Generic Drug Shortage of Platinum Agents in Ovarian Cancer Sends Cautionary Signal

Maurie Markman, MD

The well-publicized severe shortage of vitally important generic antineoplastic agents has highlighted a serious misalignment in the existing market-based and regulatory environment that permitted such an extraordinary situation to develop without meaningful resolution.

An objective observer would almost certainly conclude the stop-gap measures to temporarily improve the availability of essential drugs, including their importation from a country that had previously failed to satisfy necessary regulatory requirements, are far from a satisfactory solution. Further, one might reasonably conclude that the existing process of ensuring the procurement of agents appropriately labeled as essential medications is broken.

Several hurdles exist in creating lasting successes in this arena. Consider the remarkably serious quality issues at an Indian manufacturing plant, the absence of reasonable incentives for major American pharmaceutical companies in the oncology sphere to participate in the process of making generic drugs, the inability of any regulatory agency to create a viable solution, and existing methods of third-party payments that create a situation where such manufacturing is of limited financial viability and certainly low priority. Any reported temporary success with any of these methods is likely to be just that, temporary. For their part, hospitals have rationally joined together to optimize available cost savings associated with generic medications they must purchase, driving production to countries with the lowest labor costs.

What we are observing with drug shortages is a completely unsurprising consequence of the complex and compounding market forces and regulatory inertia. However, often quite hidden from the public are the potentially devastating consequences for patients with cancer who are unable to receive what can be described as lifesaving or life-extending medications such as cisplatin and carboplatin. 

Although it is understandable and appropriate that cancer organizations would attempt to provide guidance for clinicians faced with the painful dilemma of prioritizing drug delivery in the presence of such shortages, it is essential that the public, regulators, and government officials are not lulled into the mistaken belief that such rationing is without potentially very serious consequences for the life expectancy and quality of life of patients.

In this regard, briefly consider the treatment of patients with advanced epithelial ovarian cancer where the role of platinum agents is well-documented. Are there objective data available that document the superiority of survival outcomes associated with delivery of this drug class (cisplatin or carboplatin) compared with a situation where the agents were not available? The sobering answer is yes, both in the front line and in the setting of recurrent, potentially platinum-sensitive disease.

In data from a landmark study reported in the Journal of Clinical Oncology more than 20 years ago,1 investigators from the Gynecologic Oncology Group randomly assigned patients with advanced ovarian cancer with chemotherapy-naïve disease to either single-agent cisplatin or paclitaxel. Patients who received platinum chemotherapy experienced a substantially higher objective response rate (67% vs 42%; P < .001) and time to subsequent disease progression (median 16.4 months vs 11.2 months; P < .001).¹ Importantly, there was no difference in overall survival for patients randomly assigned to the paclitaxel arm in this study because at the time of progression (or even before this event) they were crossed over to receive cisplatin and therefore were not denied this critically important agent.

But what would have happened to these patients, or patients with advanced ovarian cancer being treated today, if a platinum agent were not available because of what has been administratively (but inadequately) labeled a drug shortage?²

The data regarding the critical role of platinum agents in recurrent ovarian cancer originate from a more complex analysis but are in fact (at least in the opinion of this commentator) equally compelling. Another landmark ovarian cancer study compared 2 nonplatinum antineoplastic agents, topotecan and pegylated-liposomal doxorubicin, in the management of recurrent, potentially platinum-sensitive disease.^3,4 Enrolled patients had recurrence/progression at least 6 months following a prior response to and discontinuation of a primary platinum-containing regimen.^3,4 A second subgroup of this trial included patients with platinum-resistant disease, but that population is not relevant to the current discussion although it should be noted there were no survival differences between the 2 antineoplastic agents examined in this specific patient subgroup.

Patients defined as having platinum-sensitive recurrence randomly assigned to pegylated liposomal doxorubicin experienced a modestly superior progression-free survival (median 28.9 weeks vs 23.3 weeks, a 5.6-week difference, P = .037) compared with topotecan.³ However, when overall survival was evaluated, the difference between the 2 treatment arms in the platinum-sensitive subgroup w surprisingly substantially greater in favor of pegylated liposomal doxorubicin (median 107.9 weeks vs 70.1 weeks, a 37.8-week difference, P = .017).³

What might explain the striking difference in the effect of therapy on time to disease progression and the patient’s ultimate survival—which includes treatment after the individual has left the clinical trial—are the specific therapies a patient received. Unfortunately, information on subsequent treatments was not uniformly collected for study participants. However, as the cancers in these specific research participants were considered to remain potentially sensitive to a platinum agent when they entered the trial, it is highly rational to suggest these individuals would be given a platinum drug at the time of disease progression when they left the trial.

Because the well-recognized observation that topotecan may result in severe bone marrow suppression (at the dosage employed in this trial of 1.5 mg/m² per day for 5 consecutive days every 3 weeks) it is likely that a substantial percentage of patients who received topotecan were unable to be administered a platinum agent or were only able to receive a limited amount. This concern would be less of an issue for those who had prior treatment with pegylated liposomal doxorubicin, which is associated with considerably less marrow suppression.

And it was the failure to receive this critically relevant antineoplastic agent in the management of their malignancy that caused the measurable and meaningful shortening of the patients’ survival.

To complete this commentary, it is relevant to note it is not only platinum agents that are essential medications in ovarian cancer management. Space does not permit further comment, but the still not-completely understood results of a phase 3 trial reported more than a decade ago revealed that the third-line delivery of a known active agent in epithelial ovarian cancer (topotecan or pegylated liposomal doxorubicin) can have a substantial effect on the individual’s ultimate survival, compared with the delivery of an apparently less active cytotoxic drug (canfosfamide).⁵

In the opinion of this commentator, ensuring the availability of well-established relatively inexpensive but currently less-profitable generic antineoplastic drugs remains a highly clinically relevant goal; and society, through its governmental representatives, must find a solution to this drug shortage problem. 

References

1. Muggia FM, Braly PS, Brady MF, et al. Phase III randomized study of cisplatin versus paclitaxel versus cisplatin and paclitaxel in patients with suboptimal stage III or IV ovarian cancer: a Gynecologic Oncology Group study. J Clin Oncol. 2000;18(1):106-115. doi:10.1200/JCO.2000.18.1.106
2. Drug shortages. FDA. Updated July 20, 2023. Accessed August 10, 2023. bit.ly/443QD6v
3. Gordon AN, Fleagle JT, Guthrie D, Parkin DE, Gore ME, Lacave AJ. Recurrent epithelial ovarian carcinoma: a randomized phase III study of pegylated liposomal doxorubicin versus topotecan. J Clin Oncol. 2001;19(14):3312-3322. doi:10.1200/JCO.2001.19.14.3312
4. Gordon AN, Tonda M, Sun S, Rackoff W; Doxil Study 30-49 Investigators. Long-term survival advantage for women treated with pegylated liposomal doxorubicin compared with topotecan in a phase 3 randomized study of recurrent and refractory epithelial ovarian cancer. Gynecol Oncol. 2004;95(1):1-8. doi:10.1016/j.ygyno.2004.07.011
5. Vergote I, Finkler N, del Campo J, et al; ASSIST-1 Study Group. Phase 3 randomized study of canfosfamide (Telcyta, TLK286) versus pegylated liposomal doxorubicin or topotecan as third-line therapy in patients with platinum-refractory or -resistant ovarian cancer. Eur J Cancer. 2009; 45(13):2324-2332. doi:10.1016/j.ejca.2009.05.016