Krivak Breaks Down Data for First-Line Maintenance Therapy Options in Advanced Ovarian Cancer

Thomas C. Krivak, MD

Director, Ovarian Cancer Center of Excellence

Director, Gynecologic Oncology Research

Co-chair, Society of Gynecologic Oncology Research Institute

West Penn Hospital, Allegheny Health Network

Pittsburgh, PA

Targeted Oncology^TM: Can you discuss the studies that support PARP inhibition as first-line maintenance therapy in advanced ovarian cancer?

KRIVAK: This is the phase 3 SOLO-1 study [NCT01844986].¹ In order to be enrolled in this trial, you had to have a BRCA1 or BRCA2 mutation. Patients with newly diagnosed advanced stage ovarian cancer were randomized 2:1 [to] olaparib [Lynparza] 300 mg twice a day compared [with] placebo. The primary end point was progression-free survival [PFS] assessed by the investigator, overall survival [OS], time to first subsequent therapy or death, time to second subsequent therapy or death, and quality of life.

There were 391 patients randomized and all patients had either a germline 1 or 2 mutation;….1 patient had a BRCA variant of uncertain significance and 2 patients had somatic mutations. This PARP inhibitior is FDA approved for germline and somatic [mutations], and there are only a few somatic patients in these data.

Most patients had no evidence of disease and had a good performance status, with most…[having a CA-125 level] that was within normal limits. The 5-year follow-up data are good because I think they highlight [that] when you have patients who have a BRCA mutation, [you] need to make sure and encourage those patients to go on maintenance therapy with PARP inhibition.² What I like to point out…is that you can see, at 3, 6, 9, and 12 months, these nice stair steps when patients were getting CT scans and being diagnosed with recurrence. You can see the median treatment duration for patients was right around 24 to 25 months. The placebo was right around 14 months.

They had very strong HRs of 0.33 [95% CI, 0.25-0.43] and I think 0.30 [95% CI, 0.23-0.41; P < .001]. But you see a nice delta of approximately 43 months in patients who were treated with olaparib vs placebo for that group. Again, the HR is 0.33.

At 5 years, you have basically more than a doubling of the patients who were progression free, from 21% to 48%. There’s no doubt about it; in this group of patients PARP inhibition helps prevent recurrence.

What were the relevant results from subgroup analyses in this study?

When you look at the complete or partial responses, it was effective. When you look at ECOG status, it was effective in zeros or ones. Irrespective of the CA-125 level at baseline, [and] BRCA1 or BRCA2 or combination BRCA1/2 mutations, the medication was effective. [In patients older] than 65 years, [it was] effective, [and] again in stage III or stage IV [disease]. Everything…shows that it favors PFS for patients who were treated with olaparib maintenance in this study.

I think these data are important when you have a placebo-controlled trial. When I hear some folks say, “I don’t want to use maintenance because patients are asymptomatic and it’s their time to feel good,” the bottom line is that when you look at the placebo-controlled group, you still have patients who have adverse effects [AEs]. To me…taking the medication [means] you’re going to have more [adverse] effects, but the majority of these… are going to be grade 1 or grade 2, although having grade 1 or grade 2 fatigue or nausea is not going to be pleasant.^1,2 A lot of these [adverse] effects could be what we call a “treat-through” kind of phenomenon, [in which] I guess your body probably has some tachyphylaxis, it gets used to this, or patients may do some dose interruptions.

Again, with the 5-year follow-up, you had no increased incidence of myelodysplastic syndromes [MDS], acute myeloid leukemia [AML], or primary malignancies, so what I would say is that with SOLO-1, we’re getting more and more information [indicating] that we can use this class of medications up front. [The adverse] effect profile was tolerable vs placebo maintenance therapy. You’re going to have adverse events [AEs], but we still do not have no [adverse] effects in patients who have advanced stage ovarian cancer [and who] went through chemotherapy and surgery.

Was there any crossover from placebo to olaparib?

When people progressed, there was crossover. Off the top of my head, I think it was right around 30% to 40%, and there was crossover with that.

Can you discuss the PRIMA trial?

