Updated Findings Show Continued Benefit of PARP in Ovarian Cancer, New Agent on the Scene in Cervical Cancer

Several late-phase results were shared during the European Society of Medical Oncology (ESMO) Virtual Congress in gynecologic malignancies, but the data presented generated excitement about the number of novel options for patients after initial treatment.

Updated findings in ovarian cancer demonstrated continued benefit for PARP inhibition as maintenance therapies following frontline treatment in advanced ovarian cancer in the phase 3 SOLO-1 trial (NCT01844986) using the PARP inhibitor olaparib (Lynparza) and in the phase 2 PRIMA/ENGOT-OV26/GOG-3012 ([PRIMA], NCT02655016), which utilized the PARP inhibitor niraparib (Zejula).

Enthusiasm also surrounded a potential new approach in cervical cancer from the phase 2 innovaTV 204/GOG-3023/ENGOT-cx6 study ([innovaTV], NCT03438396), which explored treatment with the investigational antibody-drug conjugate tisotumab vedotin.

The SOLO-1 Study

The longest duration of follow-up for any PARP inhibitor in the previously untreated advanced ovarian cancer setting was performed in the phase 3, randomized, double-blind, placebo-controlled, multicenter SOLO-1 trial, in which olaparib maintenance was given to patients with BRCA mutations. The 5-year follow-up results were presented at ESMO by Susan Banerjee, MD, PhD, FRCP, consultant medical oncologist and research lead for the Gynecology Unit at The Royal Marsden.¹

“The updated analysis after 5 years of follow-up shows that the benefit of olaparib continues substantially beyond the end of treatment,” Banerjee told Targeted Oncology in an interview.

Out of the 391 patients assessed, 260 received olaparib maintenance and 131 received placebo for up to 2 years or until progressive disease (PD). Olaparib maintenance first demonstrated an improvement in progression-free survival (PFS) in the primary analysis with the median PFS not yet reached in the olaparib arm at this timepoint compared with 13.8 months in the placebo arm (HR, 0.30; 95% CI, 0.23-0.41).

The median follow-up for the updated analysis was 4.8 years in the olaparib arm compared with 5.0 years in the placebo arm. The results showed PFS events in 45% of the olaparib-treated population versus 76% of the placebo population. The median PFS observed with olaparib maintenance was 56.0 months compared with 13.8 months in the placebo arm (HR, 0.33; 95% CI, 0.25-0.43).

“These are very encouraging results that will help us explain the potential benefits of maintenance olaparib in patients with BRCA mutations,” said Banerjee.

The PRIMA Study

A new analysis of the phase 3 randomized, double-blind, placebo-controlled, multicenter PRIMA trial presented during ESMO by Giorgio Valabrega, MD, investigated the potential difference in efficacy and safety by age of niraparib maintenance after chemotherapy in patients with advanced ovarian cancer.

“The key findings of our trial were that there is no difference in terms of safety and efficacy by adding niraparib to chemotherapy. Also, the [adverse events] that were observed in patients above 65 and 75 [years of age] in comparison to younger patients are not different,” Valabrega, associate professor, University of Torino School of Medicine, told Targeted Oncology in an interview.

The subanalysis included 444 patients from the original PRIMA study who were 65 years of age or younger. Of the patients included in this analysis, 297 received niraparib and 147 received placebo.²

A second cohort from the analysis included 289 patients aged 65 or older. Among this group, 76 patients were 75 years or older. One hundred ninety of the patients received niraparib maintenance while 99 received placebo in the younger cohort and of those 75 years or older, 54 patients received niraparib and 22 received placebo.

Demonstrating consistency with the primary analysis which showed a median PFS on 13.8 months with niraparib compared with 8.2 months in the placebo arm, niraparib maintenance prolonged PFS compared with placebo in this subanalysis. In the patients under the age of 65, the median PFS was 13.9 months with niraparib versus 8.2 months with placebo (HR, 0.61; 95% CI, 0.47-0.81). Patients aged 65 or older had a median PFS of 13.7 months with niraparib versus 8.1 months with placebo (HR, 0.53; 95% CI, 0.39-0.74). In the 75 years of age or below group, niraparib led to a median PFS of 13.8 months compared with placebo, which had a median PFS of 8.2 months (HR, 0.62; 95% CI, 0.50-0.77). Finally, in patients aged 75 of older, the median PFS was 13.8 months with niraparib versus 5.6 months with placebo (HR, 0.37; 95% CI, 0.17-0.81).

