The PRIMAry point: health-related quality of life (HRQoL)

PRIMA was the right name for the upfront phase 3 trial of switch maintenance using the poly (adenosine 5’-diphosphoribose) polymerase inhibitor (PARPi), niraparib, on so many levels. Primary is derived from the Latin primus, meaning first. PRIMA was a first-line intervention, the first trial to attempt to improve cure with a PARPi in ‘all comers’ independent of the eloquent biomarker, BRCA mutation, and the follow-on trial, FIRST (ENGOT-0V44), incorporates the immunotherapeutic PD-1 inhibitor, dostarlimab, into frontline therapy with niraparib in advanced ovarian cancer. Pothuri et al. have now reported on the patient-reported outcomes and health-related quality of life (HRQoL) with niraparib in newly diagnosed advanced ovarian cancer patients in the PRIMA trial, the data of primary importance, given that PRIMA did not improve overall survival (OS) (1,2).

The PARPi story has been a rollercoaster ride. Discovered in the 1980s, PARPi were investigated as chemo- and radio-therapy sensitizing agents inhibiting DNA damage repair, to augment efficacy (3). Inheriting or acquiring a BRCA mutation sets up ‘synthetic lethality’ where the disrupted homologous recombination repair of deoxyribonucleic acid (DNA) causes the cancer cell to be dependent on other lower fidelity DNA repair mechanisms for which PARP is an essential contributor building a polymer scaffold for DNA repair enzymes and PARPis potentially deliver the knockout blow to mutant cancer (4). After the initial demonstration of improved progression-free survival (PFS) (or time to recurrence) in platinum sensitive recurrence (recurrence >6 months after first-line therapy), there has been a shift in focus to the frontline setting in the hope of impacting OS and cures (5). Six studies have now reported survival outcomes in the first-line setting {FLAMES, PAOLA-1, PRIMA, PRIME, SOLO1, VELIA [FLAMES, PRIMA, PRIME, and VELIA are not acronyms but titles; PRIMA and PRIME all mean first and VELIA relates to the investigational drug, veliparib; PAOLA-1—Poly(ADP-ribose) Polymerase inhibitor Activity in Ovarian cAncer; SOLO—Survival with OLaparib in Ovarian cancer]} and yet we can only demonstrate an improvement in OS in patients with inherited or acquired BRCA mutations, initially in recurrent disease with a 33% improvement in OS, an extra 13-month life {SOLO2—median OS: 52 vs. 39 months [hazard ratio (HR), 0.74; 95% confidence interval (CI): 0.54–1.00]; P=0.054} (6), and in frontline therapy with a 45% better chance of being alive at 7 years [SOLO1—median OS: not reached vs. 75 months (HR, 0.55; 95% CI: 0.40–0.76); P=0.0004] (7), neither of which were statistically significant. Indeed, with the spend, SOLO1 required a P<0.0001 to declare statistical significance.

An equally powerful drive to move PARPi into the frontline has been the voluntary withdrawal of indication for later-line use by all the manufacturers, because of the consistent observation of an approximately 30% worse survival when PARPi are used in second-, third- or later-line maintenance or therapy (3).

The OS for PRIMA has recently been updated with the initial promise of benefit based on a 24-month interim analysis, with 84% alive in the niraparib group and 77% in the placebo group, though with a HR that crossed unity [non-significant (NS) (HR, 0.70; 95% CI: 0.44–1.11)]; at a median follow-up in excess of 6 years (73.9 months), the OS HR was 1.01 (95% CI: 0.84–1.23; P=0.88) (8).

Developed by Tesaro, and then GlaxoSmithKline Pharmaceuticals to extend benefit beyond those tumors with a BRCA mutation, niraparib was granted fast-track designation by the US Food and Drug Administration (FDA) and approved March, 27^th 2017 as maintenance treatment for all comers with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer in complete or partial response to platinum-based chemotherapy based on the PFS advantage in the NOVA trial (9), and as first-line therapy for all comers based on PRIMA, April 29^th, 2020 (8).

Quality of life (QoL) has its origins in Aristotle’s eudaimonia, human flourishing more than the literal translation of happiness (10). HRQoL is an increasingly important end-point in cancer trials, especially as recent analyses demonstrating that less than a third (32%) of FDA indications for new drugs approved with surrogate endpoints demonstrate a statistically significant OS advantage after approval (11,12).

