PARP Inhibitors Move Into the Limelight

Ursula A. Matulonis, MD

After a long and fitful regulatory journey, olaparib (Lynparza) became the first PARP inhibitor to enter clinical use less than 6 months ago when the FDA approved the agent as a fourth-line treatment for women with recurrent ovarian cancer with a confirmed germline BRCA (gBRCA) mutation.

Since then, research evidence has been mounting that PARP inhibitors are not just for gynecologic malignancies—or for patients whose tumors harbor inherited BRCA defects. Early clinical trials results featured at the 2015 American Association for Cancer Research (AACR) Annual Meeting in Philadelphia in April indicate that PARP inhibitors induce antitumor responses not only in ovarian cancers but also in breast and prostate cancers and possibly in other tumor types. “The concept is applicable to other cancers,” Joaquin Mateo, MD, a researcher from Great Britain who presented findings on olaparib in metastatic castration-resistant prostate cancer (mCRPC) at AACR, said in an interview. “We have to move forward. There are many other patients who may benefit— not only patients with BRCA mutations.”

Although olaparib is the most advanced PARP inhibitor, the class of agents is attracting strong interest. At least six agents are in active clinical trials (Table).

Mechanisms in Focus

While much of the clinical work conducted thus far is in early stages, researchers are looking more broadly at molecular signals for patients who might benefit from PARP inhibition, with the focus on the functions of the PARP enzymes as well as on the presence of BRCA defects.

PARPs are members of the poly (ADP-ribose) polymerase family of enzymes that have as one of their key functions the repair of damaged DNA. Cells have a number of different mechanisms that allow them to repair damaged DNA, including base excision repair (BER) and homologous recombination.

Joaquin Mateo, MD

PARPs have a particularly critical role in the BER pathway, binding to single-strand breaks in DNA and ultimately leading to the recruitment of DNA repair proteins to the sites of damage.

PARP inhibitors block the activity of the PARP enzymes. As monotherapy, the oral agent has proved most effective against tumors with mutations in BRCA1/2, tumor suppressor genes whose best-understood role is the repair of double- strand breaks in DNA.

Research presented at AACR indicated that PARP inhibition strategies, either as monotherapy or in combination with other targeted agents, could elicit responses in tumors with and without BRCA1/2 mutations.

Mateo, a clinical research fellow at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, is focusing on the molecular analysis of prostate cancer tumors for defects in genes known to be involved in DNA repair.

While the incidence of inherited BRCA2 mutations is less than 2% among patients with prostate cancer, the prevalence rises to 10% to 15% among men whose disease becomes castration resistant, said Mateo. However, he said, there are 30 to 40 genes that are of interest in DNA repair, thus widening the pool of patients who conceivably might benefit from PARP inhibition strategies.

“About one-third of patients with advanced prostate cancer would have a mutation in any of these genes involved in the DNA repair machinery,” Mateo said.

Table. PARP Inhibitors in Development

Source: NIH Clinical Trials registry. www.ClinicalTrials.gov.

Ursula A. Matulonis, MD, who is researching the efficacy of anti-PARP regimens in ovarian cancer, said a deeper understanding of the “genomic landscape” of the tumors is needed.

Matulonis is director and program leader of Medical Gynecologic Oncology in the Susan F. Smith Center for Women’s Cancers at the Dana-Farber Cancer Institute in Boston. She presented findings on a two-pronged strategy combining olaparib and the PI3K inhibitor BKM120 in women with triple-negative breast cancer (TNBC) and for patients with highgrade serous ovarian cancer.¹ She said the dual pathway inhibition approach apparently induced “a state of more homologous recombination deficiency” that made the cancers more susceptible to anti-PARP agents.

“Ovarian cancer, which is so driven by homologous recombination deficiency, is really the perfect model to study how you make that cancer cell more DNA repair deficient,” Matulonis commented during an AACR press conference where she discussed her research.

High Prostate Cancer Responses

Mateo and colleagues found a marked difference in response among men with prostate cancer who participated in the phase II multistep TOPARP study.² Overall, the study found that patients with somatic or germline defects in DNA repair genes, particularly BRCA2 and ATM, were more likely to respond to olaparib than those without the alterations, representing a unique molecularly defined treatment population.