Both ages groups were similar in terms of the number percentage of treatment-emergent adverse events (TEAEs) observed. The most common treatment-emergent TEAEs were anemia, leukopenia and hypertension. Notably, patients aged 65 years or older experienced a small increase in thrombocytopenia during treatment as did those aged 75 years of age or older. The rates of ≥3 TEAEs were also similar between the age groups.

The innovaTV 204/GOG-3023/ENGOT-cx6 Study

Results from the single-arm, multicenter, international phase 2 study innovaTV were presented during ESMO by Robert Coleman, MD, FACOG, FACS, chief scientific officer of The US Oncology Network. The result of the study was that treatment with tisotumab vedotin led to antitumor activity in patients with previously treated recurrent or metastatic cervical cancer.³

“We basically confirmed the responses that we saw in the first-in-human phase 1 and 2 study with a 24% response rate,” Coleman told Targeted Oncology.

“Importantly, 7% of those patients had complete response, which, for those of who have treated this disease, these are not common findings,” he added.

As Coleman shared, the objective response rate observed in the trial was 24% (95% CI, 15.9%-33.3%), with complete responses in 7% of the population, partial respondes in 17%, and stable disease in 49%. In terms of PD, 24% of patients progressed on treatment. The median duration of response observed with tisotumab vedotin was 8.3 months (95% CI, 4.2 to not reached). Notably, the treatment also led to a decrease in target lesion size in 79% of the patients who received tisotumab vedotin when compared with their baseline measurements.

Among the confirmed responders, the median time to response was 1.4 months (range, 1.1-5.1). It was also noted during Coleman’s ESMO presentation that responses were seen across the subgroup populations explored, regardless of tumor histology, lines of prior therapy, or responses to prior treatment.

The median PFS achieved with tisotumab vedotin was 4.2 months (95% CI, 3.0-4.4). At 6 months, the PFS rate was 30% (95% CI, 20.8%-40.1%). The median overall survival with the agent was 12.1 months (95% CI, 9.6-13.9) and the 6-month OS rate was 79% (95% CI, 69.3%-85.6%).

Treatment-related AEs (TRAEs) occurred in greater than 10% of the study population. The majority of the (TRAEs) observed in this study were grade 1 and 2 in severity. The most TRAEs of any grade were alopecia (38%), epistaxis (30%), nausea (27%), conjunctivitis (26%), and fatigue (24%). One patient in the died as a results of treatment-related septic shock.

Ocular, bleeding, and neuropathy TRAEs were also assessed in the study and bleeding TRAES were most prevalent, with grade 1 events having observed in 34% of patients. Ocular TRAEs were the second most prevalent with grade 1 events having occurred in 25% of patients. Finally, grade 1 peripheral neuropathy occurred in 17% of patients.

Data from this study led to the conclusion that tisotumab vedotin is a potential new treatment option for patients with previously treated recurrent of metastatic cervical cancer.

_References:

_{1. Banerjee S, Moore KN, Colombo N, et al. Maintenance olaparib for patients (pts) with newly diagnosed, advanced ovarian cancer (OC) and a BRCA mutation (BRCAm): 5-year (y) follow-up (f/u) from SOLO1. Presented at: 2020 ESMO Virtual Congress; September 19-21, 2020. Virtual. Abstract 811M0.}

_{2. Valabrega G, Pothuri B, Oaknin A, et al. Efficacy and safety of niraparib in older patients (pts) with advanced ovarian cancer (OC): Results from the PRIMA/ENGOT-OV26/GOG-3012 trial. Presented at: 2020 ESMO Virtual Congress; September 19-21, 2020; Virtual. Abstract 819P.}

_{3. Coleman RL, Larusso D, Gennigens C, et al. Tisotumab vedotin in previously treated recurrent or metastatic cervical cancer: results from the phase 2 innovaTV 204/GOG-3023/ENGOT-cx6 study. Presented at: 2020 ESMO Virtual Congress; September 19-21, 2020; Virtual. Abstract LBA32.}