Again, the PRIMA trial [NCT02655016],³ similarly to SOLO-1, was placebo controlled, so [it was] niraparib [Zejula] vs placebo. [This study included] high-risk, first-line patients with ovarian cancer and the patients that were suboptimal, stage IV patients who didn’t have a complete response.

It’s a double-blind, randomized, placebo-controlled trial. It was expanding the patient population beyond SOLO-1.¹ Patients could be enrolled regardless of BRCA status and they had to have high-grade serous or high-grade endometrioid adenocarcinoma. Then they were assessed for HRD using the Myriad myChoice CDx test, but also looking at BRCA mutations. Homologous recombinant proficiency would have been used in the Myriad myChoice CDx test and these patients would not have had a genomic instability score greater than 42.

Again it was a randomized trial, 2:1 randomization. The [primary] end point was PFS by blinded independent radiology review.^3,4 Stage IV [disease] was 35%, so that’s a high percentage of stage IV. When you look at prior neoadjuvant chemotherapy, greater than 65% of these patients, or greater than two-thirds, had neoadjuvant chemotherapy.

Those 2 factors are what we call significant poor prognostic factors. Again, advanced-stage ovarian cancer is a high-risk disease. But I think when you look at the PRIMA trial, they took the patients that had some of the worst prognostic variables and enrolled those patients with this treatment. You could see that the fixed dose vs the standard 300 mg once a day, and dose reductions for the most part, show that they were similar across both groups.

What were the efficacy results of this study?

Looking at the data, [they involved all-comers].3 [Median PFS] was 14 months vs 8 months, so a PFS improvement of 6 months or an HR of 0.62 [95% CI, 0.50-0.76; P < .001], and a 38% risk reduction of having any recurrence if you were treated with niraparib.…[For] OS rate at 24 months, 84% of the niraparib [group] were alive [vs] 77% of the placebo [group], so an increase of approximately 7%, [HR 0.70; 95% CI, 0.44-1.11]. Obviously, these data are not mature with few events occurring.

In the subgroup analysis of the PRIMA trial, HRD [was considered and] that would include the patients who had a genomic stability score of greater than 42 or…a germline or BRCA mutation. You can see more than a doubling of the PFS from 10 to 22 months with an HR of 0.40 [95% CI, 0.27-0.62; P < .001], so a 60% risk reduction, [which is] highly statistically significant.

[Patients that are] HRD BRCA wild type who tested negative on the germline, had a Myriad myChoice CDx test that looked somatic, [and] didn’t see a somatic test, [but for whom] the genomic instability score…is looking at loss of heterozygosity, allelic imbalance, [and] large-scale stage transitions, they are very sensitive to PARP [treatment].

[There was] more than a doubling of the PFS from 8 months to basically 20 months with an HR of 0.50 [95% CI, 0.31-0.83; P = .006], so [there was a] 50% risk of reduction across those patients. Then looking at the homologous recombination proficient [HRP] group, what you can see…is an HR of 0.68 [95% CI, 0.49-0.94; P = .02], so a 33% reduction in the risk for recurrence, and an improvement of PFS of roughly right around 3 months.³ Again, this is how niraparib got the “all-comers” for ovarian cancer, statistically significant across all groups, to improve the PFS. However, you can see how some of these biomarkers are predictive, as well as prognostic.

Again, looking at the different subgroups—looking at age, functional status, stage III or stage IV [disease], neoadjuvant chemotherapy, BRCA mutations, [and] HRD— you can see for the most part it does not cross unity, so all subgroups favored the utilization of niraparib in up-front [treatment].³ The not-determined HRD group crossed unity. To me, what this goes to show again is that in all subgroups across the PRIMA study, patients benefited by receiving the therapy with the niraparib.

What is your reaction to these data?

These are important data, I think, when we look at how we’re going to change practice, when we see PFS improved by a blind, independent radiology review, which is nice and solid. And then we want to look at OS again, [which was] 84% vs 77% at 2 years [HR, 0.70; 95% CI, 0.44-1.11].⁵

But when you look at this HRP group, the patients that seem to have the poorest outcome, we’re seeing at 2 years a 22% increase in patients who are alive, who were treated with niraparib [HR, 0.51; 95% CI, 0.27-0.97]. Again, nothing can be concluded from this because the data are not mature but looking…at the 24-month survival the one that does not cross unity with the HR is the HRP group. The patients who have what appear to be more aggressive tumors appear to have more residual disease. This is, I want to say, an unmet need, but to me these are the patients that I think we have the greatest opportunity of keeping in remission. I think these data are very encouraging with the OS, even though they are not mature, but it will be interesting to see how we get these data over the next couple of years.

