CME
Physicians: Maximum of 1.50 AMA PRA Category 1 Credits™
Released: August 17, 2022
Expiration: August 16, 2023
Angeles Alvarez Secord, MD, MHSc:
Next, we will review studies presented at ASCO in ovarian cancer, endometrial cancer, and cervical cancer.
First, I will discuss an analysis of the phase III ATHENA trial of maintenance rucaparib and/or nivolumab vs placebo in patients with newly diagnosed advanced ovarian cancer. At ASCO, Monk and colleagues21 presented results of ATHENA-MONO focused on maintenance rucaparib vs placebo.
In the previously reported ARIEL3 study, maintenance rucaparib improved PFS in patients with recurrent high‑grade ovarian cancer who responded to platinum‑based chemotherapy. In addition, PFS benefit was seen in patients with BRCA wild‑type and BRCA mutations, as well as those with homologous recombination deficient (HRD) tumors.22 First‑line maintenance therapy with PARP inhibitors has also been shown to improve PFS in other studies, including the PRIMA and PRIME trials evaluating niraparib, the PAOLA-1 trial evaluating olaparib and bevacizumab, and the SOLO-1 trial of olaparib monotherapy.23-26 The magnitude of benefit varies based on whether the patient has a BRCA mutation and the tumor HRD status. In this landscape, it is unclear which maintenance therapy is best for patients with advanced ovarian cancer.
Angeles Alvarez Secord, MD, MHSc:
The phase III placebo-controlled ATHENA trial is evaluating rucaparib and/or nivolumab as maintenance therapy using a 4-arm trial design in which the agents are assessed as monotherapy and in combination. The ATHENA‑MONO analysis presented at ASCO is a comparison of arm B, which is rucaparib and placebo, vs arm D, which is placebo/placebo. A separate analysis, ATHENA‑COMBO, is evaluating the benefit of the addition of nivolumab to rucaparib. The primary endpoint of this study is investigator‑assessed PFS. Secondary endpoints include OS, investigator‑assessed ORR, DoR, blinded independent committee review–assessed PFS, and safety. There are also exploratory analyses of PFS in subgroups and patient‑reported outcomes.
One slightly different aspect of this study design is the use of a statistical significance set with a 2‑sided P value of .025. Most studies have a 1‑sided test for superiority, but this study is evaluating both superiority and any evidence of detriment. Like other studies, ATHENA uses a hierarchical step-down, multiple comparison evaluation, first evaluating the primary endpoint, then OS, then ORR in the HRD population and then the ITT population.
Angeles Alvarez Secord, MD, MHSc:
The baseline characteristics are well balanced across both the HRD and ITT populations. The median age is very similar between treatment groups in both populations, ranging from 57-61 years. Most patients were White and had excellent performance status, stage III disease and ovarian cancer. Approximately one half of patients, 48% to 56% in each group, underwent primary surgery, although the remainder had neoadjuvant chemotherapy with interval debulking and further chemotherapy. Residual disease was present in the post‑CT scans in approximately one quarter of patients, and it was measurable in 10% of patients across the study arms.
A notable aspect of this study is that BRCA mutations were present in approximately 21% of patients in the ITT population, which is very similar to the frequency observed in real-world patient populations.
Angeles Alvarez Secord, MD, MHSc:
The investigator‑assessed PFS in the HRD population, the first part of the primary endpoint, showed a benefit with rucaparib compared with placebo, with more than a 50% reduction in disease progression. The median PFS was 28.7 months with rucaparib compared with 11.3 months with placebo, with a hazard ratio of 0.47 (95% CI: 0.31-0.72) and P = .0004. At 24 months, 56.3% of patients receiving rucaparib remained progression free compared with 35% receiving placebo.
Angeles Alvarez Secord, MD, MHSc:
In the stepdown analysis procedure, if the HRD population demonstrated a PFS benefit with rucaparib, the next step was to evaluate PFS in the ITT population. Here, the findings are similar, with a hazard ratio of 0.52 (95% CI: 0.40-0.68) in favor of rucaparib with a P <.0001. Median PFS was 20.2 months in the rucaparib arm compared with 9.2 months for placebo. In my opinion, these results are very promising.
Angeles Alvarez Secord, MD, MHSc:
In an exploratory subgroup analysis, the benefit of rucaparib was assessed across 3 different biomarker populations: HRD‑positive populations that had either BRCA mutations or had BRCA wild type and loss of heterozygosity (LOH)–high, and the HRD‑negative population, which included BRCA wild‑type tumors and is characterized by LOH low and is sometimes referred to as HR proficient. I think is important to note the biomarker that was used here. Other studies also have used LOH as a biomarker assessment, while other trials have utilized a biomarker that comprises LOH and 2 other components: telomeric allelic imbalance and large-scale state transitions.
