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Key Studies in Breast and Gynecologic Cancers: Independent Conference Coverage of the 2021 ASCO Annual Meeting

Joyce O'Shaughnessy, MD
Angeles Alvarez Secord, MD, MHSc
Released: August 12, 2021

Ovarian Cancer

Phase III of Pafolacianine Sodium Injection (OTL38) in Ovarian Cancer: Study Design

Angeles Alvarez Secord, MD:
Now I would like to highlight key studies presented for ovarian cancer. The phase III study of pafolacianine sodium injection in ovarian cancer is a very exciting study for surgeons. One of the most difficult things a surgeon faces is fully identifying all the areas of cancer, especially in patients who have undergone neoadjuvant chemotherapy. It can be very hard to determine whether a particular area is scarring from the tumor, “burnt out” tumor, or actual tumor. Thus, having the potential to identify disease that is not recognized with white light or palpation alone is of clinical interest.

Pafolacianine sodium binds to folate receptors and fluoresces under near-infrared light, so it is being evaluated intraoperatively as an adjunct to white-light imaging and palpation to identify folate receptor–positive ovarian cancer lesions. At ASCO 2021, Tanyi and colleagues presented results for the phase III study of single-dose pafolacianine sodium, also known as OTL38.47 In this study, women with high clinical suspicion of ovarian cancer who were scheduled to undergo primary cytoreduction, interval debulking, or surgery for recurrent disease received a 60‑minute infusion of OTL38 0.025 mg/kg given at least an hour prior to surgery. Patients were randomized to either white light and palpation lesion detection or near-infrared fluorescence imaging lesion detection. Some patients served as their own control, meaning that the surgeon first noted lesion sites and developed their surgical resection plan based on white light and palpation detection, then started near‑infrared fluorescent imaging, re-evaluated the patient’s peritoneal cavity, and if needed, re-established their surgical plan. After surgical resection, the fluorescent imaging was repeated to ensure that all disease was removed, and samples were submitted to a central pathology lab. The primary endpoint of this study was the efficacy to detect additional folate receptor–positive lesions. The secondary endpoints included sensitivity, false-positive rate, and safety. Of 150 patients who received the infusion, 109 patients were analyzed for the primary and secondary endpoints in the full analysis set.

Phase III of Pafolacianine Sodium Injection (OTL38) in Ovarian Cancer: Baseline Characteristics

Angeles Alvarez Secord, MD:
Overall, 134 patients had both fluorescent and white light evaluation, 6 only underwent white light and palpation detection, and 10 patients were not randomized.

The median age was 60.8 years of age. Approximately 11% of patients who received both fluorescent and white light imaging and those who were not randomized were of Hispanic or Latina ethnicity, compared with 33% of the small group of patients who had white light detection only. Most patients were White, ranging from 80% to 85% across the treatment groups, and 83.3% to 100% were postmenopausal.

Phase III of Pafolacianine Sodium Injection (OTL38) in Ovarian Cancer: Stage, Histologic Type, and Surgical Parameters

Angeles Alvarez Secord, MD:
As we typically see in this setting, most patients had advanced‑stage disease, predominantly stage III (65.3%) and IV (15.1%), and over 80% of patients had serous cancers. Mean exposure to the fluorescent imaging was approximately 18 minutes, and a total of 752 lesions were identified.

Another important aspect of this study was the type of surgery performed. We saw that 35.8% of patients had primary cytoreductive surgery, whereas 53.2% had interval debulking surgery, where it is more challenging to determine what is or is not disease.

Phase III of Pafolacianine Sodium Injection (OTL38) in Ovarian Cancer: Additional Lesions

Angeles Alvarez Secord, MD:
From 109 analyzed, 33% of participants had ≥1 folate receptor–positive ovarian cancer lesion detected by intraoperative fluorescence imaging that was not detected by normal white light or palpation on tissue not planned for resection, and this clearly exceeded the prespecified threshold of 10% (P <.001) that was prespecified in the statistical analysis plan for the study. Of importance, 39.7% of patients undergoing interval debulking had ≥1 additional lesion detected, and 17.9% of patients undergoing cytoreduction had ≥1 additional lesion detected. All results were confirmed by central pathology.

According to a postprocedural questionnaire conducted by the investigators, 56% of patients had revision of their surgical plan due to the use of the intraoperative fluorescence imaging; 50.5% of patients achieved a more complete debulking; and 62.4% of patients had a complete resection.

Phase III of Pafolacianine Sodium Injection (OTL38) in Ovarian Cancer: Sensitivity, False-Positive Rate, and Safety

Angeles Alvarez Secord, MD:
The sensitivity analysis was conducted in 2 different populations. In the overall group, sensitivity of detection of folate receptor–positive lesions was 83% (95% CI: 73.9-89.4) and the false-positive rate was 32.7% (95% CI: 25.6-40.7). In a post hoc analysis, specifically for high‑volume surgeons who had done at least 5 of these cases, the sensitivity was slightly higher at 86.5% (95% CI: 73.8-93.6), but the false-positive rate was still significant at 28.5% (95% CI: 17.7-42.6).