The first stage of the study enrolled 50 patients across seven centers in the United Kingdom. All the patients had received prior treatment with docetaxel, 48 had received abiraterone (96%), and 29 had received cabazitaxel (58%). Patients received olaparib at a dose of 400 mg twice daily continuously in a 28-day cycle.

In the full population of evaluable patients (n = 49), 16 (32.7%) responded to olaparib (95% CI: 20.0-47.5), six patients had radiological responses, as assessed by RECIST, and 11 patients had a biochemical response defined as a ≥50% decrease in prostate-specific antigen levels.

Next-generation sequencing was conducted on fresh CRPC biopsies, taken before and during treatment with olaparib. Overall, deleterious mutations were identified in the tumor samples for 16 of 49 evaluable patients (32.7%). Of these, 14 patients experienced a response to olaparib (87.5%).

All patients with a BRCA2 alteration responded to treatment with olaparib. Defects in ATM were indicative of response to olaparib, although one patient with a type of ATM alteration did not respond to therapy. In addition to these alterations, biallelic losses in other relevant genes were seen in FANCA and CHEK2. In patients without DNA repair defects (n = 28), a response to olaparib was not observed.

“These are potentially the first clinical data supporting molecular stratification of treatment in prostate cancer, and we are testing this idea in the second stage of the TOPARP trial, TOPARP-B,” Mateo said in a statement.

The next stage of the study will seek to validate the molecular signature by enrolling only participants who test positive. “For TOPARP-B, we are enrolling only patients who screen positive for the DNA repair mutations linked to response in TOPARP-A,” Mateo confirmed.

Going forward, Mateo sees many unanswered questions, such as: (1) whether all the genes involved in DNA repair are equally important in cancers; (2) whether the impact of having a combination of mutations in this pathway is different from a single mutation; (3) whether these mutations can be detected at diagnosis or when the cancer is advanced; (4) whether a blood test can be used to detect mutations; and (5) the optimal timing for administering therapy.

Combos Effective in Several Settings

Olaparib Plus BKM120

Although PARP inhibitors have shown activity as monotherapy, recent studies support greater efficacy for combination regimens.

Matulonis and colleagues are seeking to establish the maximally tolerated dose (MTD) of the combination of olaparib and BKM120 given orally on a continuous daily basis.¹ The trial also will evaluate the combination of olaparib and another PI3K inhibitor, BYL719, and those findings will be reported at a later date.

Patients were eligible for the trial if they had a confirmed diagnosis of triple-negative breast cancer or high-grade serous ovarian cancer, or a documented gBRCA mutation in either of those tumor types regardless of tumor histology.

The olaparib/BKM120 segment enrolled 46 patients with ovarian cancer and 24 patients with breast cancer. Participants in the ovarian cancer cohort were a median age of 60 years, 90% had high-grade serous tumors, and 77% had a gBRCA mutation. In the breast cancer cohort, the median age was 47.5 years, 63% had TNBC, and 58% had a gBRCA mutation.

Among the patients with ovarian cancer, the overall response rates (ORRs) were 26% (12 patients) with a PR, 48% (22 patients) with stable disease (SD), and 15% (7 patients) with progressive disease (PD). Five patients (11%) were not evaluable.

For patients with breast cancer, the ORRs were 21% (5 patients) with a PR, 50% (12 patients) with SD, and 17% (4 patients) with PD. Three patients (13%) were not evaluable. Among the responders in the breast cancer group, four patients had triple-negative tumors, including three individuals with gBRCA1 mutations and one with gBRCA wild-type. The fifth responder’s tumor was positive for estrogen and progesterone receptors and harbored a gBRCA2 mutation.

Timothy Yap, MD, PhD

“It is important that we saw responses against both BRCA-mutant and BRCA wild-type cancers,” Matulonis, who also is an associate professor of Medicine at Harvard Medical School, said in a statement. “We need to do further analysis to identify biomarkers that we can use to more effectively identify the patient population that will be most positively affected by the olaparib/ BKM120 combination.”