In this exploratory evaluation, PFS was numerically longer with rucaparib than with placebo in each of these subgroups. The largest survival benefit appears to be in patients who have a BRCA mutation. In this subgroup, median PFS was not reached (range: 25.8 months to not reached) with rucaparib compared with 14.7 months (range: 6.4 months to not reached) in the placebo group, with a hazard ratio of 0.40 (95% CI: 0.21-0.75). In the subgroup with BRCA wild type and LOH high, rucaparib showed a similar benefit, but the PFS curves of the treatment arms do come together at the tail, and the hazard ratio 95% CI crosses 1 in this group.
In the HRD‑negative or HR‑proficient subgroup, with BRCA wild type and LOH low, rucaparib appears to provide some benefit compared with placebo but with a smaller magnitude than in the other subgroups. Here, median PFS is 12.1 months with rucaparib compared with 9.1 months with placebo.
Keeping in mind that these are exploratory analyses, rucaparib appears to improve investigator‑assessed PFS regardless of BRCA and HRD status. The results were similar with BICR‑assessed PFS analysis.
Angeles Alvarez Secord, MD, MHSc:
As shown in this forest plot, rucaparib shows a PFS benefit across other patient subgroups as well, including the presence of residual disease after chemotherapy, timing of surgery, and FIGO stage at diagnosis. As mentioned, the 95% CI of the hazard ratio slightly crosses 1 in the subgroup with BRCA wild‑type and LOH‑high as well as patients with a performance status ≥1. Overall, however, investigator-assessed PFS outcomes appear to favor rucaparib across subgroups.
Angeles Alvarez Secord, MD, MHSc:
Investigator‑assessed response was also assessed. Recall that approximately 10% of patients in each treatment arm had measurable disease. This is a very small number of patients, but the confirmed ORR with rucaparib was 48.8% and 58.8% in the ITT population and HRD populations, respectively. One patient in the placebo arm had a persistent response, which is most likely due to chemotherapy. The response data demonstrate that rucaparib is an active treatment.
Angeles Alvarez Secord, MD, MHSc:
In terms of safety and tolerability, any‑grade treatment‑emergent adverse events (TEAEs) were very common in both arms, including in 92.7% of patients in the placebo arm. Grade ≥3 TEAEs occurred in 60.5% of patients receiving rucaparib compared with 22.7% of those receiving placebo. Dose interruption or dose reduction of rucaparib was required in 63.8% of patients, with dose interruption in 60.7% and dose reduction in approximately 50%. But it was relatively rare for patients to discontinue treatment due to a treatment‑emergent event; only 11.8% of patients had to discontinue rucaparib. The median treatment duration with rucaparib was 14.7 months.
There were 2 deaths due to TEAEs in the rucaparib arm; 1 patient with multiple organ dysfunction syndrome and 1 patient with a myocardial infarction and pulmonary embolism.
There were 2 cases of myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML) in the rucaparib arm; 1 patient developed MDS during treatment and 1 had AML during long‑term follow up. There were no cases of MDS or AML in the placebo arm. Increased alanine aminotransferase or aspartate aminotransferase occurred in 42.6% of patients in the rucaparib arm compared with 8.2% of patients in the placebo arm, but these were laboratory abnormalities. None of the cases met Hy’s law criteria for drug-induced liver injury.
In the ITT population, changes from baseline in patient-reported outcomes with Functional Assessment of Cancer Therapy-Ovarian (FACT‑O) Trial Outcome Index scores were similar for both treatment arms.
Angeles Alvarez Secord, MD, MHSc:
Among the most common TEAEs, grade ≥3 AEs were relatively rare. With rucaparib, the most frequent grade ≥3 AEs were anemia in 28.7% of patients, neutropenia in 14.6%, increased alanine aminotransferase or aspartate aminotransferase in 10.6%, and thrombocytopenia in 7.1% of patients. High-grade AEs were very low in all the remaining toxicities and the treatment was fairly well tolerated.
Angeles Alvarez Secord, MD, MHSc:
In conclusion, the ATHENA-MONO analysis demonstrated improved PFS with rucaparib compared with placebo as first-line maintenance therapy in patients with newly diagnosed high‑grade ovarian cancer, showing benefit across many patient subgroups including the HRD patient population and in patients with a BRCA1 or BRCA2 mutation.
Overall, the ORRs demonstrate the treatment benefit of rucaparib. There were no new safety signals, and the fact that patient‑reported outcomes were similar between the treatment arms is very reassuring. There does not appear to be a decrease in quality of life with the addition of rucaparib.