Drug-related treatment-emergent AEs (TEAEs) were mostly mild to moderate in nature. The predominant TEAEs were nausea (mild: 12%; moderate: 6.0%; severe: 0%), vomiting (mild: 2.7%; moderate: 2.7%; severe: 0%), and abdominal pain (mild: 3.3%; moderate: 1.3%; severe: 0%). It is difficult to tell whether those were due to the drug or were from the surgical procedure itself. Of importance, there were minimal severe events related to anemia in 2 patients (1.3%).

Phase III of Pafolacianine Sodium Injection (OTL38) in Ovarian Cancer: Clinical Implications

Angeles Alvarez Secord, MD:
My takeaways from the phase III study of pafolacianine sodium injection (OTL38) is that it seems to be a very promising emerging technology in terms of surgical resection to ensure the comprehensive removal of disease that is present. However, more work needs to be done to further determine if this use of interoperative fluorescence imaging with OTL38 will have an impact on survival outcomes or rates of disease recurrence. I am somewhat concerned about the high false-positive rate and the resection of lesions that may turn out not to be malignant, and whether this increases operation room time or complications. But certainly, that did not seem to be borne out in the safety analysis. I look forward to additional studies conducted with this agent and hope that the investigators will be conducting a larger, multicenter, global phase III trial.

Phase III Studies of Niraparib in BRCAm Ovarian Cancer: Study Designs

Angeles Alvarez Secord, MD:
Niraparib has been evaluated in several different types of gynecologic cancers, including ovarian cancer.48-50 The NOVA trial was the first presented in women with platinum‑sensitive, recurrent, high‑grade serous ovarian, fallopian tube, and peritoneal cancer that resulted in FDA approval of a PARP inhibitor in an all‑comer population of patients with platinum‑sensitive ovarian cancer.51

At ASCO 2021, González-Martín and colleagues52 presented a pooled analysis of 3 randomized, double‑blind phase III trials of niraparib in various settings in ovarian cancer. The analysis included PRIMA, which was conducted in women with newly diagnosed stage III or IV high‑grade serous or endometrioid disease who had achieved a CR/PR on first-line platinum-based chemotherapy, and the NOVA and NORA trials, which were conducted in women with platinum‑sensitive, recurrent, high‑grade serous ovarian, fallopian tube, or primary peritoneal cancer with at least 2 previous lines of platinum-based chemotherapy. Prespecified subgroup analyses were performed in PRIMA for patients who had a tumor BRCA mutation, and in NOVA and NORA for patients who had a germline BRCA mutation.

Treatment in all studies was niraparib 300 mg starting dose, but PRIMA and NORA initiated individualized starting dosing of 200 mg for patients with baseline body weight <77 kg or baseline platelets <150,000/μL. This individualized dosing has become more common and, in my experience, definitely reduces niraparib-associated hematologic toxicity and makes it much more manageable in our patient population.

The primary endpoint in all 3 studies was PFS by blinded independent central review per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 criteria.

Phase III Studies of Niraparib in BRCAm Ovarian Cancer: Baseline Characteristics

Angeles Alvarez Secord, MD:
A comparison of demographics of the 3 studies shows that the median age of patients was very similar in the PRIMA and NOVA trials, at approximately 57 years of age. Unfortunately, median age was not reported for the NORA trial. Overall, across the 3 pooled studies, 526 patients had a BRCA mutation. BRCA1 mutations were the most common, ranging anywhere from 60.6% to 80.0% across the treatment groups in the 3 studies; BRCA2 mutations were present in 20.0% to 39.4% of patients in each treatment arm; and 1.5% to 6.5% of patients had both BRCA1 and BRCA2 mutations in the NORA and NOVA trials, respectively.

Phase III Studies of Niraparib in BRCAm Ovarian Cancer: PFS

Angeles Alvarez Secord, MD:
PFS results with niraparib maintenance across the 3 studies were striking, regardless of whether the patients had BRCA1 or BRCA2 mutations. In the PRIMA study, the HR was 0.39 (95% CI: 0.23-0.66) for patients with a BRCA1 mutation and 0.35 (95% CI: 0.15-0.84) for patients with BRCA2 mutations, which means a 61% to 65% reduction in the risk of disease progression with niraparib. The NOVA trial reported very remarkable improvements in PFS with niraparib as well, with HRs ranging from 0.12 (95% CI: 0.05-0.33) in patients with a BRCA2 mutation to 0.39 (95%CI: 0.23-0.66) in patients with a BRCA1 mutation, with the caveat that these are small numbers of patients overall in terms of the context of the larger study. In the NORA trial, which was mainly conducted in Asia, the HR: for PFS was 0.22 (95% CI: 0.12-0.39) in patients with ovarian cancer and germline BRCA mutations. In general, I would use a PARP inhibitor regardless of the type of BRCA mutation the patient had.