Looking at safety, any treatment-related AE, you can see a high percentage of patients are going to have any type of treatment-related AE; even in the placebo group these patients still had them.⁶ [For example,] grade 3, 70%; led to discontinuation, 12%; led to dose reduction, 70%; led to dose interruption, 80%; and led to death, about 4%. I think most of the time when we have a treatment-related AE, we’re going to get a dose interruption, we’re going to get a dose reduction; and again, discontinuation of 12%, I think, is within the standard that you would expect for a phase 3 trial with up-front ovarian cancer, especially in this high-risk subgroup.

When we look at these, the dose interruptions were similar to [those in] previous niraparib trials; treatment discontinuation due to thrombocytopenia was right around 3% to 4%, and again, [the numbers for] treatment-related deaths were small. I mean they may happen, but [the numbers are] still small. Looking at anemia, nausea, and thrombocytopenia, no new signals were seen in niraparib vs the other trials that have been done.⁶ One patient was diagnosed with MDS after 9 months of niraparib therapy. Again, I would quote an MDS/acute myeloid leukemia rate of about 0.5% to 1.5%. I don’t want to downplay any of the AEs with this, and all these medications do have an AE profile. But in this high-risk group of patients, I think this medication performed outstandingly.

Please discuss the PAOLA-1 (NCT02477644) study.

The PAOLA-1 study [treated patients with] advanced ovarian cancer patients up front, but again, it’s different in that the comparator arm is going to have patients who were treated with placebo, as well as with bevacizumab [Avastin].⁷

There are patients with stage III or stage IV ovarian cancer, [whose] ECOG status is 0 to 1, [and who] had to have a complete or partial response to up-front chemotherapy. They had to be able to tolerate 2 to 3 cycles of bevacizumab. If they couldn’t tolerate 2 to 3 cycles of bevacizumab, they weren’t eligible. You could see that there was again a 2:1 randomization—olaparib plus bevacizumab vs placebo plus bevacizumab. The primary end point was PFS for randomization and it was investigator assessed. Secondary end points were OS, as well as PFS2, time to subsequent therapy…quality of life, and safety.

Do you believe veliparib has potential in this setting?

I think that veliparib is probably another [add-on]. It was presented at ESMO [European Society for Medical Oncology meeting] a few years ago before the pandemic.⁸ We had [results from] PAOLA-1, PRIMA, and the VELIA trial [NCT02470585] presented in the presidential sessions, the 3 up-front ovarian cancer maintenance treatments being presented at ESMO, which I thought was impressive, but I don’t think J&J [Johnson & Johnson] has ever gone after any type of indication at this time.

They tried to look at [whether you could] combine veliparib with chemotherapy and [examining] those things. I think that you had such strong data from GSK [GlaxoSmithKline]/ Tesaro with the up-front PRIMA trial, as well as with patients with recurrent ovarian cancer, and some other trials that we haven’t talked about such as TOPACIO [NCT02657889].⁹ Then rucaparib [Rubraca] is out there as well in the recurrent setting. I think they got the trial done and VELIA is a good trial and I like the fact that [its results were] presented and published. Because again, to me, if you were to ask what the number one goal is, my number one goal is making sure that we’re discussing maintenance treatment with our patients, and VELIA did show that maintenance treatment was beneficial as well.¹⁰

Veliparib has not been FDA approved yet, and I don’t know if J&J is going to go look at it in ovarian cancer. Talazoparib [Talzenna] is [a drug for] breast cancer, with Pfizer, so we have not seen that in the ovarian cancer space just yet.

What are your takeaways from the PAOLA-1 data?

With the PAOLA data, I think the biggest thing we always want to keep in the back of our minds is that the placebo group was not just a true placebo group, it was placebo plus bevacizumab.⁹ What you can see there is the platinum chemotherapy plus bevacizumab, and then the patient was continued on olaparib with bevacizumab or bevacizumab alone. The HR for all-comers is right around 0.59 [95% CI, 0.49-0.72], so a 41% risk reduction across the board for chance of recurrence. It has a statistically significant P value [P < .001]. At 12, 18, and 24 months, patients who were treated with olaparib and bevacizumab all had improvement in their PFS rates.