Initially, HRQoL evaluation was used to recalibrate PFS, an important surrogate of OS, using quality-adjusted (QA) time without symptoms of disease, toxicity or recurrence (Q-TWiST) (13). Delaying recurrence while discoloring HRQoL is an unfavourable trade-off, and it was encouraging to confirm that Q-TWiST still resulted in a statistically significant prolongation of QA-PFS, which was significantly longer with niraparib vs. placebo in the overall intention-to-treat population with a 4.1 months improvement (95% CI: 2.2–5.8), in contrast to the originally unadjusted 5.6 months reported in PRIMA [13.8 vs. 8.2 months (HR, 0.62; 95% CI: 0.50–0.76; P<0.001)] (8,13).

During the conduct of PRIMA, dose was adjusted from 300 to 200 mg PO QD for low body weight (<77 kg or 170 lbs) or platelets (<150,000/µL), because of excess hematologic toxicity, especially thrombocytopenia (8). The most common or important side effects of niraparib are thrombocytopenia, anemia, neutropenia, nausea, constipation, myelodysplastic syndrome or acute myeloid leukemia, which occurs in approximately 1% (8).

In Pothuri et al.’s final formal analysis of the HRQoL in PRIMA, niraparib was associated with self-reportedly worse, symptoms of constipation, nausea, vomiting, and anorexia, yet no worsening in overall HRQoL (1). It was a well-done study with patient-related outcome (PRO) adherence exceeding 80% for all instruments across all cycles. Notably, the first evaluation time point was 2 months into the study missing the worst of nausea, vomiting, and fatigue which were reported in the study as ‘low-grade’ and common, yet grade 3 nausea was reported in 6%, vomiting in 22%, and grade 3 fatigue in 9% (8). There are some significant details that are easy to miss is a cursory read of the abstract. Rather surprisingly, compared to placebo, niraparib caused worse gastrointestinal symptoms and constipation but not fatigue. Patients did not self-report any worsening from baseline of fatigue, headache, insomnia, or abdominal pain on questionnaires. Unique niraparib side-effects related to its lipid solubility, central nervous system (CNS) penetration and dopaminergic effects in contrast to other PARPi, are headache, anxiety, insomnia, and hypertension, but these could not be identified by the instruments used in the study, likely because these happened early and triggered dose reductions. Furthermore, the study was not powered for HRQoL, an all too common issue for secondary endpoints, especially frustrating when determining the sample size is well established for the instruments used in the trial [the European Organisation for Research and Treatment of Cancer QoL Questionnaire (EORTC QLQ-C30), the EORTC QLQ Ovarian Cancer Module (EORTC QLQ-OV28), the Functional Assessment of Cancer Therapy-Ovarian Symptom Index (FOSI), and 5-level EuroQol 5-Dimension Questionnaire (EQ-5D-5L) questionnaires] (13-15).

Pothuri et al.’s findings are very similar to those reported with olaparib. In SOLO2, the first phase 3 of the first approved PARPi conducted in patients with recurrent BRCA mutated ovarian cancer, 66% in the olaparib group vs. 39% in the placebo reported fatigue, yet in formal analysis, olaparib maintenance therapy did not have a significant detrimental effect on HRQoL (14).

Importantly, the study highlighted the challenges of HRQoL assessment in clinical trials, especially delayed initial evaluations missing early toxicity peaks, limitations of standardized questionnaires in capturing PARP inhibitor-specific PRO items (e.g., insomnia, hypertension), and the influence of psychological factors like the “reframing effect” of treatment hope. Increasingly, trials prioritize HRQoL as a co-primary endpoint but more creative options such as integrating mixed-methods approaches (e.g., qualitative interviews) could contextualize quantitative HRQoL data and better explore the “reframing” effect of hope. Despite these limitations, the adjusted quality-adjusted PFS (QA-PFS) analysis still favored niraparib, underscoring its clinical value even with HRQoL trade-offs.

A notable observation in the PRIMA HRQoL was the steady improvement in ‘attitude toward disease/treatment’ which was rapid until about 9 months and then plateaued. This likely reflects one of the important influences on reported HRQoL that is hard to pull out of the data, namely the ‘reframing’ effect of the very goals of being on a switch maintenance trial, where taking the tablets is imbued with the hope of a better chance of cure, and it is more than likely that this moderates observable differences. The majority of survivors (≥75%) report a positive impact of cancer on their lives (16).