Olaparib Plus AZD5363

Similarly, the combination of olaparib with the novel AKT-targeting agent AZD5363 generated responses in a variety of tumor types among patients with and without BRCA1/2 mutations who participated in the phase I ComPAKT trial.³

The two-drug regimen elicited confirmed partial responses in four patients, according to Timothy Yap, MD, PhD, a clinician-scientist and consultant medical oncologist at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust in London who helped lead the trial.

The responders included one patient with BRCA1/2 wild-type ovarian cancer, two patients with BRCA1/2-mutant breast cancer, and one person with BRCA1-mutant ovarian cancer, Yap said in a statement.

In addition, two patients have experienced ongoing, prolonged disease stabilization, including one person with breast cancer of unknown BRCA status and another with peritoneal mesothelioma. Another patient with BRCA1/2-mutant advanced prostate cancer achieved a radiologic response measured by MRI and prostate-specific antigen levels that is ongoing after 11 months, Yap said.

“These early results are very exciting because preclinical data had suggested that the olaparib and AZD5363 combination had the potential to be effective in a much wider population of patients than just those harboring germline BRCA1/2 mutations,” said Yap.

The trial evaluated the combination regimen in patients with 10 different tumor types: six ovarian, three breast, two colorectal, two mesothelioma, two prostate, and one each of bladder, cervical, gastrointestinal stromal tumor, pancreatic, and uterine.

Lead study author Vasiliki Michalarea, MD, also of The Institute of Cancer Research, said the next step in the research involves an expansion phase at the established dosing level and schedule with two cohorts: (1) patients with gBRCA1/2-mutated cancers including individuals who have received prior PARP inhibitors and have platinum-resistant tumors; and (2) patients with advanced cancers with clinical features of BRCAness or relevant somatic mutations.

BRCA Link Complex

The question of which patients would most benefit—or benefit at all—from PARP inhibition therapy looms as one of the largest unsolved research questions about the class of agents and has helped complicate the path to regulatory approval for the first-in-class olaparib.

In December 2014, the FDA granted an accelerated approval to olaparib as monotherapy in patients with advanced ovarian cancer whose tumors test positive for deleterious or suspected deleterious gBRCA mutations and who already have been treated with three or more prior lines of chemotherapy. The BRACAnalysis CDx test was approved as a companion diagnostic.

The approval was based on a 34% objective response rate and a 7.9-month median duration of response among 137 patients with measurable gBRCA-mutated ovarian cancer who received olaparib monotherapy after ≥3 lines of chemotherapy.⁴

The pivotal findings stemmed from a single-arm phase II study of olaparib in patients with deleterious or suspected deleterious gBRCA-mutated advanced cancers, and on safety data from several other olaparib studies, according to Astra-Zeneca, the company developing the drug.^5,6

Previously, Ledermann et al7 had reported that the median progression-free survival (PFS) was significantly longer among patients with a BRCA mutation who had received olaparib compared with placebo (11.2 months vs 4.3 months, respectively; P <.0001). Study 19, as the trial has been called, randomized 265 participants to olaparib or placebo from August 2008 until February 2010.⁷

Notably, 14% of the patients with a BRCA mutation had aberrations of somatic (acquired) origin, as opposed to germline (inherited) mutation. Investigators said this patient group was too small to analyze formally, but that the outcomes suggest that olaparib is “most effective in tumours with a BRCA mutation, irrespective of whether the mutation originates in the germline or tumour DNA.”⁶ Additionally, the researchers found that PFS was longer with olaparib versus placebo among patients with wild-type BRCA (7.4 months vs 5.5 months, respectively; P = .0075), although the benefit is not as pronounced as among those with the aberration.