This is similar to the PRIMA trial where we had HRD, HRD-positive with BRCA wild type, and then…HRP or unknown [participants].^3,9,10 What you can see is in the HRD subgroup, you had an HR of 0.33 [95% CI, 0.25-0.45]. [In] the HRD excluding tumor BRCA, you had an HR of 0.43 [95% CI, 0.28-0.66]. In the HRP, you had an HR of 0.92 [95% CI, 0.72-1.17]. [There was] a delta of 17 months vs 37 months for the olaparib/bevacizumab vs bevacizumab alone in the BRCA-mutated patients, as well as HRD patients. When you get rid of the BRCA-mutated patients and you focus on the BRCA wild type or HRD-positive [patients], you can see again, the bevacizumab group’s down to 16 months’ PFS and the olaparib/bevacizumab’s goes down to 28 months; so a 12-month delta and then again, 16 months in the HRP or unknown subgroups.

The difference here is, you saw in the PRIMA trial it was 8 to 9 months vs 5 months in the niraparib vs placebo group. With the indication for olaparib/bevacizumab for [patients who were] HRD positive with BRCA mutations, as well as HRD positive with genomic instability with BRCA wild type.³

Are there notable safety signals in PAOLA-1?

[Yes, and] there are AEs greater than 10%, such as the cytopenias, fatigue, nausea, and hypertension.⁹ You can see that in the placebo group vs olaparib plus bevacizumab, you do have an increase in the percentage of patients who did have grade 3 toxicity. I always look at some of these and look at the anemia. It seems like anemia can occur. I’ve seen it with olaparib early on or occur after about 12 to 13 months. The bottom line is that many of these AEs are on par with [those of] studies such as SOLO-1, Study 19 [NCT00753545], and SOLO-2 [NCT01874353] as well.

_REFERENCES

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_{2. Banerjee S, Moore K, 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. Ann Oncol. 2020;31(suppl 4):S551-S589. doi:10.1016/annonc/annonc276}

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_{4. Gonzalez-Martin A, Pothuri B, Vergote I, et al: Niraparib therapy in patients with newly diagnosed advanced ovarian cancer (PRIMA/ENGOT-OV26/GOG-3012 study). 2019 ESMO Congress. Abstract LBA1. Presented September 28, 2019.}

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_{6. González-Martín A, Pothuri B, Vergote IB, et al. Niraparib therapy in patients with newly diagnosed advanced ovarian cancer (PRIMA/ENGOT-OV26/GOG-3012 study). Ann Oncol. 2019;30(suppl 5):v851-v934. doi:10.1093/annonc/mdz394}

_{7. Ray-Coquard I, Pautier P, Pignata S, et al; PAOLA-1 Investigators. Olaparib plus bevacizumab as first-line maintenance in ovarian cancer. N Engl J Med. 2019;381(25):2416-2428. doi:10.1056/NEJMoa1911361}

_{8. Coleman RL, Fleming GF, Brady MF, et al. Veliparib with first-line chemotherapy and as maintenance therapy in ovarian cancer. N Engl J Med. 2019;381(25):2403- 2415. doi:10.1056/NEJMoa1909707}

_{9. Konstantinopoulos PA, Waggoner S, Vidal GA, et al. Single-arm phases 1 and 2 trial of niraparib in combination with pembrolizumab in patients with recurrent platinum-resistant ovarian carcinoma. JAMA Oncol. 2019;5(8):1141-1149. doi:10.1001/jamaoncol.2019.1048}

_{10. Ray-Coquard IL, Pautier P, Pignata S, et al. Phase III PAOLA-1/ENGOT-ov25 trial: olaparib plus bevacizumab (bev) as maintenance therapy in patients (pts) with newly diagnosed, advanced ovarian cancer (OC) treated with platinum-based chemotherapy (PCh) plus bev. Ann Oncol. 2019;30(suppl 5):v894-v895. doi:10.1093/annonc/mdz394.053}