It has been our consistent experience that qualitative research really does have a role in dissecting the complex issues play into the patient experience. Fatigue is the most prevalent side effect of PARPi switch maintenance (4). And yet while milder than fatigue experienced on intravenous chemotherapy, it negatively impacts functioning and sense of self, isolates and is felt to be the necessary price paid for preventing recurrence (17).

Nocebo (the reverse of the placebo effect) in part explains how hard it is to demonstrate, in clinical trials, what we see so clearly in clinic. In SOLO2, all the participants experienced one or more adverse event (AE) whilst on placebo, one quarter of AEs appeared to be related to placebo, and 22% of participants reported at least one grade ≥3 AEs, with 5 % experiencing grade 3 fatigue on placebo (18).

The clinician priming the patient with anticipated toxicities, encouraging them that side effects will improve after peaking at approximately 2–4 weeks into treatment, and giving a prophylactic script for antiemetics sets expectations that interpret the experience of side effects. The physical, social, emotional, and spiritual well-being of patients on treatment, living under the threat of recurrence, complicate and impact her ability to lead a fulfilling life (19). Placebo is less often deception with a sham, than harnessing the power of belief and framing issues in a very specific context (20,21).

HRQoL is inevitably subjective. It is the lived experience of illness and its treatments. Exploring the gap between our expectations of health and our experience of illness, how fear frames what’s at stake, and in the cancer arena, the emotional and existential challenges of cancer profoundly challenge our thin veneer of invulnerability. It’s worth reading or rereading David Spiegel’s seminal piece in the New England Journal of Medicine (22), as his concepts have been taken forward by Alia Crum’s lab at Stanford (mbl.stanford.edu) and confirmed in the recently published randomized controlled trial that showed a brief mindset-focused digital intervention was effective at improving physical, social, emotional, and functional QoL (HRQoL), and reducing distress (23).

In our population of ovarian cancer survivors, thriving can be a struggle for the majority, with 56% reporting fear of cancer recurrence, 26% of patients with scores suggestive of post-traumatic stress disorder (PTSD), and only 9% of survivors reporting either an interest in sex or being sexually active, survivorship is a rocky road (24). Perhaps most encouragingly, we have moved on from benchmarking to intervention. Alexi Wright and Joanna Arch have piloted REVITALIZE, an acceptance-based telehealth intervention for women with ovarian cancer who experience PARP inhibitor-related fatigue (25). REVITALIZE uses the cognitive behavioral principles of acceptance and commitment therapy (ACT) with the aim of accepting and then detaching from negative thoughts. The pilot demonstrated preliminary efficacy with 86% compliance over 3 months, and significantly reduced fatigue interference (Cohen’s d=0.94, P=0.008) fatigue severity (d=0.54, P=0.049), improved fatigue levels (d=0.62, P=0.04) relative to written guidance (enhanced usual care). REVITALIZE also showed promise for improved fatigue self-efficacy, fatigue catastrophizing, anxiety, depression, and QoL (ds =0.60–0.86, P≥0.05) with formal testing in a phase 3 being rolled out in 2025.

The power of HRQoL data is that it tells the real story of the experience of illness and its treatments. Getting to grips with what it really is like to be the patient is fundamental to our mission of curing, caring and accompanying those with illness. We need more cures. Short of that, our goal has to be to improve HRQoL, the primary point of what we do. When we don’t improve it, the next best thing is to extend survival without compromising it. When we do neither, that should drive the engine of innovation to do better.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Annals of Palliative Medicine. The article has undergone external peer review.

Peer Review File: Available at https://apm.amegroups.com/article/view/10.21037/apm-24-166/prf

Funding: None.

Conflicts of Interest: The author has completed the ICMJE uniform disclosure form (available at https://apm.amegroups.com/article/view/10.21037/apm-24-166/coif). R.T.P. reports grants from AstraZeneca, consulting fees from Aadi Bioscience, AstraZeneca, GSK Inc., ImmunoGen Inc., Merck & Co., Roche Pharma, Sutro Biopharma and Tubulis Gmbh. He serves on DSMBs for AstraZeneca, EQRx, & Roche Pharma. He reports royalties from BMJ Publishing, UptoDate, Elsevier Ltd., Wolters Kluwer Health, & Wiley Blackwell; payment for educational events has come from Research to Practice, ExpertConnect, ReachMD, & CMEO Outfitters. The author has no other conflicts of interest to declare.

Ethical Statement: The author is accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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