The exciting part about looking at these data collectively is that we see the benefit for PARP inhibitors across populations. Most of the studies conducted in the United States and in Europe reflect limited patient diversity and predominantly include patients who are White. It is incredibly important to be able to see the similar efficacy results across broader patient populations.

Phase III Studies of Niraparib in BRCAm Ovarian Cancer: Hematologic TEAEs in ≥20% of Overall Population

Angeles Alvarez Secord, MD:
Hematologic TEAEs with niraparib were very similar to what has been previously reported, with no new or emerging safety signals.53 What I did find surprising was the fact that the rate of hematologic toxicity was higher in women in the NORA trial, with women who were predominantly of Asian descent, and this signal was present to some degree even in patients who were treated with placebo. It is unclear if this safety profile reflects how these individuals tolerated previous chemotherapy, whether it was due to how niraparib was dosed, or if it reflects a pharmacodynamic or pharmacogenomic effect in terms of how the drug is metabolized in women of Asian descent.

Phase III Studies of Niraparib in BRCAm Ovarian Cancer: Nonhematologic TEAEs of Any Grade in ≥20% of Overall Population

Angeles Alvarez Secord, MD:
Nonhematologic toxicity showed similar patterns to what we saw previously. The frequency of adverse events was very similar in PRIMA in the frontline setting and in NOVA in the second‑line maintenance setting. Again, the NORA trial reported higher incidence of some AEs, such as increases in liver enzymes (alanine aminotransferase: 23.7%; γ-glutamyl transferase: 22.0%) and respiratory tract infections (20.9%), which I believe warrants further evaluation. Overall, however, there were no new emergent safety concerns. 

Phase III Studies of Niraparib in BRCAm Ovarian Cancer: Clinical Implications

Angeles Alvarez Secord, MD:
My takeaway from the pooled analysis of these 3 trials is that niraparib has shown efficacy in multiple ovarian cancer settings and niraparib is clearly a standard-of-care therapeutic option in frontline and second-line maintenance settings in women with platinum‑sensitive recurrent ovarian cancer. Although no new safety signals emerged, it is worthwhile to note that healthcare providers should be very vigilant regarding hematologic and nonhematologic toxicity parameters when treating patients who are of Asian descent.

Phase II of Adavosertib With or Without Olaparib in PARP Inhibitor–Resistant Ovarian Cancer (EFFORT): Study Design

Angeles Alvarez Secord, MD:
Westin and colleagues presented another key study in patients with ovarian cancer experiencing progression after a PARP inhibitor—the EFFORT trial. EFFORT is a randomized, noncomparative, 2‑arm phase II study. This study is incredibly important right now due to the increasing use of PARP inhibitor maintenance therapy and emergence of PARP inhibitor resistance. To overcome this resistance, we need to better understand the underlying molecular biology, then evaluate novel combinations in adaptive trial designs. 

The EFFORT study was conducted in women with recurrent epithelial ovarian, peritoneal, or fallopian tube cancer who had documented progression on any PARP inhibitor that was given either as treatment or maintenance therapy.54 Unlimited previous therapies were allowed, and patients had Eastern Cooperative Oncology Group (ECOG) performance status of 0‑1 and measurable disease per RECIST version 1.1 criteria. In the monotherapy arm, 39 patients received adavosertib given at 300 mg daily on Days 1-5 and 8-12 every 3 weeks. In the combination arm, 41 patients received adavosertib at 150 mg daily on Days 1-3 and 8-10, and olaparib given at 200 mg twice daily on Days 1-21 every 3 weeks. This dosing regimen is quite complex and will require in-depth and ongoing discussions with patients to ensure compliance with their therapy. The primary endpoint was ORR. Secondary endpoints include DoR, disease control rate, survival outcomes, and safety. Patients also had optional tumor biopsies at the time of progression.

EFFORT: Patient Demographics

Angeles Alvarez Secord, MD:
The median age of participants in this trial was approximately 60 years (range: 36-76); 4% of patients were Hispanic/Latina, 54% were non-Hispanic/Latina, and 42% were of unknown ethnicity. Regarding race, 78% of participants were White, 11% were Asian, and 11% were other races. Patients were either treated at MD Anderson Cancer Center (58%) or Dana‑Farber Cancer Institute (42%).

EFFORT: Baseline Characteristics

Angeles Alvarez Secord, MD:
The median number of previous therapies was 4 (range: 1-11); 93% of patients had high‑grade serous cancer overall; 44% in the adavosertib monotherapy and 52% in the adavosertib plus olaparib arm had BRCA mutations; 61% of patients in the monotherapy and 67% of patients in the combination arm had platinum‑resistant disease.

