raise some important unanswered questions:
- PAOLA-1: The lack of an olaparib-alone arm means “we can’t disentangle the effects of olaparib and bevacizumab.”
- PRIMA: Niraparib conveyed a significant benefit in homologous recombination–proficient tumors, “but is this clinically meaningful?”
- VELIA: Lack of a maintenance arm containing veliparib alone means “we can’t distinguish whether or not there is an effect of veliparib with chemotherapy or whether the effect comes during maintenance. This has implications for how to use this drug in practice.”
According to Dr. Ledermann, the following questions are critical: Should PARP inhibitors be used in all patients, or should they be restricted to patients with BRCA mutations and HRD positivity? How will their first-line use affect their use in recurrent disease? Will patients benefit from re-challenge with the same or a different PARP inhibitor? What will be the effect of adding other drugs to PARP inhibitors to improve their activity?
He commented: “What we can conclude, however, is this: In 2018, front-line PARP inhibitor therapy began in ovarian cancer in BRCA-mutated patients, and this heralded a change in treatment. Now in 2019, we have new front-line data that introduce a paradigm shift in the way we are going to treat ovarian cancer in the coming years.”
DISCLOSURE: PRIMA/ENGOT-OV26/GOG-3012 was funded by Tesaro. PAOLA-1/-ENGOT-ov25 was funded by ARCAGY Research, AstraZeneca, Merck, and Hoffmann–LaRoche. VELIA/GOG-3005 was funded by AbbVie. Dr. Coleman has served as a consultant or advisor to Clovis Oncology, Genentech/Roche, Esperance, the National Comprehensive Cancer Network, AstraZeneca/MedImmune, Genmab, GamaMabs Pharma, Tesaro, OncoMed, Sotio, Oncolytics, and AbbVie and has received travel funding from Merck, Astra/Zeneca/MedImmune, Array Biopharma, Clovis, Roche/Genentech, Research to Practice, GOG, Sotio, and Vaniam Group. Dr. Mirza has financial relationships with AstraZeneca, Biocad, Boehringer Ingelheim, Clovis Oncology, Geneos, Genmab, KaryopharmTherapeutics, Merck, Oncology Venture, Pfizer, Roche, Seattle Genetics, Sera Prognostics, Sotio, Tesaro-GSK, and ZaiLab; and has a leadership role with KaryopharmTherapeutics and Sera Prognostics. Dr. Banerjee has given lectures and served on advisory boards for AstraZeneca, Clovis Oncology, GamaMabs Pharma, Merck Serono, PharmaMar, Seattle Genetics, Roche, and Tesaro; has received travel grants from NuCana; has received institutional grant funding from AstraZeneca and Janssen. Dr. Oaknin has served on advisory boards for AstraZeneca, Clovis Oncology, Genmab, Inmunogen, PharmaMar, Roche, and Tesaro; has received support for travel/accommodations from AstraZeneca, PharmaMar, and Roche; and has received institutional funding from AbbVie Deutschland, Abililty Pharmaceuticals, Advaxis Inc, Aeterna Zentaris, Amgen, SA, Aprea Therapeutics AB, Clovis Oncology Inc, Eisai Ltd, F. Hoffmann–La Roche Ltd, Regeneron Pharmaceuticals, Immunogen Inc, Merck, Sharp & Dohme de España SA, Millennium Pharmaceuticals Inc, Pharma Mar SA, Tesaro Inc, and Bristol-Myers Squibb. Dr. González-Martin received institutional research funding from Roche and has served as a consultant or advisor to AstraZeneca, Tesaro, and Pharmamar. Dr. Ray-Coquard disclosed financial relationships with AstraZeneca, Roche, Tesaro, Clovis, Pharmamar, Genmab, Pfizer, -GamaMabs, Agenus, Avaxis, MSD, Merck Serono, Amgen, and Lilly. Dr. Ledermann disclosed financial relationships from advisory boards with AstraZeneca and Clovis Oncology, Roche, TesaroBio, Merck/MSD, Pfizer, Seattle Genetics, Cristal Therapeutics, and Artios Pharma; has received grant funding from AstraZeneca and MSK; has received lecture fees from AstraZeneca and TesaroBio; and has received a travel grant from Clovis Oncology.
REFERENCES
1. González-Martin A, et al: Niraparib therapy in patients with newly diagnosed advanced ovarian cancer. 2019 ESMO Congress. Abstract LBA1. Presented September 28, 2019.
2. González-Martin A, et al: Niraparib in patients with newly diagnosed advanced ovarian cancer. N Engl J Med. September 28, 2019 (early release online).
3. Ray-Coquard IL, et al: Phase III PAOLA-1/ENGOT-ov25 trial. 2019 ESMO Congress. Abstract LBA2_PR. Presented September 28, 2019.
4. Coleman RL, et al: VELIA/GOG-3005. 2019 ESMO Congress. Abstract LBA3. Presented September 28, 2019.
5. Coleman RL, et al: Veliparib with first-line chemotherapy and as maintenance therapy in ovarian cancer. N Engl J Med. September 28, 2019 (early release online).