The responses illustrate the complexity of the signaling pathways at work in ovarian cancer. “Up to 50% of patients with high-grade serous ovarian cancer are deficient in homologous recombination—a key pathway for repair of DNA damage—due to germline or somatically acquired BRCA1 or BRCA2 mutations, epigenetic inactivation of BRCA1, or BRCA-independent defects in the homologous recombination pathway,” according to Ledermann and colleagues.⁷

Long Regulatory Road

The initial results from Study 19, which evaluated olaparib as maintenance therapy in platinum-sensitive, relapsed, high-grade serous ovarian cancer, demonstrated a PFS benefit for the drug but no significant difference in overall survival.⁸

The findings from that 2012 interim analysis had not yet been correlated with mutation status and, even before the peer-reviewed publication of the data, AstraZeneca already had announced that it was ending its development program for olaparib as a maintenance therapy in ovarian cancer.⁹ Two years later, the company revived the program, based on the findings from the subgroup analysis of BRCA mutation—positive tumors.

Olaparib’s future, however, appeared insecure again in June 2014 when the FDA’s Oncologic Drugs Advisory Committee (ODAC) recommended against approving the drug. In briefing documents, FDA staffers had expressed concern that the application relied upon a sample size from a retrospective analysis that could not reliably predict that the benefits of the therapy in a maintenance setting would outweight the risks of toxicities, such as myelosuppression, fatigue, and gastrointestinal disturbances.¹⁰

After a negative 11-2 ODAC vote, AstraZeneca said it submitted “a major amendment” to its new drug application, offering additional data that the FDA had requested and ultimately gaining the approval.

At the AACR conference, Matulonis referenced the rocky road that olaparib traveled before it was approved and the need to press forward in oncology research.

“If you followed the olaparib approval for ovarian cancer, that took many years and ups and downs in the field. I think we as clinicians have to be driven—if we see something that is active and exciting and well tolerated and is benefiting patients, then we really hold that flag up and continue to push for funding, push the FDA, push companies, etc.”

Associated editor Tony Berberabe, MPH, and freelance writer Jane de Lartigue, PhD, contributed to this report.

References

1. Matulonis UA, Wulf G, Birrer M, et al. Phase I of oral BKM120 or BYL719 and olaparib for high grade serous ovarian cancer or triple negative breast cancer: final results of the BKM120 plus olaparib cohort. Presented at: 2015 AACR Annual Meeting; April 18-22, 2015; Philadelphia, PA. Abstract 8972.
2. Mateo J, Sandhu S, Miranda S, et al. Phase II trial of the PARP inhibitor olaparib in sporadic and unselected metastatic castration resistant prostate cancer (mCRPC). Presented at: 2015 AACR Annual Meeting; April 18-22, 2015; Philadelphia, PA. Abstract CT322.
3. Michalarea V, Lorente D, Lopez J, et al. Accelerated phase I trial of 2 schedules of the combination of the PARP inhibitor olaparib (Ola) and AKT inhibitor AZD5363 (AZD) using a novel intrapatient (intrapt) dose escalation design in advanced cancer pts. Presented at: 2015 AACR Annual Meeting; April 18-22, 2015; Philadelphia, PA. Abstract 8529.
4. Lynparza [prescribing information]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2014.
5. LYNPARZA™ approved by the US food and drug administration for the treatment of advanced ovarian cancer in patients with germline BRCA-mutations [press release]. London, England: AstraZeneca; December 19, 2014.
6. Kaufman B, Shapira-Frommer R, Schmutzler RK, et al. Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 mutation [published online November 3, 2014]. J Clin Oncol. 2015;33(3):244-250.
7. Ledermann J, Harter P, Gourley C, et al. Olaparib maintenance therapy in patients with platinum sensitive relapsed serous ovarian cancer: a preplanned retrospective analysis of outcomes by BRCA status in a randomised phase 2 trial [published online May 31, 2014]. Lancet Oncol. 2014;15(8):852-861.
8. Ledermann J, Harter P, Gourley C, et al. Olaparib maintenance therapy in platinum-sensitive relapsed ovarian cancer. N Engl J Med. 2012;366(15):1382-1392.
9. AstraZeneca updates on olaparib and TC-5214 development programmes [press release]. London, England: AstraZeneca; December 20, 2011.
10. US Food and Drug Administration. FDA briefing document Oncologic Drugs Advisory Committee meeting on June 25, 2014. http://goo.gl/TrntXX. Published June 2014. Accessed April 13, 2015.