In my opinion, this is very clinically relevant data that is similar to findings in other studies evaluating PARP inhibitor–maintenance strategies in the frontline setting, such as the PRIMA and PRIME trials. I strongly believe that this treatment should be part of conversations with patients about the pros and cons of PARP inhibitor therapies. I would strongly recommend rucaparib maintenance as an option for patients with a BRCA mutation as well as patients who have tumors with HRD. For patients who do not have a BRCA mutation or HRD cancers, I think the utility of rucaparib in the frontline setting is less clear. Although there is a PFS benefit, there are tradeoffs to therapy. I certainly look forward to many more conversations about the role of this treatment in newly diagnosed ovarian cancer.
Angeles Alvarez Secord, MD, MHSc:
Next, we will review the OS findings from the ORZORA trial that evaluated maintenance olaparib in the platinum‑sensitive setting. This single-arm phase IV study was conducted in patients with relapsed ovarian cancer and was designed to evaluate the benefit of olaparib in patients with either a somatic or germline BRCA mutation. It also included an exploratory cohort of patients with non‑BRCA homologous recombination repair mutations. The primary analysis reported clinical activity in both groups of patients.27 At ASCO 2022, Pignata and colleagues presented the data regarding OS outcomes.28
Angeles Alvarez Secord, MD, MHSc:
ORZORA was an open‑label, single‑arm, multicenter phase IV trial. It enrolled 181 patients with platinum-sensitive relapsed ovarian cancer, who all received maintenance olaparib at 400 mg twice daily until disease progression. The 400-mg twice-daily dose was used because this study utilized the capsule formulation of olaparib.
The primary endpoint was investigator‑assessed PFS in the BRCA germline and somatic mutation cohorts. Key secondary endpoints were OS, second PFS or death, time to first or second subsequent therapy, quality of life by FACT-O, and tolerability. An exploratory analysis was conducted in patients with predefined non‑BRCA homologous recombination repair mutations.
Angeles Alvarez Secord, MD, MHSc:
The median OS of these various cohorts were similar, ranging from 43.2 to 47.4 months. These results suggest that even patients with a non‑BRCA homologous recombination repair mutation may derive benefit from the addition of an olaparib maintenance strategy; in this study, that group had a median OS of 44.9 months.
The OS rate at 36 months ranged anywhere from 56.6% to 62.6% across the cohorts, so again we see a very high benefit of maintenance olaparib.
Angeles Alvarez Secord, MD, MHSc:
As shown in the safety summary, no new safety signals emerged for olaparib. Approximately 48.6% of patients in the primary analysis required olaparib interruption due to an AE. In the final analysis, that was only 51.4%, showing that most patients were able to tolerate olaparib for even a prolonged period. Dose discontinuation continued to be very rare, with an incidence of 6.2% in the final analysis.
In the primary analysis, 2 patients (1.1% of the total group) had developed MDS or AML. There were 4 additional cases in the final analysis, bringing the percentage to 3.4%. It was very unlikely for patients to develop a new primary malignancy; at the final analysis just 3 patients had developed a new malignancy, for a frequency of 1.7%.
Anemia was the most common ≥3 AEs observed with olaparib.
Angeles Alvarez Secord, MD, MHSc:
In conclusion, maintenance olaparib demonstrated similar OS benefit in patients with platinum‑sensitive recurrent ovarian cancer in all the BRCA mutation subgroups. The reported exploratory analysis suggests potential for similar activity in patients who have non‑BRCA homologous recombination repair mutations as well. The safety profile for olaparib was consistent with the primary analysis.
I still think we need to be cognizant of long‑term follow-up for MDS and AML in these patients. However, the findings demonstrate a benefit with maintenance olaparib for patients with BRCA germline and somatic mutations and potentially those with non‑BRCA‑related mutations.
Angeles Alvarez Secord, MD, MHSc:
It is important to evaluate the results in the context of other studies of PARP inhibitor maintenance in the frontline setting. There has been a plethora of data in this area, first from the SOLO-1 trial of olaparib vs placebo in patients with BRCA mutations with advanced disease, then the PRIMA trial evaluating niraparib vs placebo, and lastly from the PAOLA‑1 trial evaluating the addition of olaparib to bevacizumab vs bevacizumab.23,25,26 These studies resulted in the approval of PARP inhibitors as a first‑line maintenance strategy in women with ovarian cancers.