All patients had to have previously received treatment with a PARP inhibitor prior to enrolling on the study, and most patients also had received at least 1 additional line of therapy after that PARP inhibitor and before enrolling on trial (range: 0-5). Olaparib was the most frequently received PARP inhibitor in 51% of patients, followed by niraparib in 22.5% of patients, rucaparib in 22.5%, and talazoparib in 4% of patients. Overall, the previous PARP inhibitor indication was maintenance therapy in 45% of patients and treatment in 55% of patients. 

Clinical benefit from a previous PARP inhibitor, defined as CR, PR, or stable disease with more than 2 cycles, was seen in 86% of patients in the overall population, in 91.0% in the monotherapy arm, and in 82% of patients treated in the combination arm.

EFFORT: Efficacy in Evaluable Patients

Angeles Alvarez Secord, MD:
I will discuss the efficacy in each arm separately since this was a noncomparative study. In the adavosertib monotherapy arm, the ORR was 23% and included 8 patients with a PR. No patients in this arm had a CR. The median DoR was 5.5 months (range: 2.8 to not reached) and the CBR was 63% (range: 48%-76%). In the adavosertib plus olaparib arm, the ORR was 29% and included 10 patients with a PR and no CRs were seen in this arm. Median DoR was 6.4 months (range: 2.8-14.6), and the CBR was quite impressive at 89% (range: 76%-96%).

EFFORT: Efficacy in EFFORT: Efficacy in BRCAm Subgroups

Angeles Alvarez Secord, MD:
When patients were stratified by BRCA status, a very interesting signal emerged in patients who had tumors containing a wild‑type BRCA gene. Patients with wild‑type BRCA treated in the adavosertib monotherapy arm showed an ORR of 31% with a CBR of 69% (range: 41%-89%). Of note, patients with wild‑type BRCA treated with adavosertib and olaparib had an ORR of 39% and a CBR of 94% (range: 73%-100%). This is a really interesting high signal of antitumor activity in that specific patient subgroup. These findings need to be further evaluated to gain a better understanding of the underlying molecular biology because we do not know why we would see a lower response rate with a mutated BRCA gene compared with patients with a wild‑type BRCA gene with this combination. Moreover, this was a small number of patients overall. However, it is an interesting signal that warrants further exploration.

EFFORT: Overall TRAE Incidence and Management

Angeles Alvarez Secord, MD:
One issue that we see with adavosertib, either as a single agent or in a combination, is the high frequency of adverse events. TRAEs were seen in 97% of patients who received adavosertib monotherapy and 100% of those who received adavosertib plus olaparib combination. Overall, AEs were manageable and there was a relatively low rate of drug discontinuation, with 5% of patients in the monotherapy arm and 10% of patients in the combination arm discontinuing due to an AE. However, 54% of patients in the adavosertib arm required dose reduction and 72% had to undergo dose interruption. In the adavosertib and olaparib arm, 56% of patients required dose reductions and 85% had to undergo dose interruption. Therefore, this is clearly a challenging treatment to administer due to AEs.


Angeles Alvarez Secord, MD:
The most predominant AEs of any grade with monotherapy and combination, respectively, were diarrhea (33% and 34%), neutropenia (21% and 15%), thrombocytopenia (18% and 27%), fatigue (18% and 19%), and nausea (18% and 19%). Overall, the safety profile was similar to what we have seen and expected with this combination and is manageable but challenging.

EFFORT: Clinical Implications

Angeles Alvarez Secord, MD:
The EFFORT study is an incredibly important trial for identifying opportunities and treatment regimens for the challenging population of women whose disease has progressed after receiving a PARP inhibitor. With most of our patients now receiving a PARP inhibitor in the maintenance setting, either in the frontline maintenance setting or as maintenance in platinum‑sensitive recurrent ovarian cancer, we can anticipate a significant influx of patients who fall into this group. Right now, unfortunately, we have a dearth of clinical trials to offer them, and studies like EFFORT are sorely needed to evaluate agents such as adavosertib that have meaningful antitumor activity and clinical benefit.

However, adavosertib is associated with some challenges. We must think about how we can deliver these drugs in the real world, not just within a clinical trial setting. Adavosertib has a complicated treatment dosing and schedule, and we must consider how to help patients take their therapy correctly, such as with pill boxes or reminders. Patient compliance and adherence to treatment are often not as high as clinicians may expect and are an ongoing challenge.55

Finally, but also important, there is the issue of how to best manage toxicities with adavosertib. The EFFORT trial was conducted at sites with substantial experience performing complex clinical trials. For broader use, we will need to ensure that resources, such as clinical education, are available to prepare clinical site staff about administering these drugs safely.

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