The phase III VELIA study evaluated another PARP inhibitor, veliparib, together with chemotherapy as induction therapy followed by maintenance veliparib and also demonstrated a benefit of PARP maintenance with higher magnitude of benefit for select groups, including patients with BRCA mutations or HR-deficient disease.29 The ATHENA‑MONO analysis adds to this body of data and shows yet another PARP inhibitor demonstrating improvement in PFS when given as maintenance in the frontline setting.21
I also want to mention the PRIME study, presented at the 2022 Society of Gynecologic Oncology Annual Meeting, evaluating niraparib in Chinese patients with advanced‑stage disease. This trial design had some differences regarding central assessment of PFS and the biomarker test used, which was likely similar to the myChoice biomarker test.
There are some differences across these trials, but when considered together there appears to be a strong PFS benefit with PARP inhibitor maintenance therapy, with the greatest magnitude of benefit in patients who have a BRCA mutation. There also appears to be benefit, but to a lesser degree, in patients with a BRCA wild‑type gene and tumors with HRD status for niraparib in PRIMA, olaparib plus bevacizumab in PAOLA-1, and rucaparib in ATHENA-MONO.
Most recently, with the addition of the ATHENA-MONO and PRIME results, we also are seeing further support for the benefit of a PARP inhibitor in patients with HRD‑negative or HR-proficient tumors, which was first reported in the PRIMA trial.23 In the future, I anticipate many discussions about the role of PARP inhibitors across this patient population and whether they might be used for all patients vs with a more selective management approach due to larger benefit in patients with BRCA mutations or HRD disease.
An open question remains on how to counsel patients with HR-proficient ovarian cancer. I believe you must review the pros and cons of PARP inhibitor therapy in the context of how much clinical benefit you think your patient may receive and what their goals of therapy are, while also taking into consideration the patient’s preferences.
Angeles Alvarez Secord, MD, MHSc:
Next, I will move to platinum‑resistant ovarian cancer and discuss updated OS results from the randomized phase II trial of relacorilant plus nab‑paclitaxel in this patient population. Patients with recurrent platinum‑resistant disease have a high likelihood of chemotherapy resistance and, as a result, have very limited treatment options.30,31 There is an urgent unmet need to identify novel therapeutics for platinum-resistant disease.
Cortisol contributes to chemotherapy resistance by binding to the glucocorticoid receptor and blocking apoptotic pathways used by cytotoxic agents, and high glucocorticoid receptor expression in ovarian cancers is associated with worse outcomes.31 Relacorilant selectively modulates the glucocorticoid receptor that inhibits cortisol’s antiapoptotic effects and augments the activity of cytotoxic agents.32
A randomized phase II trial evaluated relacorilant dosed either intermittently or continuously in combination with nab‑paclitaxel in patients with platinum‑resistant recurrent disease (NCT03776812). Previously, Colombo and colleagues33 reported that intermittent dosing of relacorilant plus nab-paclitaxel significantly improved PFS compared with nab‑paclitaxel alone.
The updated OS analysis from that study was presented at the 2022 ASCO Annual Meeting.34
Angeles Alvarez Secord, MD, MHSc:
This open-label study had 3 treatment arms. Patients were randomized to receive intermittent relacorilant plus nab-paclitaxel, continuous relacorilant plus nab-paclitaxel, or nab-paclitaxel alone. Intermittent relacorilant was dosed at 150 mg on Days 1, 2, 7-9, 14-16, and 28 of every cycle. Continuous relacorilant was dosed at 100 mg daily, although escalation to 150 mg daily was allowed beginning in cycle 2 at the physician’s discretion. Intravenous nab‑paclitaxel was given on Days 1, 8, and 15, at 80 mg/m2 in combination with relacorilant and at 100 mg/m2 alone.
The primary endpoint was PFS by the Response Evaluation Criteria of Solid Tumors (RECIST), version 1.1. The primary analysis showed improved PFS with the intermittent dosing vs nab-paclitaxel alone, with a hazard ratio of 0.66 (95% CI: 0.44-0.98) and a P <.05. Essentially, adding intermittent relacorilant to nab-paclitaxel reduced the risk of progression by 34%.
The secondary endpoints included OS, ORR, DoR, and safety.
Angeles Alvarez Secord, MD, MHSc:
Patient characteristics were similar across the 3 treatment arms. The median age was approximately 60 years. This was a patient population with a poor prognosis; in addition to having recurrent platinum‑resistant disease, 34.5% to 38% of patients in each arm had platinum‑refractory disease, which is the most challenging to manage. The incidence of primary platinum‑refractory disease ranged from 1.7% to approximately 12.0%, with the highest percentage among the patients receiving the intermittent dosing schedule.
Patients were heavily pretreated, with a median of 2.5-3.0 previous therapies (range: 1-5). Nearly all the patients had been previously treated with a taxane, 52% to 64% of patients had been previously treated with bevacizumab, and 30% to approximately 47% had been treated with a prior PARP inhibitor.
Lastly, approximately 10% to 15% of patients across the 3 study arms had a BRCA1 mutation and 3% to 8% had a BRCA2 mutation.
Angeles Alvarez Secord, MD, MHSc:
In general, intermittent relacorilant was associated with lower toxicity than continuous relacorilant in combination with nab-paclitaxel. Prophylactic granulocyte-colony stimulating factor was administered to all patients receiving relacorilant to lower the risk of neutropenia. Grade ≥3 neutropenia was uncommon in the intermittent and nab‑paclitaxel dosing arm, occurring in only 6.7% of patients, but it was seen in 26.3% of those receiving relacorilant continuous dosing. Grade ≥3 neutropenia occurred in 15% of patients receiving nab-paclitaxel alone. Of note, 46.7% of these patients also received granulocyte-colony stimulating factor per the investigator’s standard practice, which may help explain these lower rates.
Grade ≥3 anemia affected 13.3% of patients receiving intermittent relacorilant and 19.3% of those receiving continuous dosing. Many patients experienced peripheral neuropathy, which is not surprising given that these patients had nearly all received prior taxane therapy. But no grade ≥3 events were seen in the intermittent dosing arm, and they were seen in 15.8% of patients in the continuous relacorilant dosing arm.
Angeles Alvarez Secord, MD, MHSc:
As previously reported, the addition of intermittent relacorilant to nab-paclitaxel significantly improved PFS.33 Median PFS was 5.6 months in the intermittent dosing arm, 5.3 months in the continuous dosing arm, and 3.8 months with nab‑paclitaxel alone. For intermittent relacorilant vs nab-paclitaxel alone, the hazard ratio was 0.66 (95% CI: 0.44‑0.98) with a P = .038.
ORR was similar across treatment arms, but DoR was prolonged with intermittent relacorilant dosing, with a hazard ratio of 0.36 (95% CI: 0.16-0.77) and P = .006.
Angeles Alvarez Secord, MD, MHSc:
Median OS was 13.9 months with intermittent dosing compared with 11.3 months with continuous dosing and 12.2 months with nab‑paclitaxel alone. This numerical improvement with addition of intermittent relacorilant to nab-paclitaxel did not reach significance, with a hazard ratio of 0.67 (95% CI: 0.43-1.03) and P = .066. However, it is challenging to identify an OS benefit in patients with ovarian cancer who are receiving subsequent therapy.
Angeles Alvarez Secord, MD, MHSc:
Subgroup analyses of OS shows a remarkable difference among patients with prior bevacizumab, with a stronger apparent benefit with intermittent relacorilant than is seen in the other subgroups, which were comparable with each other. If intermittent relacorilant plus nab-paclitaxel is active in patients previously treated with bevacizumab, that could be of great clinical interest, because many of our patients are treated with bevacizumab. This regimen might be a good clinical tool to fill a need for a key patient subpopulation.
Angeles Alvarez Secord, MD, MHSc:
Patients without primary platinum‑refractory disease also appeared to show a more pronounced benefit with intermittent relacorilant. Compared with nab-paclitaxel alone, the hazard ratio with intermittent dosing was 0.63 (95% CI: 0.39-0.99) and the 95% CI did not cross 1; P = .45. But numerically, there was a very minimal difference: median OS was 13.9 months with intermittent dosing vs 12.3 months with continuous dosing and 12.2 months with nab‑paclitaxel alone, and the survival curves track similarly.
Angeles Alvarez Secord, MD, MHSc:
Overall, the phase II PFS and OS findings support further evaluation of this very novel therapy, which is planned in the phase III ROSELLA trial. The phase III ROSELLA trial will randomize patients with advanced, recurrent ovarian cancer to receive intermittent relacorilant 150 mg orally with nab‑paclitaxel 80 mg/m2 or physician choice of chemotherapy, which can include liposomal doxorubicin, paclitaxel, topotecan, or nab‑paclitaxel (NCT05257408). The primary endpoint will be centrally assessed PFS, and secondary endpoints will include OS, ORR, DoR, and safety.
From a clinical point of view, I think it will be easy to recruit for the ROSELLA study of relacorilant. There is much interest in targeting chemotherapy resistance via the glucocorticoid receptor pathway. In the phase II study of relacorilant plus nab-paclitaxel, we saw that the survival benefits were numerically small and appear to signal of better activity with the intermittent relacorilant dosing scheme in support of the phase III ROSELLA study design.
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